EP1192009B1 - Verfahren zur erzeugung eines aerosols - Google Patents

Verfahren zur erzeugung eines aerosols Download PDF

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Publication number
EP1192009B1
EP1192009B1 EP00938249.0A EP00938249A EP1192009B1 EP 1192009 B1 EP1192009 B1 EP 1192009B1 EP 00938249 A EP00938249 A EP 00938249A EP 1192009 B1 EP1192009 B1 EP 1192009B1
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EP
European Patent Office
Prior art keywords
liquid
fluid
particles
supply means
gas
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EP00938249.0A
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English (en)
French (fr)
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EP1192009A4 (de
EP1192009A1 (de
Inventor
Joan Rosell
Alfonso Ganan-Calvo
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Universidad de Sevilla
Aradigm Corp
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Universidad de Sevilla
Aradigm Corp
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/02—Spray pistols; Apparatus for discharge
    • B05B7/04—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge
    • B05B7/0416—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid
    • B05B7/0441—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid with one inner conduit of liquid surrounded by an external conduit of gas upstream the mixing chamber
    • B05B7/0475—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid with one inner conduit of liquid surrounded by an external conduit of gas upstream the mixing chamber with means for deflecting the peripheral gas flow towards the central liquid flow
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/02—Spray pistols; Apparatus for discharge
    • B05B7/04—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge
    • B05B7/0416—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid
    • B05B7/0483—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid with gas and liquid jets intersecting in the mixing chamber

Definitions

  • This application generally relates to the creation of an aerosol created by the directed flow of fluids.
  • Devices for creating finely directed streams of fluids and/or creating aerosolized particles of a desired size are used in a wide range of different applications, such as, for example, finely directed streams of ink for ink jet printers, or directed streams of solutions containing biological molecules for the preparation of microarrays.
  • the production of finely dispersed aerosols is also important for (1) aerosolized delivery of drugs to obtain deep even flow of the aerosolized particles into the lungs of patients; (2) aerosolizing fuel for delivery in internal combustion engines to obtain rapid, even dispersion of any type of fuel in the combustion chamber; or (3) the formation of uniform sized particles which themselves have a wide range of uses including (a) making chocolate, which requires fine particles of a given size to obtain the desired texture or "mouth feel" in the resulting product, (b) making pharmaceutical products for timed release of drugs or to mask flavors and (c) making small inert particles which are used as standards in tests or as a substrate onto which compounds to be tested, reacted or assayed are coated.
  • EP-A-0 899 017 discloses a method according to the preamble of claim 1, comprising a liquid atomization process based on the formation of a capillary microjet upon sucking a liquid by means of a high speed gas flow through a small diameter orifice.
  • the liquid sucked forms a stationary capilar jet having a very small diameter, and accelerated and stabilized by the tangential viscous efforts exerted by the gas on the liquid surface, going through the orifice and coming out to the outside wherein finally the microjet is broken up into microdroplets having an extremely small size and scarce dispersity.
  • the disclosed process applies to mechanisms requiring homogenous atomization of liquids and specially to the electronic injection of fuel.
  • a “violent focusing” method comprises the steps of forcing a first liquid through a feeding tube and out of an exit opening of the feeding tube positioned inside a pressure chamber which is continually filled with a second fluid which may be a second liquid immiscible in the first liquid or a gas.
  • the exit opening of the feeding tube is positioned such that the liquid flowing out of the tube flows toward and out of an exit or discharge orifice of the chamber surrounding the exit opening of the feeding tube.
  • the first liquid exiting the tube is focused to a substantially reduced diameter and subjected to a violent action created by the second liquid or gas, breaking up the flow into particles substantially smaller than if the reduced diameter flow underwent spontaneous capillary breakup.
  • the exit opening of the feeding tube preferably has a diameter in the range of about 5 to about 10,000 microns and the exit opening of the tube is positioned at a distance in a range of from about 5 to about 10,000 microns, more preferably about 15 to about 200 microns from an entrance point of the exit orifice.
  • a stream of the first liquid flows out of the tube and is focused by the flow of the second liquid or gas in the surrounding pressure chamber.
  • the focused stream then exits out of the discharge orifice of the pressure chamber, destabilizing and forming small particles.
  • the size of the particles of the first liquid is governed by the balance between the surface tension forces of the first liquid particle formed, and the amplitude of the turbulent pressure fluctuations at, and outside of the exit orifice of the pressure chamber. When the particles are sufficiently small that their surface tension forces substantially match the amplitude of the pressure fluctuation then the particles are stabilized and will not break up into still smaller particles.
  • the method is carried out by forcing a liquid from a liquid supply means, e.g. a tube.
  • the liquid exits the supply means into a pressure chamber filled with a second fluid which is preferably a gas.
  • the chamber has an exit port preferably positioned directly in front of and preferably downstream of the flow of liquid exiting the supply means.
  • the exit port may be positioned slightly upstream of the liquid supply means exit.
  • the liquid is focused by the gas to substantially smaller dimensions as it exits the supply means e.g. a tubular stream of liquid one unit in diameter is focused to a stream 1/2 - 1/400 of a unit in diameter or smaller depending on operating conditions.
