The present invention relates to aerosol generators.
Aerosol generators are known which comprise a vibratable member and a plate body operatively connected to the vibratable member. The plate body has an upper surface, a lower surface, and a plurality of apertures extending from the upper surface to the lower surface. The orifices are tapered such that when liquid is supplied from one surface and the orifice plate is vibrated using a vibrating member, liquid droplets are ejected from the opposite surface. Details of such known systems are disclosed, for example, in US6235177, US2007/0023547a and US7066398, the entire contents of which are incorporated herein by reference.
In patent US7066398 it is disclosed that by including the action of a piezoelectric transducer, i.e. a device applying vibrations using an electrical signal, liquid is ejected through and from the upper part of the orifice plate, which is subjected to dynamic cyclic stresses, bending inwards and downwards.
Such orifice plates typically vibrate between 100 and 200kHz over sustained periods. These periods may vary as some nebulizers are intermittently reused for up to 1 year (which may be approximately equal to an 800 x 15 minute nebulization period) and other nebulizers are used continuously for short periods of time up to 1 week.
Callister D.W., Materials Science and Engineering-An Introduction, John Wiley andsons, 2007, p227-245 discloses that the system is subjected to dynamic and fluctuating stresses resulting in fatigue failure. The term "fatigue" is used because this type of failure typically occurs after repeated stress or cycling over an extended period of time. In these cases, the yield strength σ of the material is lower at stress levelsTSAnd is generally lower than the yield strength sigma of the materialYFailure may occur.
The combination of high frequency and this harsh service life places significant stress on the orifice plate. Orifice plate failure is not uncommon. This problem indicates that a failure in the orifice plate itself causes the nebulizer to stop working and thus fails to provide the patient with aerosolized medicament.
Various attempts have been made to address this, but the problem still remains.
One attempt has been to provide an orifice plate of a non-metallic material, such as a flexible polymer, but such materials generally do not have the rigidity to effectively provide the desired amplitude to the aerosol liquid. Other attempts have been to have the atomizer head forming the vibrating orifice plate as a replaceable component of the atomizer that can be replaced frequently. However, this presents a number of economic problems.
Detailed Description
In the present invention, the orifice plate is formed from a palladium-nickel alloy comprising about 89% palladium and about 11% nickel. As shown in fig. 1, there is a fine, substantially equiaxed, grain microstructure through the thickness of the aperture plate. The average grain width (W) is 0.2 μm to 2.0. mu.m, and in some cases 0.2 μm to 1.0. mu.m. The average grain width was about 0.5 μm for the best results. However, grain widths of up to 5 μm and possibly up to 8 μm also provide sufficient fracture resistance.
Since the grain structure is equiaxed (L/W ═ 1), the grain length (L) is equal to the grain width.
The grain width was obtained from SEM (scanning electron microscope) photographs, using the line truncation method, for calculating the average grain size:
wherein:
is the average grain size of the grains,
c is the total length of the test line used,
n is the number of grain boundaries intercepted on the line,
m is the magnification of the micrograph
The grain structure was studied using a focused ion beam microscope (FIB) and FIB FEI 200 machine. Using a gallium source (Ga)+) And +30keV ion beam, and milling a trench with a width of 10 μm, a length of 20 μm and a depth of 6 μm. The samples were then challenged at 45 °, imaged at 20000X magnification, and grain size, shape and distribution were observed.
The aperture plate of fig. 1 also has a generally equiaxed, randomly oriented grain microstructure with an average grain width of about 0.5 μm throughout the entire thickness of the aperture plate. The sheet has a metallurgical structure, i.e. has a good resistance to fatigue crack initiation and crack propagation.
