MXPA98002160A

MXPA98002160A - Atomized nozzle

Info

Publication number: MXPA98002160A
Application number: MXPA/A/1998/002160A
Authority: MX
Inventors: J Yule Andrew
Original assignee: Quillin Helen
Priority date: 1995-09-27
Filing date: 1998-03-19
Publication date: 1998-11-12

Abstract

The spray nozzle assembly and the method for generating a respirable aerosol formed by appropriately sized drops from a liquid medicament for medicinal inhalation therapy. The nozzle assembly comprises a gas nozzle (2) for producing a gas jet and a liquid nozzle (3) for ejecting the liquid to be atomized into the gas jet in a downstream position of the gas nozzle ( 2). The gas nozzle (2) and the liquid nozzle (3) are configured in such a way that the gas jet impinges on the liquid in a liquid angle to atomize the liquid. The nozzle assembly and method can create a breathable aerosol using a gas / mass ratio of liquid less than 0

Description

ATOMIZING NOZZLE This invention relates to the spray nozzles used for portable aerosols such as so-called aerosols and pump-type atomizers, intended for the application of liquid pharmaceutical products Spray-type sprayers are used throughout the world to administer a wide range of products, for example, hair spray, furniture wax, cleaners, paint, insecticides and medications. Until recently, chlorofluorocarbons (CFC's) were the most common of the propellant gases used in aerosols because they are inactive, are miscible with a wide range of products, are easily liquefiable under low pressures, provide a substantially constant amount of product flow and they can produce a spray of drops with average diameters in the range of 3 to 100 micrometers. However, in the 1970s it was confirmed that the CFCs were probably responsible for the REF: 27002 reduction of the protective ozone layer of the Earth and, in 1987, most countries signed the Montreal Protocol to progressively reduce the use of CFCs and, since then, have agreed to eliminate the use of CFCs for applications not essential towards the end of nineteen ninety five. A notable exemption to this date for the suspension of such use is related to metered dose inhalers (MDI's) for medicines, which are considered an essential application of CFCs, but even this use of CFCs will be finally eliminated.

Gases such as air and nitrogen have the advantages of not causing environmental damage, of not being flammable and of not causing adverse health effects if inhaled. Such gases can be used to propel liquid from a container, but with a simple orifice or a spiral orifice very high pressures are required to produce a fine spray suitable for an MDI.

There are other types of aerosol generators for the supply of liquid pharmaceutical products in research and hospital applications, such as nebulizers. However, these generally contain baffles to eliminate larger droplets and use high air flows that make them unsuitable for use in convenient portable atomizers.

It is also possible to force liquid at high pressure through a very small orifice (5-10 micrometers in diameter) to produce drops of about 5 micrometers in diameter, but these methods are inconvenient or non-economic for large scale manufacturing, mainly due to the difficulty of making very small holes in an appropriate material, and, to prevent clogging of the orifice, the need for exceptional cleaning in the manufacture of the parts, together with the ultrafiltration of the fluid to be sprayed.

Many of the drugs used in the treatment of respiratory diseases are insoluble in vehicles such as water and are supplied as suspensions. The drug particles are produced in a breathable size of 1-5 micrometers. Particles of this size tend to block the very small holes (5 to 10 microns) used by the known devices.

For the application of veterinary and some human vaccines, high pressure pumps (125-500 bars) operated either by spring or by gas (called needleless injectors) are commonly used to inject a jet of drug through the skin ( intradermal injection) without the use of needles, and attachments are available to convert the jet into a mist for the administration of drugs to the nasal passages of larger animals such as pigs. However, the smallest drop size obtainable is of the order of 40 micrometers, and the range of application for these injectors is limited.

Compressed air atomizers such as air guns and commercial paint sprays consume large amounts of air, and to obtain 5 micrometer drops with water, for example, a ratio of the gas to the mass of the larger liquid is required. 36: 1 which is inconvenient for portable sprinklers.