  • a focused cylindrical stream of one unit in diameter would be expected to undergo Rayleigh breakup and form particles which are about 1.89 times the diameter of the focused stream.
  • the liquid stream is first focused by the gas flowing out of the chamber thereby forming a stream with a much smaller diameter. That stream leaves the chamber and forms particles which are smaller in diameter than the focused stream.
  • the nozzles and methods of the present invention are capable of producing extremely small particles.
  • a cylindrical liquid supply means having a diameter of 1000 units.
  • the stream from such a supply means would be expected to undergo normal Rayleigh breakup of the 1000 unit diameter stream to form spherical particles having a diameter of about 1.89 x 1000 or 1890 units in diameter.
  • the stream having a diameter of 1000 units is focused to a stream or jet of smaller dimension by a surrounding gas the jet might have a diameter of one tenth that size or 100 units. That 100 unit diameter focused jet would be expected to undergo normal Rayleigh breakup to form particles having a diameter of 1.89 x 100 or 189 units.
  • Focusing the diameter of the stream to a narrow focused jet or "stable microjet” jet has been referred to as flow focusing technology.
  • the diameter of the jet (d j ) can be any reduced dimension smaller than that of liquid stream exiting the supply means, e.g. can have a cross-sectional diameter of from about one half to about 1/100 the area of the stream exiting the liquid supply means.
  • the liquid flow exiting the supply means with a diameter of 1000 units is focused as it leaves the supply means so that the end of the exiting drop exiting the liquid supply tube is focused by the surrounding gas to a reduced dimension (e.g. 1 ⁇ 2 to 1/100 the cross-sectional diameter of the liquid supply means).
  • a reduced dimension e.g. 1 ⁇ 2 to 1/100 the cross-sectional diameter of the liquid supply means.
  • the 1000 unit stream is reduced to a diameter of about 100 units. That 100 unit end of the drop is subjected to turbulent action by the gas exiting the pressure chamber thereby forming particles which are 10 units in diameter.
  • the method of the invention can produce particles which are substantially smaller than (e.g. 1 ⁇ 2 to 1/100) the size of particles produced using flow focusing technology.
  • flow focusing technology can produce particles which are substantially smaller than (e.g. 1 ⁇ 2 to 1/100) the size of particles produced by normal capillary breakup of a stream.
  • each configuration or embodiment will comprise a means for supplying a liquid or first fluid and a means for supplying a second fluid (preferably a gas) in a pressure chamber which surrounds at least an exit of the means for supplying a liquid.
  • the liquid supply means and pressure chamber are positioned such that turbulent action takes place between the liquid exiting the liquid supply means and the second fluid, a liquid or a gas, exiting the supply chamber.
  • the exit opening of the pressure chamber is downstream of and more preferably it is directly aligned with the flow path of the means for supplying the liquid.
  • the means for supplying a liquid is often referred to as a cylindrical tube (tube shape could be varied, e.g. oval, square, rectangular).
  • the first fluid or liquid can be any liquid depending on the overall device which the invention is used within.
  • the liquid could be a liquid formulation of a pharmaceutically active drug used to create dry particles or liquid particles for an aerosol for inhalation or, alternatively, it could be a hydrocarbon fuel used in connection with a fuel injector for use on an internal combustion engine or heater or other device which bums hydrocarbon fuel.
  • the second fluid is generally described herein as being a gas and that gas is generally air or an inert gas.
  • the first fluid is a liquid and the second fluid may be a gas or a liquid provided the first and second fluids are sufficiently different from each other (e.g. immiscible). It is possible to have situations wherein the liquid exits either the liquid supply means or the pressure chamber vaporizes to a gas on exit. Such is not the general situation. Notwithstanding these different combinations of liquid-gas, and liquid-liquid, the invention is generally described with a liquid formulation being expelled from the supply means and interacting with surrounding gas flowing out of an exit of the pressure chamber. Further, the exit of the pressure chamber is generally described as circular in cross-section and widening in a funnel shape ( Fig. 1 ), but could be any configuration.
  • the nozzle 1 is comprised of two basic components which include the pressure chamber 2 and the liquid supply means 3.
  • the pressure chamber 2 is pressurized by fluid flowing into the chamber by the entrance port 4.
  • the liquid supply means 3 includes an inner tube 5 where liquid flows.
  • the inner tube 5 of the liquid supply means 3 is preferably supplied with a continuous stream of a fluid which fluid is preferably in the form of a liquid.
  • the pressure chamber 2 is continuously supplied with a pressurized fluid which may be a liquid or a gas.
  • a pressurized fluid which may be a liquid or a gas.
  • the fluid is a liquid the liquid is preferably insoluble and incompatible with the liquid being provided from the inner tube 5 (e.g. oil and water which do not readily mix and form a distinct interface).
  • the inner tube 5 of the liquid supply means 3 includes an exit point 6.
  • the pressurized chamber 2 includes an exit point 7.
  • the exit point 7 of the pressure chamber is preferably positioned directly downstream of the flow of liquid exiting the exit point 6.