For aperture plates requiring higher processing temperatures (perhaps about 1000 c) during assembly to assemble the aperture plate into a nebulizer, focused ion beam microscopy (FIB) is not suitable because the average grain size is larger than those of aperture plates that do not require such high temperatures during assembly. A more suitable technique for the evaluation of grain size is the use of surface scanning electron microscopy. Fig. 1(c) (i) shows a micrograph of the lower surface, and fig. 1(c) (ii) shows a micrograph of the upper surface. Lines visible on the surface show the grain boundaries. The scale bar is 50 μm, which is a measure of the magnification used.
In combination with the microstructure, the orifice plate geometry most preferably ensures that the vibrating plate is crack free and prolongs the fatigue life of the atomizer throughout the vibration cycle of the present invention.
The Natural Frequency (NF) of the orifice plate has been found to play an important role in determining the fatigue life of the orifice plate. Statistical analysis with a 'p square' value of 0.025 worked and we have found that a reduced vibration frequency corresponding to the orifice plate (NF) extended the fatigue life of the atomizer.
In the life test, the orifice plate was subjected to approximately 810 atomization cycles, each lasting 15 minutes of atomization. For example, for a vibration frequency of 142kHz, the total number of vibration cycles of the orifice plate per lifetime of the atomizer is:
142000 cycles/sec 15 sec 60 sec 810.10 ≈ 1.04 ≈ 1011Number of cycles
The total number of vibration cycles during the lifetime of the atomizer is therefore very high and this places considerable stress on the orifice plate.
It was determined that lowering the vibration frequency from 142kHz to 133kHz (only 9kHz reduction) would reduce the vibration frequency by 7 x 109The number of vibration cycles:
133000 cycles/sec 15 sec 60 sec 810.7 sec 10 ≈ 9.7 sec10Number of cycles
142kHz-133kHz＝9kHz＝1.04*1011Number of cycles-9.7 x 1010Number of cycles 7 x 109Number of cycles
It is known from the literature that circular plates have vibration model specifying features. In analyzing the natural frequencies of the vibration model and the circular part, Bower [ Bower A., Applied Mechanics of Solids, CRC Press, 2010, p 694] finds the formula for the natural frequency of vibration:
wherein:
Jnis a function of the Bessel function,
ω(m，n)is the natural frequency of the frequency at which,
r is the radius of the plate or plates,
h is the thickness of the plate,
p is the mass density of the particles,
T0is the radial force per unit length.
From this formula, the natural frequency of the vibrating plate can be determined. E.g. ω(0，1)The formula for the first natural frequency is expressed as:
therefore, the natural frequency depends on the geometrical characteristics of the vibration plate, i.e., the thickness and the plate radius (or diameter).
FEA (finite element analysis) model analysis was aimed at simulating the vibration behavior of the aperture plate of the present invention and determining and predicting the effect of the dominant factors on the vibration characteristics of the aperture plate-vibration mode and Natural Frequency (NF) -fig. 2.
Our simulation results show that the thickness of the plate and the Natural Frequency (NF) are directly related-fig. 3, the dome diameter of the plate and the Natural Frequency (NF) are inversely related-fig. 6, and this correlates with our experimental data.
To reduce the plate's vibrational response (NF), the thickness of the orifice plate may be reduced or the diameter of the dome increased.
For example, the plate thickness is reduced by 3 μm, the natural frequency will be lowered by 9kHz, and this will contribute to increasing the fatigue life of the vibration plate as described above.
In the present invention we provide an orifice plate having a generally equiaxed microstructure. The fatigue life can be further improved by using lower specification thicknesses and natural frequency ranges.
The vibratory orifice plate has an increased fatigue life and provides suitable atomization over an extended period of time.
The present invention provides an improved orifice plate, namely:
the service life of the atomizer is prolonged;
eliminates the risk of premature and unpredictable failure of the nebulizer;
eliminating the risk of returning product from hospitals and patients; and is
The risk that fragments of the orifice plate may escape from the atomizer is eliminated.
Vibrating mesh nebulizers are now commonly used to treat a number of respiratory ailments which require the delivery of nebulized medicament to the lungs.