Rolling nozzles in which a liquid is atomized by intrusion of multiple jets of fluid, one on top of another, for example, jets of air and liquid, are known. U.S. Patent No. 5,385,304 discloses an air-assisted spray atomizing nozzle in which a jet of liquid is atomized into a mixing chamber by the shearing action of several air jets directed substantially perpendicularly to the liquid jet. The nozzle can be used to supply liquid in a state of fine atomization and appropriate applications include use for the supply of agricultural chemicals and pesticides, cleaning systems and scouring systems for coal furnaces.

It is believed that the disclosed nozzle will provide high air efficiency through the use of opposite air cross flows and the air / mass ratio of the described system liquid is 0.13 to 0.27. Although the size of the dew particles is not defined, the nozzle is described as generating a spray of fine droplets of liquid, and the applications discussed suggest that it can produce smaller droplets up to a minimum of 50 micrometers in diameter .

For the MDI's used in the treatment of certain respiratory diseases it is essential that the aerodynamic particle size is less than 15 micrometers, preferably less than 10 micrometers, so that the droplets are able to penetrate and deposit in the regions tracheobronchial and alveolar lung. For a spray composed of droplets with a range of sizes, more than 5% by weight of the droplets should have an aerodynamic diameter of less than 6.4 micrometers, preferably more than 20% by weight of the particles have an aerodynamic diameter of less than 6.4. micrometers Inhalers can also be designed to deliver drugs to the pulmonary alveoli to provide an absorption pathway in the bloodstream of drugs that are poorly absorbed by the digestive tract.

In order to reach the alveoli, it is essential that the aerodynamic diameter of the particles be less than 10 micrometers, preferably 0.5-5 micrometers.

Current thinking suggests that to create smaller dew drops from the nozzles of the incident fluid, it is necessary to increase the gas / mass ratio of the liquid (GLR - from its acronym in English: gas to liquid ratio) which results in a associated increase in the size of the gas reservoir required to supply the necessary mass of propellant. However, for the application of such technology in portable inhalation devices, it is desirable for the gas / mass ratio of the liquid (GLR - of its acronym in English: gas to liquid ratio) that is small in order to limit the size of the container required. The alternative of using manual or digital control, or the primed pump to measure and produce the liquid and gas flows also requires that the volume and pressure of the necessary gas be minimized to allow the size of a small pump and minimize the effort necessary for the patient.

The purpose of this invention is to provide an atomizer nozzle assembly design suitable for a portable inhalation device that is capable of being used to produce an aerosol of droplets of suitable size for inhalation, without the use of conventional propellants.

In accordance with this invention, an atomizing nozzle assembly is provided for generating a breathable aerosol composed of conveniently sized drops of a liquid medicament for medicinal inhalation therapy, the nozzle assembly comprising a gas nozzle to produce a jet of gas as well as a liquid nozzle to expel the liquid that will be atomized into the gas stream in a downstream position of the gas nozzle into which the gas nozzle and the liquid nozzle are configured such that the gas jet impinges on the liquid at an acute angle to atomize the gas. liquid.

This invention additionally provides an atomizing nozzle assembly which comprises at least one nozzle for ejecting the liquid to be atomized and at least one nozzle for producing a gas jet, at least one liquid nozzle and at least one gas nozzle, which are configured in such a way that the liquid is impacted by the gas jet to produce a respirable aerosol of drops of adequate size for medicinal inhalation therapy, the ratio of the flow velocity of the gas being with respect to the mass of the liquid smaller than 0.5.

By using a liquid and gas nozzle configuration within which the gas jet impinges on the liquid at an acute angle it is possible to create a breathable aerosol with a gas / mass ratio of the liquid (GLR - from its acronym in English: gas to liquid ratio) less than 0.5.

It is preferable that the ratio of the flow velocity of the gas to the mass of the liquid is 0.2 or less.

It is desirable that the gas nozzle be at least partially obscured by the liquid nozzle in such a manner that the liquid is expelled by the liquid nozzle directly into the gas jet.

Preferably, the liquid nozzle should be beveled.

It is convenient that the diameter of the exit orifice of the gas and liquid nozzles be between 50 micrometers and 200 micrometers.