  • the liquid supply means exit and the exit of the pressure chamber are configured and positioned so as to obtain two effects (1) the dimensions of the stream exiting the liquid supply means are reduced by the fluid exiting the pressure chamber; and (2) the liquid exiting the liquid supply means and the fluid exiting the pressure chamber undergo a violent interaction to form much smaller particles than would form if the stream of liquid in reduced dimensions underwent normal capillary instability, e.g. formed spherical particles 1.89 times the diameter of the cylindrical stream.
  • the exit port of the chamber 2 is directly aligned with the flow of liquid exiting the liquid supply means 3.
  • An important aspect of the invention is to obtain small particles 8 from the liquid 9 flowing out of the exit port 6 of the inner tube 5.
  • Obtaining the desired formation of particles 8 is obtained by correctly positioning and proportioning the various components of the liquid supply means 3 and the chamber 2 as well as the properties of the fluids including the speed of these fluids which flow out of both the liquid supply means 3 and the chamber 2.
  • the liquid 9 is held within the inner tube 5 which is cylindrical in shape.
  • the inner tube 5 holding the liquid 9 may be asymmetric, oval, square, rectangular or in other configurations including a configuration which would present a substantially planar flow of liquid 9 out of the exit port 6.
  • the nozzle of the invention applies to all kinds of round (e.g., axi-symmetric) and planar (e.g., symmetric two-dimensional) configurations that have a convergent passage for the outer fluid.
  • a round but not axi-symmetric geometry would be one in which the surfaces of the orifice plate are faceted at different azimuthal angles.
  • Formation of the microjet and its acceleration and ultimate particle formation are based on the abrupt pressure drop associated with the steep acceleration experienced by the liquid on passing through an exit orifice of the pressure chamber which holds the second fluid (i.e. the gas).
  • the creation of the violently focused aerosol may occur as follows.
  • the strong radial fluid flow (10) that exists in the very narrow gap between the points 6 and 7 becomes circulatory as it passes through and out of the orifice of the exit 7 of the pressure chamber 2.
  • the liquid (9) meniscus is sucked in towards the center of the exit point 7 of the chamber 2.
  • the gas 10 exits the hole at point 7 its strong circulatory motion induces the fluid dynamic effect referred to as a vortex breakdown. This is an instability in which fluid particles gain so much centrifugal inertia that they spin off away from the axis.
  • a dashed line C---C' is shown running through the center of the inner tube 5 in which the liquid 9 flows as well as the exit of the chamber 2.
  • the line C--C' represents the plane of symmetry intersection of the plane of view.
  • the line B--B' represents the bisector of the convergent passage near the center of the nozzle.
  • the area referred to as the "convergent passage" is the region which is the open area between the terminal face 11 of the liquid supply means 3 and the front face 12 of the chamber 2.
  • the primary characteristic of the present invention is the facilitation of a strongly convergent (imploding) flow of outer fluid 10 towards and around the inner liquid 9.
  • the fluid 10 in the pressure chamber should preferably not merely flow parallel to the liquid 9 exiting the liquid supply means, i.e. should preferably not intersect at a 0 degree angle.
  • the fluid 10 in the pressure chamber should preferably not flow directly perpendicular to the liquid stream 9 exiting the liquid supply means, i.e. should preferably not interact at a 90 degree angle or more.
  • convergence of the two fluids is preferably at an angle of more than 0 degrees and less than 90 degrees.
  • the fluid 10 of the pressure chamber could, in some situations be directed at the liquid 9 from the liquid supply means at an angle of 90 degrees or more, i.e., at an angle such that the fluid 10 is flowing back toward the liquid 9 and is converging on the liquid 9 at an angle of up to 150 degrees.
  • Flow convergence improves the transfers of momentum and kinetic energy from the outer fluid 10 to the inner liquid 9 required to breakup the inner fluid 9 into particles 8. Improving the efficiency of such transfer results in energy savings for a given amount of inner liquid 9 atomized and a given droplet size requirement.
  • a greater efficiency of atomization is achieved by transferring a greater fraction of pressure energy originally in the outer fluid 10 per unit mass of the outer fluid to the inner liquid 9.
  • the outer fluid 10 In order to generate significant convergence in the outer fluid 10 towards the inner liquid 9, the outer fluid 10 must be admitted into a path that gives it a sufficiently high converging speed. Specifically, the following design constraints shown in Figure 3 are preferred.
  • the convergent passage separation between R and P must be chosen appropriately. This distance can be defined as the distance between points R and P in Figure 2 .
  • this variable regulates the relative average velocity between the inner liquid 9 and the outer fluid 10 at the point of encounter (inner rim of tube exit indicated by point P' in Figures 2 and 3 ).
  • a very narrow convergent passage is one in which frictional losses dissipate the outer fluid momentum significantly. Widening such a passage will encourage coupling between outer fluid 10 and inner liquid 9.
  • the separation between R and P is made too wide, then the effect of efficient atomization is lost, because the fastest speed is encountered then in the discharge orifice, not at the end of the convergent passage.
  • ⁇ 0.25; while for planar-two dimensional configurations, ⁇ equals 0.5.