As described in US20070023547A, the orifice plate of the present invention is constructed from a relatively thin plate that may be formed into a desired shape and includes a plurality of orifices that can be used to produce fine droplets of liquid when the orifice plate is vibrated. Techniques for vibrating the orifice plates described above are generally disclosed in US patents 5164740, 5586550, and 5758637, which are incorporated herein by reference. Configuring the orifice plate allows for the production of relatively small droplets at a relatively fast rate. For example, the orifice plate of the present invention may be used to produce droplets having a size of from about 2 microns to about 10 microns, and more typically from about 2 microns to about 5 microns. In some cases, an orifice plate may be used to generate a spray that is beneficial to the pulmonary drug delivery regime. Also, the orifice plate may produce a spray having a respirable fraction of about 70%, preferably greater than about 80%, and more preferably greater than about 90%, as described in US patent 5758637.
In some embodiments, the fine droplets may be produced at a rate of about 2 microliters per second to about 25 microliters per second per 1000 pores. Thus, the orifice plate may be configured with a plurality of orifices sufficient to produce an aerosolized volume of about 2 microliters to about 25 microliters in less than about 1 second. The above-described production rates are particularly beneficial for pulmonary drug delivery, where the desired dose is aerosolized at a rate sufficient to allow the aerosol drug to be inhaled directly. Thus, there is no need to use an absorption chamber to collect the droplets until the prescribed dose is produced. In this way, the orifice plate can be applied to an aerosol generator, atomizer, or air filter that does not use a carefully designed absorption chamber.
The orifice plate may be used to deliver a variety of drugs to the respiratory system. For example, the orifice plate may be used to deliver drugs with effective therapeutic agents, such as hormones, peptides, and other drugs that require precise dosing including topical treatments for the respiratory system. Examples of liquid medicaments that may be aerosolized include medicaments in the form of solutions, such as aqueous solutions, ethanol solutions, water/ethanol mixed solutions, and the like, colloidal suspensions, and the like. The invention may also find application in the nebulization of various other types of liquids, such as insulin.
The palladium-nickel alloy orifice plates of the present invention may be used in a variety of liquids that do not significantly corrode the orifice plate. Examples of liquids that may be used without significantly corroding the orifice plate include albuterol, chromatin, and other inhalation solutions that are often delivered by a jet nebulizer, and the like.
The palladium-nickel alloy has a low elastic modulus. The stress that causes amplitude is proportional to the amount of elongation and the modulus of elasticity. By providing an orifice plate having a lower modulus of elasticity, the stress on the orifice plate is significantly reduced.
The aperture may be configured to have a shape in order to improve droplet yield while maintaining the droplets within a specified size range. More particularly, the orifice is preferably tapered so that the cross-section of the orifice narrows at the drop outlet. In one case, the angle of the aperture (or exit angle) at the exit is from about 30 ° to about 60 °, more preferably from about 41 ° to about 49 °, and more preferably about 45 °. The above-described exit angle ensures that the flow rate is increased while minimizing the droplet size. Thus, the orifice plate may find particular application in an inhaled drug delivery system.
The orifices of the orifice plate typically have an outlet with a diameter of about 1 micron to about 10 microns, which is about 2 microns to about 10 microns in size in order to produce droplets. In another case, for an aperture plate of at least about the first 15 microns, it is preferred that the exit angle of the taper be within a specified range of angles. In addition to the above, the shape of the holes is less critical. For example, the angle of the taper may increase toward the opposite surface of the orifice plate.
The orifice plate of the present invention may be configured in a dome shape as generally described in US patent 5758637. As described above, for optimum performance, the orifice plate vibrates at a frequency of about 125kHz to about 155kHz when atomizing a liquid. Further, when atomizing a liquid, the liquid may be placed on a back surface of the orifice plate, wherein the liquid adheres to the back surface by surface tension. When the orifice plate is vibrated, droplets are ejected from the front as generally described in US patents 5164740, 5586550 and 5758637.