The gas and liquid nozzles are suitably configured to give an angle of incidence of flow of between 30a and 90a. Preferably, the gas and liquid nozzles are configured to provide a fluid incidence angle of between 40a and 60a.

It is convenient that the outlet port of the liquid nozzle be positioned at no more than 10 diameters from the exit orifice of the gas nozzle. downstream of the outlet of the gas nozzle. It is preferable that the liquid nozzle be positioned between 1 and 4 diameters of the gas nozzle outlet hole downstream of the gas nozzle outlet hole.

In a further aspect of the present invention there is provided a method for generating a respirable aerosol of droplets of suitable size for medicinal inhalation therapy of a liquid medicament by introducing said liquid into a gas jet wherein the gas jet impinges in the liquid at an acute angle in the direction of liquid flow.

The present invention also provides a method for creating a respirable aerosol of droplets of suitable size for medicinal inhalation therapy from a liquid medicament by introducing said liquid into a gas jet in such a manner that the liquid is drawn by it. gas jet, the ratio of the gas flow velocity to the mass of the liquid being less than 0.5.

It is preferable that the ratio of the flow velocity of the gas to the mass of the liquid is 0.2 or less In a preferable device, the shapes and sizes of the gas and liquid supply nozzles are chosen to maximize the inhalable proportion of the aerosol while minimizing the amount of gaseous propellant required. This requires that the liquid ejection nozzle has a shape and position that interrupts the gas jet in such a manner that the dispersion of the liquid occurs through the cross section of the gas flow and in particular in the high velocity gas regions. and that, the turbulence, the formation of vortices and the production of shock waves created by the interaction of the gas jet with the liquid nozzle act to propitiate the dispersion in small drops and the dispersion of drops in the jet of? jas.

The invention will now be described with reference to the accompanying drawings in which: Figures la, Ib, lc and ld are section, end and schematic views showing the configuration of the liquid and gas nozzles according to the invention; Figures 2a, 2b, 2c and 2d are graphs showing the percentage by mass of droplets with a diameter smaller than 6.4 micrometers created with variation of parameters relative to the gas and liquid nozzles as shown in figures la, Ib and lc.

Figures 3a, 3b and 3c are perspective and sectional views showing the alternative shapes and arrangements of the gas and liquid nozzle configurations according to the invention.

Figure 4 is a graph showing the average size of the drop produced by a nozzle according to the invention with variation in the flow velocities of the liquid; Y Figure 5 is a graph showing the average drip speeds produced by a nozzle according to the invention.

Referring to FIGS. 1, 1, 1, and 1, a preferred form of spray nozzle assembly 1 consists of a cylindrical gas nozzle 2 having a circular hole 125 microns in internal diameter, and a bevelled liquid nozzle 3 of a diameter similar internal but having an elliptical outlet hole partially positioned in front of the gas nozzle 2. The liquid nozzle 3 is arranged in such a way that the outlet of the liquid is positioned at approximately 1 diameter of the downstream outlet orifice of the gas outlet hole. The lateral position of the liquid nozzle 3 relative to the gas nozzle 2 can be expressed as a percentage of obscuration of the gas nozzle and is determined according to Figure 1c by the equation: L = 100r / D (%) The gas and liquid nozzles can be made of hypodermic stainless steel 316 or any other suitable material. The gas nozzle 2 and the liquid nozzle 3 define an acute angle of 40a between them.

When used, the air 4 is expelled at the speed of sound through the gas nozzle 2 and the liquid 5 is introduced under pressure into the gas jet at a speed of about 1.4 m / s through the liquid nozzle 3. For the purposes of the experimental results provided below, the liquid used is water. However, the liquid may, for example, be an aqueous suspension or a solution of a medicament or other bioactive molecule. Bioactive molecules suitable for this purpose include proteins, peptides, oligonucleosides and genes such as the DNA complex with an appropriate lipid carrier, for example, the DNA complex encoding the transmembrane conductivity regulatory protein of cystic fibrosis ( CFTR- of its acronym in English: cystic fibrosis transmembrane conductance regulator) with a cationic lipid, which is useful for the treatment of cystic fibrosis.