  • H must be large enough to preclude excessive friction between the outer fluid and the convergent passage walls that can slow down the flow and waste pressure energy (stagnation enthalpy) into heat (internal energy).
  • An approximate guiding principle is that H should be greater than H min , defined as a few times the thickness of the viscous boundary layer ⁇ L that develops inside the outer fluid 10 in its acceleration through the convergent passage: H min ⁇ ⁇ L ⁇ ⁇ 1 to 10
  • ⁇ L L ⁇ ⁇ 2 / ⁇ 2 ⁇ P o ⁇ 2 0.5 0.5
  • ⁇ 2 is the dynamic viscosity coefficient of the outer fluid 10
  • ⁇ 2 is its density
  • P o2 is the pressure of the outer fluid 10 in the upstream chamber.
  • ⁇ is a numerical factor, which generally is between 1 and 10.
  • the inner liquid 9 coming out of the inner tube 5 gets funnel-shaped into a jet that gets thinner as it flows downstream.
  • the jet can have a variety of different configurations, e.g. a circular cross-section, or a flat planar one. Any configuration can be used which provides flows through the center of the discharge orifice 7, and can become much thinner as it enters the discharge orifice 7 than at the exit 6 of the inner tube 5. This phenomenon has previously been termed "flow-focusing" (see WO 99/31019 published June 24, 1999 ).
  • the forces responsible for the shaping of the inner liquid 9 are believed to arise from the pressure gradients that set within the outer fluid 10 as it flows through the discharge orifice 7.
  • a round inner liquid jet is expected to attain a diameter dj determined by the 1 ⁇ 2 power law with liquid flow rate Q (in volume per unit of time, e.g. cubic meter per second; Ga ⁇ án-Calvo A. M., 1998): d j ⁇ 8 ⁇ ⁇ 1 / ⁇ 2 ⁇ ⁇ P g 1 / 4 ⁇ Q 1 / 2 ⁇ 1 is the inner liquid density, ⁇ is pi, and ⁇ P g is the pressure drop in the outer fluid between the upstream value and the value at the point where d j is taken and ⁇ means approximately equal to with about a ⁇ 10% error margin.
  • This equation will be herein referred to as the "flow-focusing" formula and only applies for a uniform velocity distribution along the inner liquid jet radius.
  • a notable consequence of flow-focusing is that the inner liquid is stabilized towards the center of the discharge orifice.
  • the exit of both the inner tube 5 and the chamber 2 at point 7 were of equal diameter.
  • the inner liquid 9 was observed to flow through the center of the discharge orifice without impacting or wetting its side walls. (Due to the random nature of the drop trajectories under conditions of very high inner liquid flow rates used for violent focusing, a small degree of wetting has indeed been detected, but is associated with an insignificant fraction of the inner liquid.)
  • Characteristics of supersonic flow such as shock waves may improve atomization. However, such are not believed to be required.
  • Unique characteristics of the present invention include: (f) High frequency of droplet generation, (g) Low requirements on liquid pressure, (h) Low sensitivity of drop size to inner liquid flow rate, (i) Little apparent effect of atomizer size on droplet size.
  • the data demonstrate that the droplets are much smaller than predicted from the spontaneous capillary breakup, such as Rayleigh breakup in axi-symmetric configurations; (Rayleigh 1882) of an inner liquid column of size dj equal to that predicted by the flow-focusing formula discussed earlier. Or, what is the same, for given values of the liquid properties and operational variables, the final size of the droplets is many times smaller than the flow-focusing diameter dj discussed earlier. As a result, the frequency of droplet production is much higher than predicted by spontaneous capillary breakup of the flow focused jet. Accordingly, particles formed via the method described here are substantially smaller (e.g. 1/2 the size or less or 1/20 the size or less) than would be obtained due to spontaneous capillary break-up of the stream exiting the tube 5 and chamber 2. (See Figure 7 )
  • the inner liquid 9 does not have to be pushed out of its inner tube 5 with a sufficiently high pressure capable of maintaining a stable liquid jet in the absence of outer fluid flow and solid surfaces in its way. It is not necessary for the inner liquid to form a stable microjet structure. Further, pre-existent inner liquid jet structure coming directly out of the exit opening 6 is not required because, a explained in (c), the liquid meniscus is focused by the action of the outer fluid pressure forces.
  • Figures 6-9 show results for aerosols produced by methods of the present invention using dry air and dry nitrogen as outer fluids 10, and a range of liquids as inner fluids 9: distilled water, 2-propanol, 20 % (v/v) by volume of ethanol in water (“20%EtOH”), and 0.1 % weight in volume (w/v) Polysorbate-20 in distilled de-ionized water (“0.1%Tween”). Tests were performed in four separate experiments with different atomizers. The atomizers were of an axi-symmetric type and had dimensions as specified below in Table A.
  • the droplet size was determined by phase Doppler anemometry (Lefebvre 1989; Bayvel and Orzechowski 1993) along the axis of the aerosol plume a few centimeters downstream from the exit of the atomizer.
  • This measurement technique led to notoriously low rates of validated counts, i.e. low rates of detected light pulses ("bursts").
  • bursts low rates of detected light pulses
  • This problem appears to result from a combination of high droplet concentrations and high velocities.