The aperture plate of the present invention may be constructed using an electrodeposition process wherein metal is deposited on a conductive mandrel from solution by an electrolytic process. In one embodiment, the orifice plate is formed using an electroforming process, wherein metal is electroplated on a precisely fabricated mandrel having an inverse profile, dimensions, and requiring a surface finish on the machined orifice plate. When the desired thickness of deposited metal is achieved, the orifice plate is separated from the mandrel. Electroforming techniques are generally described in e.paul degormo, "Materials and Processes in Manufacturing," McMillan Publishing co., inc., new york, 5.sup.th Edition, 1979, the entire contents of which are incorporated herein by reference.
A mandrel for use in fabricating an orifice plate may include a conductive surface having a plurality of spaced apart insulating islands. Thus, when a core rod is put into the solution and an electric current is applied to the core rod, the metallic material in the solution is deposited on the core rod.
Various other techniques may be used to configure the pattern of insulating material on the electroformed mandrel. Examples of techniques that may be used to create the desired pattern include exposure, screen printing, and the like. This pattern is then used to control the onset of material plating and continues throughout the plating process. Various insulating materials may be used to prevent plating on conductive surfaces, such as photoresist, plastic, and the like. As previously mentioned, once the insulating material is disposed on the mandrel, it may be selectively machined to achieve a desired topography. Examples of processes that may be used include baking, curing, periodic heating, engraving, cutting, molding, and the like. The above-described process may be used to form a curved or angled surface on the insulating pattern, which may then be used to modify the angle of the orifice plate outlet.
Referring now to fig. 5, an orifice plate 10 is illustrated. The orifice plate 10 includes a plate body 12 having a plurality of tapered orifices 14 formed therein. The plate body 12 is constructed of palladium-nickel alloy as described above. The plate body 12 may have a dome shape as described in the previously incorporated by reference US patent 5758637. The plate body 12 includes an upper or front face 16 and a lower or rear face 18. In operation, liquid is supplied to the back face 18 and droplets are ejected from the front face 16.
Referring to fig. 6, the structure of the aperture 14 is illustrated in more detail. The bore 14 is tapered from the back side 18 to the front side 16. Each bore 14 has an inlet 20 and an outlet 22. With such a configuration, liquid is supplied to the back surface 18 through the inlet 20 and exits through the outlet 22. As shown, the plate body 12 also includes a widened portion 24 adjacent the outlet 22. As described in more detail below, the widened portion 24 is created using a manufacturing method to produce the orifice plate 10.
Also as shown in fig. 7, the cone angle of the bore 14 as it approaches the exit 22 may be defined as the exit angle theta. The exit angle is selected to maximize the ejection of droplets through the outlet 20 while keeping the droplets within a specified size range. The exit angle θ may be in the range of about 30 to about 60, more preferably about 41 to about 49, and more preferably about 45. Meanwhile, the outlet 22 may have a diameter of about 1 micron to about 10 microns. Furthermore, it is preferred that the exit angle θ extends over a vertical distance of at least 15 micrometers, i.e. that the exit angle θ is within the above-mentioned range at any point within this vertical distance. As shown, beyond the above-mentioned perpendicular distance, the hole 14 may widen outward beyond the exit angle θ.
In operation, liquid is applied to the back surface 18. Under the oscillation of the orifice plate 10, droplets are ejected through the outlet 22. In this way, a droplet is pushed out of the front face 16. Although the outlet 22 is shown as being inset from the front face 16, other manufacturing methods may be used to configure the outlet 22 directly on the front face 16.