The drugs suitable for this purpose are, for example, for the treatment of respiratory diseases such as asthma, bronchitis, pulmonary diseases of chronic obstruction and bronchial infections. Additional medications can be selected from any other suitable drug useful in inhalation therapy and which can be presented as an aqueous suspension or solution. In this way, appropriate medicaments can be selected from, for example, analgesics, such as codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations such as diltiasem; anti-allergenic compounds such as cromoglycate, ketotitofen or neodocromil; anti-infectives such as, for example, cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines and pentamidine; antihistamines such as metapyrilene; anti-inflammatories such as, for example, futiicason, flunisolide, budesonide, tipredane, or triamcinolone acetonide; antitussives such as, for example, noscapine; bronchodilators such as salmeterol, salbutamol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol orciprenaline, or (-) -4-amino-3,5-dichloro- (- (((6- (2- (2-pyridinyl) ethoxy (-hexyl (amino (methyl (benzenemethano); diuretics, such as amiloride; anticholinergic drugs such as ipratropiu, atropine or oxitropium; hormones such as cortisone, hydrocortisone or prednisolone; xanthines such as, for example, aminophylline, choline theophyllinate, lysine theophyllinate or theophylline and therapeutic proteins and peptides such as insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments can be used in the form of salts (such as, for example, alkali metals or amines salts or such as acid addition salts) or as esters low alkylsters) or as solvants (such as hydrates) to optimize the activity and / or stability of the drug. The preferred medications are salbutamol, salbutamol sulfate, salmeterol, salmeterol xinafoate, fluticasone propionate, beclometasone dipropionate and terbutaline sulfate. It should be clear that the suspension or solution of the medicament may consist purely of one or more active ingredients.

The shape and position of the liquid nozzle 3 causes an interaction with the air jet in such a way that the liquid flows mainly towards the tip of the nozzle 6 and separates from the nozzle to atomize rapidly in the high velocity zone of the gas forming a slow-moving spray. Slow-moving aerosols are particularly suitable for expelling into the tracheobronchial and alveolar regions of the lung by reducing the amount of droplet incidence in the back of the throat, which tends to happen with faster-moving aerosols. The slow-moving aerosols are also beneficial for the user by facilitating the coordination of the activation of the mechanism with the act of inhalation. The size of the droplets is controlled, inter alia, by the respective gas and liquid flow velocities, as well as by the shapes of both nozzles.

The position of the liquid nozzle 3 in front of the gas nozzle 2 causes turbulence, vortex diffusion and shock wave formation in the air jet which benefits the atomization of the liquid 5 and, as described with reference to Figure 2a shown above, it has been found that the use of a beveled hole in place of a straight-edge orifice allows to increase the flexibility with respect to the relative lateral position of the liquid nozzle with respect to the gas nozzle by relaxing the tolerance required during its manufacture.

Figure 1 shows how the liquid and gas nozzles can be incorporated into a single modulated component. The nozzles themselves can be manufactured by a laser driller or by injection molding with or without hypodermic capillary inserts.

Figure 2a shows the results of the tests performed with the spray nozzle with a bevelled liquid orifice as described above and with a spray nozzle with a liquid orifice of straight edges using different liquid flow rates but a flow velocity of constant gas, in order to determine how the lateral position of the liquid nozzle relative to the gas nozzle (percentage of obscuration) affects the percentage of the mass of fine particles created; that is, droplets with a diameter smaller than 6.4 micrometers as measured by the deposition of the aerosol in the second state of the even incidence device. It is evident in figure two 2a that the optimal results at fluid flow velocities of 1.0. ml / min and 1.2 ml / min are obtained at a darkening of approximately 50%, it is believed that the deterioration of the characteristics of the aerosol with different darkening values is marked to a lesser extent with the beveled hole than with the edge hole. straight.

Figure 2b shows the variation in the creation of the mass of fine particles with variation in the gas / mass ratio of the liquid (GLR - for its acronym in English: gas to liquid ratio) for one of the spray nozzles with bevelled liquid hole and for a spray nozzle with a straight-edge liquid orifice using different percentages of darkening at a constant rate of liquid flow. This demonstrates that a significant improvement in atomization efficiency is obtained using the beveled liquid orifice with a mass of fine particles with more than 20% of the mass of fine particles reaching a gas / mass ratio of the liquid (GLR). in English: gas to liquid ratio) of around 0.12.

