Nebulizer reservoir aperture plates and their manufacture

Abstract

A nebulizer aperture plate (100, 800) and a method of manufacturing it are described. A plate has a first inlet-side surface and a second outlet-side surface, with the first surface being processed such as by chemical etching to perform material subtraction to provide an arrangement of blind recesses (801, 901) in the plate. Alternatively, the blind recesses (102) may be provided by electrodeposition around pillars of resist (104) having shapes corresponding to the recesses. There is then laser drilling of aerosol-forming apertures (805, 806) in the bases of the blind recesses, so that the recesses become liquid supply cavities to the apertures. The laser drilling is through thin material, only the blind bases (105, 803) of the recesses. The recesses have a large surface area within aperture length of the outlet surface to allow drilling of the desired number of apertures. By the methods the liquid supply cavities are manufactured using techniques which are generally well established and suited to the dimensions required, and the apertures are drilled also using well established laser drilling technology, especially as the lengths of the apertures is small.

Description

[0001] “Nebulizer Reservoir Aperture Plates and their Manufacture”

[0002] Introduction

[0003] The invention relates to aperture plates (or “vibrating membranes”) for aerosol generation, for example atomisers and nebulizer devices for pulmonary treatment. It is particularly suited to nebulizer use; however, it may be applied to other situations such as humidification, spray coating, spray cooling, spin-spray deposition of thin films, spray drying, mass spectrometry, liquid fuel injection, inkjet printing, 3D prototyping, soft robotic actuation or moisture removal.

[0004] The ideal nebulizer is one which assures a consistent and accurate droplet size in combination with an output rate that can be varied according to the application such as delivery of a drug to a targeted lung area as efficiently as possible. For example, delivery of the aerosol to the deep lung such as the bronchi, bronchioles and alveolar regions requires a small and repeatable particle size typically in the range of 1 - 5 pm, but it could be larger for other applications such as humidification. In general, outputs greater than 0.1 ml / min are often required, preferably a multiple of this rate, especially for administration of drugs to children. For example, it is desired that pulmonary aerosol administration of medications may be performed at a high enough flow rate so that administration by injection is not needed.

[0005] Currently, aperture plates are produced by a variety of different means, including electroforming and machining such as laser drilling. US 6,235,177 (Aerogen) describes an approach based on electroforming, in which a wafer material is built onto a mandrel by a process of electro-deposition where the liquefied metals in the plating bath (typically Palladium and Nickel) are transferred from the liquid form to the solid form on the wafer. Material is transferred to the conducting surface on the mandrel and not to the photo resist areas which are non-conducting. Areas are masked with non-conductive photoresist where metallic build-up is not required. After the conclusion of the plating process, the mandrel / wafer assembly is removed from the bath and the wafer peeled from the mandrel for subsequent processing into an aperture plate. However, a problem with this approach is that the hole size is dependent on the plating time and the thickness of the resulting wafer.

[0006] W02013 / 186031 (Stamford Devices Limited) describes an approach in which a photoresist is applied in an arrangement of vertical columns in one phase to provide aerosol-forming apertures and in a second pass to provide liquid supply cavities. The latter provide a reservoir layer. WO201 1 / 139233 (Agency for Science, Technology and Research) describes a micro sieve manufactured using SU8 material with photo-masking.

[0007] US4844778 (Stork Veco) describes manufacture of a membrane for separating media, and a separation device incorporating such a membrane. The manufacturing method includes a two-step photolithographic procedure.

[0008] US7316067 (The Technology Partnership) describes an approach which involves laser drilling of the aerosol-forming apertures. WOOO / 29167 (Aradigm) also describes such an approach.

[0009] US2005 / 0054208 (Fedorov et al) describes manufacture of an electrospray structure for pressure wave ionization by etching silicon to provide structures with an inverted pyramid shape.

[0010] Laser drilling requires the removal of large volumes of material, which must be ablated quickly to minimise the laser machining time for a single aperture plate. The speed and volume of material removed using the laser machining process generates heat and can cause distortion of the wafer with subsequent variability in quality and shape of the exit holes and leading to poor consistency and low yield.

[0011] The invention is directed towards providing reservoir aperture plates for improved flow rates and small droplet sizes (VMDs), and methods for manufacture of such aperture plates.

[0012] References

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[0038] Summary of the Invention

[0039] We describe in some examples a method of manufacturing an aperture plate for vibration to provide an aerosol, the method comprising: in a first stage forming recesses each having a circular inlet opening and a blind base, said recesses being provided in a first surface of a plate of a material also having an opposed second surface, and in a second stage laser drilling a plurality of aerosol forming apertures in the base of each of the recesses, to form said recesses into liquid supply cavities in the first surface which are in fluid communication with a plurality of the drilled apertures which extend to the second surface.

[0040] The following parameters are set out as being preferred for all of the cavities and apertures as applicable, however it is envisaged that they may only apply to a subset of them, in which case some benefits of the invention are achieved.