Fig. 8 is a graph of fogging simulation data including vibration of an orifice plate 10 similar to the orifice plate of fig. 1. In the graph of fig. 8, the orifice plate was vibrated at about 180kHz when a large amount of water was applied to the back side. The exit diameter of each hole was 5 microns. In the simulation, the emergence angle varied from about 10 ° to about 70 °. (note that the exit angle in FIG. 8 is from the centerline to the hole wall). As shown, the maximum flow rate per orifice occurs at about 45 °. Relatively high flow rates can also be achieved in the range of about 41 to about 49. An exit angle theta in the range of about 30 deg. to about 60 deg. also produces a high flow rate. Thus, in this embodiment, a single orifice is capable of ejecting about 0.08 microliters of water per second when ejecting water. For many drug solutions, a well plate containing about 1000 wells, each well having an exit angle of about 45 °, can produce a dose of about 30 microliters to about 50 microliters in about one second. Due to the fast yield, the aerosolized medicament can be inhaled by the patient in a small inhalation maneuver without first collecting in the absorption chamber.
Electroforming apparatus and methods that may be used to construct an aperture plate are disclosed in US2007/0023547 a. Referring to FIG. 9, one embodiment of an electroformed mandrel 26 that may be used to construct the orifice plate 10 of FIG. 5 is described. The mandrel 26 includes a body 28 having a conductive surface 30. The body 28 may be made of a metal such as stainless steel. As shown, the conductive surface 30 is geometrically flat. However, sometimes the conductive surface 30 may be shaped according to the desired shape of the machined orifice plate. A plurality of insulating islands 32 are disposed on the conductive surface 30. Islands 32 extend above conductive surface 30 for use in electroforming a well in a well plate as described in more detail below. The islands 32 may be spaced apart at a distance required to machine a hole in the orifice plate. Likewise, the number of islands 32 may vary depending on the particular needs.
Referring now to fig. 10, the structure of the islands 32 is illustrated in more detail. As shown, the islands 32 are generally conical or dome-shaped in geometry. Conveniently, the islands 32 may be defined by a height h and a diameter D. Thus, it can be said that each island 32 comprises a slope or average angle of slope defined by the arctangent of 1/2 (D)/h. The average angle of the slope may be varied to produce a desired exit angle on the orifice plate as described above.
As shown, the island 32 is comprised of a bottom layer 34 and a top layer 36. As described in more detail below, the use of the above-described layers helps to obtain the desired conical or dome shape. However, the islands 32 may sometimes be constructed from only a single layer or multiple layers.
Referring to fig. 11, one method for forming the insulating islands 32 on the rods 28 is illustrated. The process begins with providing an electroformed mandrel, as shown in step 38. A photoresist is then coated on the mandrel, as shown in step 40. As one example, the thin film of photoresist may comprise a thick film photoresist having a thickness of about 7 to about 9 microns. The thick film photoresist may comprise Hoechst Celanese AZ P4620 positive photoresist. Conveniently, such photoresist may be pre-baked in a convection oven at about 100 ℃ for about 30 minutes in air or other environment. A mask having a pattern of circular areas is placed on the photoresist film, as shown in step 42. The photoresist film is then exposed to form a pattern of insulating islands, as shown in step 44. Conveniently, the photoresist is exposed to an alkaline developer such as Hoechst CelaneseAZ400K developer. Although a positive photoresist is used above, a negative photoresist known in the art may be used.
The island is then processed to form the desired shape by heating the mandrel to allow the island to flow and solidify in the desired shape, as shown in step 46. The conditions of the heating cycle of step 46 can be controlled by the degree of flow (or dome) and the degree to which curing occurs, thereby affecting the durability and stability of the pattern. In one case, the core rod is slowly heated to a high temperature to achieve the desired amount of flow and solidification. For example, the mandrel and photoresist are heated from room temperature to an elevated temperature of about 240 ℃ at a rate of about 2 ℃ per minute. The mandrel and photoresist are then held at this elevated temperature for about 30 minutes.
In some cases, it may be desirable to add a photoresist layer over the insulating islands to control their angle and further improve the shape of the islands. Thus, if the desired shape has not been obtained, steps 40-46 can be repeated over the islands to provide additional photoresist layers, as shown in step 48. Generally, when additional layers are added, the mask will contain circular regions of smaller diameter so that the added layers have a smaller diameter to help form the dome shape of the islands. Once the desired shape is obtained, the process ends, as shown in step 50.