  • Validation count rates lower than 50% have been excluded from the sets of data presented here. As a consequence, all of the droplet size measurements in experiments 3 and 4 with were excluded from the graphs.
  • Figure 6 is a graph of the volume median diameter (VMD) vs the liquid supply flow rate for four different liquids.
  • VMD 1.89 ⁇ 8 ⁇ ⁇ 1 / ⁇ 2 ⁇ ⁇ P g 1 / 4 ⁇ Q 1 / 2
  • VMD / d o 1.89 ⁇ 8 / ⁇ 2 1 / 4 ⁇ Q / Q o 1 / 2
  • the proposed atomization system obviously requires delivery of the liquid to be atomized and the gas to be used in the resulting spray. Both should be fed at a rate ensuring that the system lies within the desired parameter window. Multiplexing is effective when the flow-rates needed exceed those obtained for an individual cell. More specifically, a plurality of feeding sources 3 or holes therein forming tubes 3 may be used to increase the rate at which aerosols are created. The flow-rates used should also ensure the mass ratio between the flows is compatible with the specifications of each application.
  • the gas and liquid can be dispensed by any type of continuous delivery system (e.g. a compressor or a pressurized tank the former and a volumetric pump or a pressurized bottle the latter). If multiplexing is needed, the liquid flow-rate should be as uniform as possible among cells; this may entail propulsion through several capillary needles, porous media or any other medium capable of distributing a uniform flow among different feeding points.
  • a compressor or a pressurized tank the former and a volumetric pump or a pressurized bottle the latter e.g. a compressor or a pressurized tank the former and a volumetric pump or a pressurized bottle the latter.
  • liquid supply means 3 may be planar with grooves therein, but need not be strictly planar, and may be a curved feeding device comprised of two surfaces that maintain approximately the same spatial distance between the two pieces of the liquid supply means.
  • curved devices may have any level of curvature, e.g. circular, semicircular, elliptical, hemi-elliptical, etc.
  • a device of the invention may be used to provide particles for drug delivery, e.g. the pulmonary delivery of aerosolized pharmaceutical compositions.
  • the device would produce aerosolized particles of a pharmaceutically active drug for delivery to a patient by inhalation.
  • the device is comprised of a liquid feeding source such as a channel to which formulation is added at one end and expelled through an exit opening.
  • the feeding channel is surrounded by a pressurized chamber into which gas is fed and out of which gas is expelled from an opening.
  • the opening from which the gas is expelled is positioned directly in front of the flow path of liquid expelled from the feeding channel.
  • Various parameters are adjusted so that pressurized gas surrounds liquid flowing out of the feeding channel in a manner so as to reduce the dimension of the flow which is then broken up on leaving the chamber.
  • the aerosolized particles are inhaled into a patient's lungs and thereafter reach the patient's circulatory system.
  • the method of the invention is also applicable in the mass production of dry particles.
  • Such particles are useful in providing highly dispersible dry pharmaceutical particles containing a drug suitable for a drug delivery system, e.g. implants, injectables or pulmonary delivery.
  • the particles formed of pharmaceutical are particularly useful in a dry powder inhaler due to the small size of the particles (e.g. 1-5 microns in aerodynamic diameter) and conformity of size (e.g. 3 to 30% difference in diameter) from particle to particle.
  • Such particles should improve dosage by providing accurate and precise amounts of dispersible particles to a patient in need of treatment.
  • Dry particles are also useful because they may serve as a particle size standard in numerous applications.
  • the first fluid is preferably a liquid
  • the second fluid is preferably a gas, although two liquids may also be used provided they are generally immiscible.
  • Atomized particles are produced within a desired size range (e.g., 1 micron to about 5 microns).
  • the first fluid liquid is preferably a solution containing a high concentration of solute.
  • the first fluid liquid is a suspension containing a uniform concentration of suspended matter. In either case, the liquid quickly evaporates upon atomization (due to the small size of the particles formed) to leave very small dry particles.
  • the device of the invention is useful to introduce fuel into internal combustion engines by functioning as a fuel injection nozzle, which introduces a fine spray of aerosolized fuel into the combustion chamber of the engine.
  • the fuel injection nozzle has a unique fuel delivery system with a pressure chamber and a fuel source.
  • Atomized fuel particles within a desired size range e.g., 5 micron to about 500 microns, and preferably between 10 and 100 microns
  • Atomized fuel particles within a desired size range are produced from a liquid fuel formulation provided via a fuel supply opening. Different size particles of fuel may be required for different engines.
  • the fuel may be provided in any desired manner, e.g., forced through a channel of a feeding needle and expelled out of an exit opening of the needle.
  • a second fluid e.g.
  • a pressure chamber which surrounds at least the area where the formulation is provided (e.g., surrounds the exit opening of the needle) is forced out of an opening positioned in front of the flow path of the provided fuel (e.g. in front of the fuel expelled from the feeding needle).
  • Various parameters are adjusted to obtain a fuel-fluid interface and an aerosol of the fuel, which allow formation of atomized fuel particles on exiting the opening of the pressurized chamber.