Figure 2c shows the variation in the mass of fine particles created with variation in the gas / mass ratio of the liquid (GLR - from its acronym in English: gas to liquid ratio) at selected fluid flow velocities and with obscurations of the nozzle of gas using a beveled liquid nozzle. This figure demonstrates that the improved modification results from the gas / mass ratio of the liquid (GLR - from its acronym in English: gas to liquid ratio) increased and that a deposition of 20% is reached at a gas / mass ratio of the liquid (GLR). - of its abbreviations in English: gas to liquid ratio) of around 0.12 with a darkening of 50%.

Figure 2d shows the optimal dimming of the gas nozzle by different gas flow rates using a constant liquid flow rate of 1.0 ml / min. For manufacturing purposes it is desirable to have the ability to achieve the required aerosol characteristics over the range of liquid orifice positions in order to tolerate manufacturing inaccuracies. This also helps achieve consistent modification over the lifetime of the nozzle. . With figure 2d it is clear that for the creation of 20% of droplets with a smaller diameter of 6.4 micrometers, the flow velocities of the gas of 120ml / min and higher will allow a certain tolerance in the darkening.

The increase in the flow velocity of the liquid allows the flow velocity of the gas to be proportionally increased to maintain the same gas / mass ratio of the liquid (GLR - from its acronym in English: gas to liquid ratio), and similar trends are found to those shown in figure 2d, but where the optimal characteristics of the aerosol are presented at greater obscurations. Using nozzles with a diameter of 125 micrometers and gas / liquid mass ratio (GLR) values of 0.2 as well as liquid flow velocities of 1.2 ml / min and 1.8 ml / Min, optimal obscurations of 50 +/- 5% and 75 +/- 5% are displayed Figure 3a shows an alternative nozzle assembly design which is similar to that shown in Figures 1-lc but in which the gas nozzle 6 has a rectangular profile. Such a gas nozzle profile can reduce the possibility of penetration of the liquid jet through the gas jet causing loss of atomization or partial atomization. By proper design of liquid and gas nozzles it would be possible to increase the atomization efficiency by diffusion of the increased gas by agitation around the exit hole of the liquid nozzle.

Figure 3b shows another nozzle assembly in which the gas nozzle 7 has a profile similar to that shown in figures 1? to lc, and the liquid nozzle 8 has a circular hole with straight edges. The sheet 9 is positioned partially in front of the gas nozzle 7, which helps generate turbulence, agitation diffusion and discharge waves in the gas jet to aid atomization and dispersion of the liquid. The sheet 9 can be additionally manufactured to vibrate and increase its effect.

Figure 3c shows an additional nozzle assembly in which the gas nozzle laterally incorporates wall extensions 10 and the liquid nozzle has a separation section 11 to increase the shape of the aerosol and the mixture of the liquid with the gas.

Figure 4 shows the average size of the droplets produced by the atomizer using two nozzles with a diameter of 125 micrometers with a bevelled liquid exit hole. Two methods are used to define the average diameter of the drops; Dv, 0.5 is the average diameter of the volume and D32 is the average diameter of Sauter. The measurements were carried out using the Malvern ST 2600 laser diffraction instrument in the 100 mm downstream position from the liquid nozzle. The results show that for a constant atomization air flow rate the size of the drop increases in relation to the increase in the flow velocity of the liquid edl. However, full drop size distributions for liquid flow rates of 1.0 ml / min and 1.2 ml / min show that 21.3% by mass of the drops produced have a diameter smaller than 6.3 micrometers, which is sufficient to provide the necessary operating conditions for an MDI.