[0041] In some preferred examples, pitch of the cavities is in the range of 40 pm to 500 pm, preferably in the range of 150 pm to 400 pm. In some preferred examples, the cavity diameter is in the range of 40 pm to 400 pm. In some preferred examples, the cavity diameter is in the range of 120 pm to 300 pm. In some preferred examples, the cavity diameter is in the range of 150 pm to 200 pm. In some preferred examples, the cavity depth is in the range of 10 pm to 100 pm, preferably in the range of 20 pm to 70 pm, and more preferably in the range of 30 pm to 60 pm.

[0042] In some preferred examples, the apertures are drilled in the recess bases at locations whereby the apertures have a length in the range of 3 pm to 12 pm, optionally 3 pm to 8 pm, and also optionally 4 pm to 7 pm. In some preferred examples, at least a majority of the blind recesses each have a central lower surface circumvented by a circle defined by half of the recess opening diameter, in which said lower surface is no more than 12 pm from the second surface.

[0043] In some preferred examples, the plate thickness is in the range of 13 pm to 112 pm. In some preferred examples, the outlet diameter of the apertures (E) is in the range of 0.5 pm to 5.0 pm, optionally 1.0 pm to 4.0 pm. In some preferred examples, the number of apertures drilled per cavity is in the range of 2 to 300, preferably in the range of 5 to 300, and more preferably in the range of 25 to 300. In some preferred examples, the aperture plate diameter when flat is in the range of 3 mm to 8 mm, optionally in the range of 4 mm to 7 mm.

[0044] In some preferred examples, the first stage is performed by providing a plate with a planar first surface and forming the blind recesses by selectively removing material from said first surface in a material subtraction step.

[0045] In some preferred examples, the material subtraction is performed by chemical etching with use of a photolithographic mask, and preferably the etching comprises wet etching. In some preferred examples, the material of the plate comprises steel, preferably Hastelloy or stainless steel. In some preferred examples, the cavities have funnel shaped side walls.

[0046] In some preferred examples, the first stage is performed by material addition, for example electrodeposition. In some preferred examples, the blind recesses are formed by material addition to have a plurality of recesses having side walls which are at an angle of no more than 20° with respect to a longitudinal axis between the first surface and the second surface. In some preferred examples, the electrodeposition is around pillars of resist, said pillars providing a shape for the recess.

[0047] In some preferred examples, the electrodeposition does not extend over the tops of the resist pillars. In some alternative preferred examples, the electrodeposition extends over the tops of at least some of the resist pillars to provide an inwardly extending overhang or rim around an opening of each cavity.

[0048] In some preferred examples, the materials which are deposited are selected from one or more of palladium, platinum, gold, nickel, silver, cobalt, copper or alloys thereof. In some preferred examples, the second stage comprises parallel laser drilling. In some preferred examples, the second stage is performed for at least some recesses by multibeam laser drilling to drill apertures simultaneously. In some preferred examples, the multibeam laser drilling comprises scanned mask imaging.

[0049] In some preferred examples, the apertures have side walls which are tapered with an angle of more then 10° to an aperture longitudinal axis, and percussion laser drilling is performed with closed loop feedback provided by an optical detection mechanism on an underside of the plate opposite to that upon which the laser energy is applied, and the laser drilling controller adjusts the energy profile used for laser drilling for control of hole size. In some preferred examples, percussion drilling is performed during the second stage. In some preferred examples, the laser drilling is performed using an Ultra Short Pulse (USP) laser system.

[0050] We also describe an aerosol generator aperture plate comprising liquid supply cavities with circular openings in an inlet surface and aerosol-forming apertures in an outlet surface, said apertures being in fluid communication with said cavities, wherein: the cavities have characteristics of being formed by etching blind recesses in a plate, and the apertures have characteristics of being laser drilled through bases of the recesses.

[0051] In some preferred examples, the cavities have characteristics of being formed by chemical wet etching. In some preferred examples, the aperture plate is of steel material, preferably Hastelloy or stainless steel.

[0052] We also describe an aerosol generator aperture plate comprising liquid supply cavities in an inlet surface and aerosol-forming apertures in an outlet surface, at least some of said apertures being in fluid communication with said cavities, wherein: the cavities have characteristics of being formed by electrodeposition around resist pillars conforming to the cavities, and the apertures have characteristics of being formed by laser drilling.

[0053] In some preferred examples, pitch (A) of the cavities is in the range of 40 pm to 500 pm, optionally 150 pm to 400 pm. In some preferred examples, the cavity diameter is in the range of 40 pm to 400 pm, optionally in the range of 120 pm to 300 pm. In some preferred examples, the cavity diameter is in the range of 150 pm to 200 pm, optionally in the range of 10 pm to 100 pm. In some preferred examples, the cavity depth is in the range of 20 pm to 70 pm, preferably 30 pm to 60 pm. In some preferred examples, the apertures have a length in the range of 3 pm to 12 pm, optionally 3 pm to 8 pm. In some preferred examples, at least a majority of the cavities each have a central lower surface circumvented by a circle defined by half of the cavity opening diameter, in which said lower surface is no more than 12 pm from the second surface.