  • Fuel injectors of the invention have two significant advantages over prior injectors. First, fuel generally does not contact the periphery of the exit orifice from which it is emitted because the fuel stream is surrounded by a gas (e.g. air) which flows into the exit orifice. Thus, clogging of the orifice is eliminated or substantially reduced. In addition, formation of carbon deposits around the orifice exit is also substantially reduced or eliminated. Second, the fuel exits the orifice and forms very small particles which may be substantially uniform in size, thereby allowing faster and more controlled combustion of the fuel.
  • a gas e.g. air
  • Molecular assembly presents a 'bottom-up' approach to the fabrication of objects specified with enormous precision.
  • Molecular assembly includes construction of objects using tiny assembly components, which can be arranged using techniques such as microscopy, e.g. scanning electron microspray.
  • Molecular self-assembly is a related strategy in chemical synthesis, with the potential of generating nonbiological structures with dimensions as small as 1 to 100 nanometers, and having molecular weights of 10 4 to 10 10 daltons.
  • Microelectro-deposition and microetching can also be used in microfabrication of objects having distinct, patterned surfaces.
  • Atomized particles within a desired size range can be produced to serve as assembly components to serve as building blocks for the microfabrication of objects, or may serve as templates for the self-assembly of monolayers for microassembly of objects.
  • the method of the invention can employ an atomizate to etch configurations and/or patterns onto the surface of an object by removing a selected portion of the surface.

Claims (7)

  1. Verfahren, das die folgenden Schritte aufweist:
    eine Flüssigkeit aus einer Ausgangsöffnung einer Flüssigkeitszufuhreinrichtung zu drücken;
    ein Fluid in eine Druckkammer zu drücken, die die Ausgangsöffnung der Flüssigkeitszufuhreinrichtung umgibt, wobei das Fluid derart geliefert wird, dass das Fluid: (a) aus der Ausgangsöffnung austretende Flüssigkeit in einen Strom fokussiert, der kleinere Abmessungen als die Ausgangsöffnung hat; (b) der aus der Flüssigkeitszufuhreinrichtung austretenden Flüssigkeit ein Moment verleiht und mit ihr interagiert; dadurch gekennzeichnet, dass das Fluid so geliefert wird, dass das Fluid: (c) die Flüssigkeit destabilisiert, um Partikel der Flüssigkeit zu formen, wobei die mittleren Abmessungen von geformten Partikeln geringer als die Abmessungen des fokussierten Flüssigkeitsstroms sind; und (d) den Flüssigkeitsstrom aus der Druckkammer transportiert.
  2. Verfahren nach Anspruch 1, wobei das in die Druckkammer gedrückte Fluid ein Gas ist, und wobei (e) das Gas schnell zur Flüssigkeit gemäß Stromlinien konvergiert, die einen Winkel von 45° oder mehr bezüglich der Flüssigkeit bilden.
  3. Verfahren nach Anspruch 1, wobei das in die Druckkammer gedrückte Fluid eine Flüssigkeit ist, die nicht mit der Flüssigkeit in der Flüssigkeitszufuhreinrichtung vermischt werden kann.
  4. Verfahren nach Anspruch 1, wobei die aus der Flüssigkeitszufuhreinrichtung austretende Flüssigkeit auf Abmessungen fokussiert wird, die 1/2 oder weniger als die Abmessungen der Ausgangsöffnung der Flüssigkeitszufuhreinrichtung betragen.
  5. Verfahren nach Anspruch 2, wobei Partikel, die durch die Destabilisierung der Flüssigkeit in (c) geformt werden, 1/10 oder weniger als das mittlere Volumen der Partikel haben, deren Bildung bei einem normalen Rayleigh-Breakup erwartet werden, und das Gas auf die Flüssigkeit in einem Winkel von 45° bis weniger als 90° konvergiert.
  6. Verfahren nach Anspruch 2, wobei das Gas in (e) die Flüssigkeit in Partikel aufbricht, die klein genug sind, damit Oberflächenspannungskräfte der Partikel in (e) im Wesentlichen der Amplitude von Druckschwankungen entsprechen, die von der Flüssigkeit und dem Gas erzeugt werden, die aus der Druckkammer austreten.
  7. Verfahren nach Anspruch 1, wobei die Ausgangsöffnung der Flüssigkeitszufuhreinrichtung eine Öffnung mit einer Querschnittskonfiguration hat, die aus der Gruppe ausgewählt wird, die besteht aus einem Kreis, einem Oval, einem Quadrat und einem rechteckigen Längsschlitz.