Figure 5 shows the average drip velocity at axial distances starting from the liquid nozzle along the line The aerosol produced by the atomizer using two nozzles with a diameter of 125 micrometers to 40 (with a gas flow rate of 180 ml / min.) The measurements were made using a Doppler Doppler anemometer. They are less than those provided by MDI based on conventional propellants.This reduction in drip velocity allows for a smaller deposition in the oropharyngeal region when it is sprayed in the mouth to allow the release of the drug into the respiratory tract. Different on the supply by MDI based on conventional propellants allowing a rduction in local effects as well as a systemic exposure due to oral absorption.

It will be highly appreciated that an atomizing device can comprise the plurality of the eitomizing nozzle assemblies as described arranged in order.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims

1. The spray nozzle assembly to generate a breathable spray of drops of suitable size for a medicinal inhalation therapy of a liquid medicament, the nozzle assembly which comprises a gas nozzle to produce a gas jet and a liquid nozzle to eject the liquid to be atomized into the gas stream downstream of the gas nozzle, characterized in that the gas nozzle and the liquid nozzle are configured in such a way that the gas jet impinges on the liquid at an acute angle to atomize the liquid.

2. The spray nozzle assembly / characterized in that it comprises at least one nozzle for ejecting the liquid to be atomized and at least one nozzle for producing a gas jet, at least one liquid nozzle and at least one gas nozzle the which are configured in such a way that the liquid is stuffed by the gas jet producing a breathable aerosol formed by drops of appropriate size for a medicinal inhalation therapy, in which the ratio of the flow velocity of the gas with respect to the mass of the liquid is less than 0.5.

3. The spray nozzle assembly according to claim 2, characterized in that the ratio of the gas to the mass of the liquid is 0.2 or less.

4. The spray nozzle assembly according to any of the preceding claims, characterized in that the gas nozzle is at least partially obscured by the liquid nozzle in such a way that the liquid is ejected directly from the liquid nozzle towards the interior of the gas jet.

5. The atomizer nozzle assembly according to any of the preceding claims, characterized in that the liquid nozzle is bevelled in such a way that the plane of its outlet orifice is approximately parallel to the plane of the exit orifice of the gas nozzle.

6. The atomizer nozzle assembly according to any of the preceding claims, characterized in that both the liquid and gas nozzles have a diameter of orifice of between 50 micrometers and 200 micrometers.

7. The spray nozzle assembly according to any of the preceding claims, characterized in that the gas nozzle as well as the liquid nozzle are configured in such a way that the gas jet impinges on the liquid at an angle of between 40 ° and 60 °. °.

8. The spray nozzle assembly according to any of the preceding claims, characterized in that the outlet orifice of the liquid nozzle is positioned at no more than 10 diameters from the exit orifice of the gas nozzle downstream from the outlet orifice of the nozzle. the gas nozzle.

9. The spray nozzle assembly according to claim 8, characterized in that the outlet orifice of the liquid nozzle is positioned between 1 and 4 diameters of the gas nozzle downstream of the outlet outlet of the gas nozzle.

10. The atomizing nozzle assembly comprising the plurality of atomizing nozzle assemblies according to any of claims 1 to 10 arranged in any order.

11. The method for creating a breathable spray of drops of appropriate size for medicinal inhalation therapy from a liquid medicament by introducing said liquid into a gas jet, characterized in that the jet of gas impinges on the liquid at an acute angle towards the direction of the flow of the liquid.

12. The method according to claim 11, characterized in that the ratio of the flow velocity of the gas to the mass of the liquid is less than 0.5.

13. The method for creating a respirable aerosol of appropriately sized drops from a liquid medicament for medicinal inhalation therapy by introducing said liquid into a gas jet, such that said liquid is drawn by said jet of liquid. gas, the ratio of the flow velocity of the gas to the mass of the liquid being less than 0.5.

14. The method according to claim 12 or 13, characterized in that the ratio of the flow velocity of the gas to the mass of the liquid is 0.2 or less.

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

16. The method according to any of claims 11 to 15, characterized in that the liquid is introduced to the gas jet by means of a nozzle having an outlet orifice diameter ranging from 50 micrometers to 200 micrometers.

17. The method according to any of claims 11 to 16, characterized in that the gas impinges on the liquid at an angle of between 40 ° and 60 °