Referring to fig. 12 and 13, a process of manufacturing the orifice plate 10 is explained. As shown in step 52 of fig. 13, a mandrel having a pattern of insulating islands is provided. Conveniently, the mandrel may be the mandrel 26 of fig. 9 as illustrated in fig. 12. The process then proceeds to step 54, where the mandrel is placed in a solution containing the material to be deposited on the mandrel. As one example, the solution may be a Pallatech PdNi plating solution, purchased from Lucent Technologies, that contains palladium nickel to be deposited on the mandrel 26. An electrical current is applied to the mandrel to electrodeposit material on the mandrel 26 and form the orifice plate 10, as shown in step 56. Once the orifice plate is formed, it may be stripped from the mandrel 26, as shown in step 56.
The time during which the current is applied to the core rod can be varied in order to obtain the desired exit angle and the desired exit opening on the orifice plate 10. Further, the kind of the solution into which the core rod is immersed may also be varied. Still further, the shape and angle of the island 32 may vary as the exit angle of the aforementioned aperture varies. By way of example only, a mandrel that can be used to produce an exit angle of about 45 ° is prepared by depositing a first photoresist island having a diameter of 100 microns and a height of 10 microns. A second photoresist island having a diameter of 10 microns and a thickness of 6 microns was deposited over the center of the first island. The core rod was then heated at a temperature of 200 ℃ for 2 hours.
Referring now to FIG. 14, another embodiment of the orifice plate 60 is illustrated. The orifice plate 60 includes a plate body 62 having a plurality of tapered orifices 64 (only one shown for ease of illustration). The plate body 62 has a rear face 66 and a front face 68. The holes 64 are tapered from the back 66 to the front 68. As shown, the holes 64 have a constant angle of taper. Preferably, the taper angle is in the range of about 30 ° to about 60 °, more preferably about 41 ° to about 49 °, and more preferably about 45 °. The aperture 64 also includes an outlet 70 having a diameter of about 2 microns to about 10 microns.
Referring to fig. 15, one method that may be used to construct the orifice plate 62 is described. This process uses an electroformed mandrel 72 having a plurality of insulating islands 74. Conveniently, the islands 74 are configured in a geometrically conventional conical or dome shape and are configured using any of the processes described herein above. To form the orifice plate 60, the mandrel 72 is placed in a solution and an electrical current is applied to the mandrel 72. The plating time is controlled so that the front face 68 of the orifice plate 60 does not extend to the top of the island 74. The amount of plating time can be controlled to control the height of the orifice plate 60. Likewise, the size of the outlet 72 can be controlled by varying the plating time. Once the desired height of the orifice plate 60 is achieved, the current is discontinued and the mandrel 72 is removed from the orifice plate 60.
Referring now to fig. 16, the application of the orifice plate 10 to atomize a volume of liquid 76 is illustrated. Conveniently, the orifice plate 10 is connected to a cup-shaped member 78 having a central window 80. The orifice plate 10 is placed over the window 80 with the back surface 18 adjacent the liquid 76. The piezoelectric transducer 82 is coupled to the cup-shaped member 78. The interface 84 may also provide a convenient route to connect the aerosol generator with other components of the device. In operation, current is applied to the transducer 82 to vibrate the orifice plate 10. The liquid 76 adheres to the back surface 18 of the orifice plate 10 by surface tension. When the orifice plate 10 vibrates, droplets are ejected from the front as shown.
As previously mentioned, the orifice plate 10 may be configured to facilitate atomization in a volume of about 4 microliters to about 30 microliters of liquid at a time, that is, in a time of less than about one second per about 1000 orifices. Further, each droplet may be produced such that they have a respirable fraction of greater than about 90%. In this way, the medicament can be aerosolized and then inhaled directly by the patient.
The invention is not limited to the specific embodiments described above, which may vary in construction and detail.