EP00938249.0A 1999-06-11 2000-06-09 Verfahren zur erzeugung eines aerosols Expired - Lifetime EP1192009B1 (de)

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Families Citing this family (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060169800A1 (en) * 1999-06-11 2006-08-03 Aradigm Corporation Aerosol created by directed flow of fluids and devices and methods for producing same
US20030051728A1 (en) 2001-06-05 2003-03-20 Lloyd Peter M. Method and device for delivering a physiologically active compound
US6805853B2 (en) 2001-11-09 2004-10-19 Alexza Molecular Delivery Corporation Delivery of diazepam through an inhalation route
US6759029B2 (en) 2001-05-24 2004-07-06 Alexza Molecular Delivery Corporation Delivery of rizatriptan and zolmitriptan through an inhalation route
US20070122353A1 (en) 2001-05-24 2007-05-31 Hale Ron L Drug condensation aerosols and kits
JP2005503425A (ja) 2001-05-24 2005-02-03 アレックザ モレキュラー デリヴァリー コーポレイション 所定の吸入ルートによる薬剤エステルの送出
EP1392258B1 (de) 2001-05-24 2008-11-26 Alexza Pharmaceuticals, Inc. Verabreichung von alprazolam, estazolam, midazolam oder triazolam durch inhalation
JP4834861B2 (ja) * 2001-09-25 2011-12-14 株式会社イノアックコーポレーション 流体混合機構
EP1446104B2 (de) 2001-11-01 2011-08-03 Novartis AG Sprühtrocknungsverfahren
AU2002363947A1 (en) 2001-11-21 2003-07-24 Alexza Molecular Delivery Corporation Delivery of caffeine through an inhalation route
US9339459B2 (en) 2003-04-24 2016-05-17 Nektar Therapeutics Particulate materials
JP2006507921A (ja) 2002-06-28 2006-03-09 プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ 流体分散のための方法および装置
US10533998B2 (en) 2008-07-18 2020-01-14 Bio-Rad Laboratories, Inc. Enzyme quantification
US20060078893A1 (en) 2004-10-12 2006-04-13 Medical Research Council Compartmentalised combinatorial chemistry by microfluidic control
GB0307428D0 (en) 2003-03-31 2003-05-07 Medical Res Council Compartmentalised combinatorial chemistry
GB0307403D0 (en) 2003-03-31 2003-05-07 Medical Res Council Selection by compartmentalised screening
EP2266687A3 (de) * 2003-04-10 2011-06-29 The President and Fellows of Harvard College Erzeugung und Kontrolle von Fluiden
WO2004104490A1 (en) 2003-05-21 2004-12-02 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
US20040235308A1 (en) 2003-05-22 2004-11-25 Dainippon Screen Mfg. Co., Ltd. Substrate treatment method and sustrate treatment apparatus
JP4630870B2 (ja) 2003-08-27 2011-02-09 プレジデント アンド フェロウズ オブ ハーバード カレッジ 流体種の電子的制御
US20050221339A1 (en) 2004-03-31 2005-10-06 Medical Research Council Harvard University Compartmentalised screening by microfluidic control
US9477233B2 (en) 2004-07-02 2016-10-25 The University Of Chicago Microfluidic system with a plurality of sequential T-junctions for performing reactions in microdroplets
ES2264608B2 (es) * 2004-09-30 2007-08-16 Universidad De Sevilla Dispositivo y procedimiento para la atomizacion neumatica de liquidos mediante flujo implosivo de gas.
US7968287B2 (en) 2004-10-08 2011-06-28 Medical Research Council Harvard University In vitro evolution in microfluidic systems
ES2265270B1 (es) * 2005-04-18 2008-01-01 Universidad De Sevilla Procedimiento y dispositivo para micro-mezclado de fluidos mediante celula de reflujo.
JP4875628B2 (ja) * 2005-01-17 2012-02-15 ウニベルシダ デ セビリャ 還流セルを通して流体をミクロ混合するための手順およびデバイス
US9039273B2 (en) 2005-03-04 2015-05-26 President And Fellows Of Harvard College Method and apparatus for forming multiple emulsions
WO2007081386A2 (en) 2006-01-11 2007-07-19 Raindance Technologies, Inc. Microfluidic devices and methods of use
US9562837B2 (en) 2006-05-11 2017-02-07 Raindance Technologies, Inc. Systems for handling microfludic droplets
US20080014589A1 (en) 2006-05-11 2008-01-17 Link Darren R Microfluidic devices and methods of use thereof
EP2077912B1 (de) 2006-08-07 2019-03-27 The President and Fellows of Harvard College Fluorkohlenstoffemulsionsstabilisierende tenside
US8772046B2 (en) 2007-02-06 2014-07-08 Brandeis University Manipulation of fluids and reactions in microfluidic systems
EP2121088B1 (de) 2007-03-09 2016-07-13 Alexza Pharmaceuticals, Inc. Erhitzungseinheit zur verwendung in einer arzneimittelabgabevorrichtung
US7776927B2 (en) 2007-03-28 2010-08-17 President And Fellows Of Harvard College Emulsions and techniques for formation
US8592221B2 (en) 2007-04-19 2013-11-26 Brandeis University Manipulation of fluids, fluid components and reactions in microfluidic systems
US9091434B2 (en) 2008-04-18 2015-07-28 The Board Of Trustees Of The University Of Alabama Meso-scaled combustion system
WO2010009365A1 (en) 2008-07-18 2010-01-21 Raindance Technologies, Inc. Droplet libraries
US20100176063A1 (en) * 2009-01-12 2010-07-15 Yuri Kokotov Method for coalescence induced liquid-liquid separations and apparatus thereof
US8528589B2 (en) 2009-03-23 2013-09-10 Raindance Technologies, Inc. Manipulation of microfluidic droplets
US20120211084A1 (en) 2009-09-02 2012-08-23 President And Fellows Of Harvard College Multiple emulsions created using jetting and other techniques
EP2486409A1 (de) 2009-10-09 2012-08-15 Universite De Strasbourg Markiertes nanomaterial auf siliziumbasis mit verbesserten eigenschaften und seine verwendung
US10837883B2 (en) 2009-12-23 2020-11-17 Bio-Rad Laboratories, Inc. Microfluidic systems and methods for reducing the exchange of molecules between droplets
WO2011100604A2 (en) 2010-02-12 2011-08-18 Raindance Technologies, Inc. Digital analyte analysis
US9366632B2 (en) 2010-02-12 2016-06-14 Raindance Technologies, Inc. Digital analyte analysis
US10351905B2 (en) 2010-02-12 2019-07-16 Bio-Rad Laboratories, Inc. Digital analyte analysis
US9399797B2 (en) 2010-02-12 2016-07-26 Raindance Technologies, Inc. Digital analyte analysis
WO2011150368A1 (en) 2010-05-28 2011-12-01 Arizona Board Of Regents Acting For And On Behalf Of Arziona State University Apparatus and methods for a gas dynamic virtual nozzle
US20120048963A1 (en) 2010-08-26 2012-03-01 Alexza Pharmaceuticals, Inc. Heat Units Using a Solid Fuel Capable of Undergoing an Exothermic Metal Oxidation-Reduction Reaction Propagated without an Igniter
EP3447155A1 (de) 2010-09-30 2019-02-27 Raindance Technologies, Inc. Sandwichassays in tröpfchen
WO2012109600A2 (en) 2011-02-11 2012-08-16 Raindance Technologies, Inc. Methods for forming mixed droplets
WO2012112804A1 (en) 2011-02-18 2012-08-23 Raindance Technoligies, Inc. Compositions and methods for molecular labeling
WO2012162296A2 (en) 2011-05-23 2012-11-29 President And Fellows Of Harvard College Control of emulsions, including multiple emulsions
US8841071B2 (en) 2011-06-02 2014-09-23 Raindance Technologies, Inc. Sample multiplexing
CN103764265A (zh) 2011-07-06 2014-04-30 哈佛学院院长等 多重乳剂和用于配制多重乳剂的技术
US8658430B2 (en) 2011-07-20 2014-02-25 Raindance Technologies, Inc. Manipulating droplet size
EP2777818A1 (de) 2013-03-15 2014-09-17 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Verfahren und Vorrichtung zur Herstellung eines intermittierenden Flüssigkeitsstrahls
EP2991768B1 (de) 2013-04-30 2018-11-21 Arizona Board of Regents on behalf of Arizona State University Vorrichtung und verfahren für kubische lipidphaseninjektion für membranproteinuntersuchungen
US11901041B2 (en) 2013-10-04 2024-02-13 Bio-Rad Laboratories, Inc. Digital analysis of nucleic acid modification
US9944977B2 (en) 2013-12-12 2018-04-17 Raindance Technologies, Inc. Distinguishing rare variations in a nucleic acid sequence from a sample
EP3090063B1 (de) 2013-12-31 2019-11-06 Bio-Rad Laboratories, Inc. Verfahren zur detektion von latentem retrovirus
DK3268072T3 (da) 2015-03-11 2024-01-22 Alexza Pharmaceuticals Inc Anvendelse af antistatiske materialer i luftvejen til termisk aerosolkondensationsproces
CN108348933B (zh) 2015-08-28 2022-01-28 明尼苏达州大学董事会 喷嘴和混合流体流的方法
US10647981B1 (en) 2015-09-08 2020-05-12 Bio-Rad Laboratories, Inc. Nucleic acid library generation methods and compositions
ES2663217B1 (es) * 2016-10-10 2019-02-07 Ingeniatrics Tecnologias S L Aparato y método para mezclar al menos dos líquidos
WO2019241488A1 (en) 2018-06-14 2019-12-19 Regents Of The University Of Minnesota Counterflow mixer and atomizer
US10369579B1 (en) 2018-09-04 2019-08-06 Zyxogen, Llc Multi-orifice nozzle for droplet atomization
CN115228642A (zh) * 2022-08-02 2022-10-25 北京航空航天大学 小流量分散流雾化喷嘴及低流速雾化器

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05138080A (ja) * 1991-11-25 1993-06-01 Matsushita Electric Ind Co Ltd 霧化装置
US5868322A (en) * 1996-01-31 1999-02-09 Hewlett-Packard Company Apparatus for forming liquid droplets having a mechanically fixed inner microtube
ES2140998B1 (es) * 1996-05-13 2000-10-16 Univ Sevilla Procedimiento de atomizacion de liquidos.
US5884846A (en) * 1996-09-19 1999-03-23 Tan; Hsiaoming Sherman Pneumatic concentric nebulizer with adjustable and capillaries
JP2002508250A (ja) 1997-12-17 2002-03-19 ユニバーシィダッド デ セビリヤ 均一なサイズの球状微粒子を生成するデバイスおよび方法

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