[0054] In some preferred examples, the plate thickness is in the range of 13 pm to 112 pm.

[0055] In some preferred examples, the aperture (106) outlet diameter (E) is in the range of 0.5 pm to 5.0 pm, optionally 1.0 pm to 4.0 pm. In some preferred examples, the number of apertures per cavity is in the range of 2 to 300, preferably 25 to 300.

[0056] In some preferred examples, the aperture plate diameter when flat is in the range of 3 mm to 8 mm, optionally 4 mm to 7 mm.

[0057] We also describe an aerosol generator comprising an aperture plate of any of any example described herein, a support for the aperture plate, and a vibration generator for causing vibration of the aperture plate.

[0058] We also describe a nebulizer comprising an aerosol generator as described herein, a drive for delivering power to activate the vibration generator, and a means of delivering liquid to the cavities of the aperture plate.

[0059] Additional Statements

[0060] We also describe a method of manufacturing an aperture plate for vibration to provide an aerosol, the method comprising:

[0061] (a) in a first stage providing a plate of a material with a first side and a second side, in which there are cavities on the first side, the cavities each having an inlet opening and a blind base, and

[0062] (b) in a second stage drilling at least one aerosol forming aperture in the base of each of a plurality of the cavities. Accordingly, the cavities on the first side provide an inlet side for liquid supply, by gravity or pumping, and the drilling provides apertures for delivering aerosol droplets out of the second side which is an outlet side. In some preferred examples, a plurality of apertures are drilled in the blind bases of the cavities. In some preferred examples, the first stage is performed by providing a plate with a planar first side surface and forming the cavities by removing material from said first side in a material subtraction step.

[0063] In some preferred examples, the material subtraction is performed by chemical etching, which may be dry etching or wet etching, and optionally the first stage is performed by wet etching with a masking layout to provide a plurality of blind cavities with sloped side walls and a substantially flat base. In some preferred examples, the material of the plate is selected from corrosion resistant stainless steels and an alloy of Nickel or Titanium.

[0064] In some preferred examples, the cavities are formed by material subtraction to have a plurality of cavities having side walls which are at an angle of greater than 20° with respect to a cavity longitudinal axis. In some preferred examples, the first stage is performed by material addition. In some preferred examples, the first stage is performed by electrodeposition. In some preferred examples, the electrodeposition covers islands of resist on a mandrel so that the material forms recesses over said islands, said recesses providing said cavities.

[0065] In some preferred examples, the cavities are formed by material addition to have a plurality of cavities having side walls which are at an angle of no more than 20° with respect to a cavity longitudinal axis. In some preferred examples, the electrodeposition is around pillars of resist, the electrodeposition not extending over the tops of the pillars. In some preferred examples, the cavities are formed by material addition to have a plurality of cavities having side walls which are at an angle of no more than 20° with respect to a cavity longitudinal axis. In some preferred examples, the materials which are deposited are palladium or platinum or gold or nickel or silver or cobalt or copper or alloys thereof.

[0066] In some preferred examples, the first stage is performed by printing, and the printed materials are selected from metals such as titanium, tungsten, cobalt-chrome, stainless steel, nickel-based alloys, gold, platinum, palladium and silver and polymer materials such as Polyamide, Polyimide, Polyetherimide, ABS and Polycarbonate In some preferred examples, the first stage is performed by manipulation of a blank plate of material. In some preferred examples, the manipulation is embossing, optionally hot embossing. In some preferred examples, the manipulation is stamping. In some preferred examples, the manipulation is rolling. In some preferred examples, the materials for first stage material manipulation are stainless steel, nickel, titanium, cobalt or alloys thereof.

[0067] In some preferred examples, the cavities have funnel shaped side walls. In some preferred examples, the cavities are formed by material manipulation to have a plurality of cavities having side walls which are at an angle of greater than 20° with respect to a cavity longitudinal axis. In some preferred examples, the method comprises the further step of electropolishing surfaces of the first side and / or the second side.

[0068] In some preferred examples, the cavities provided by the first stage have a diameter in the range of 10 pm to 150 pm and a depth such that the remaining material thickness at the base of the liquid supply cavity is between 1 pm and about 20 pm.

[0069] In some preferred examples, the apertures provided by the second stage have a diameter in the range of 1 pm to 10 pm. In some preferred examples, the apertures provided by the second stage have a separation in the range of 4 pm to about 80 pm. In some preferred examples, the number of apertures provided by the second stage to each of at least some cavities is in the range of 1 to 50

[0070] In some preferred examples, the second stage is performed by laser drilling. In some preferred examples, the second stage comprises parallel laser drilling. In some preferred examples, the second stage is performed by multibeam laser drilling to drill holes simultaneously. In some preferred examples, the multibeam laser drilling comprises techniques such as scanned mask imaging. In some preferred examples, the apertures have side walls which are tapered with an angle of less than 10° to the longitudinal axis and percussion laser drilling is performed.

[0071] In some preferred examples, the apertures have side walls which are tapered with an angle of more than 10° to the longitudinal axis and percussion laser drilling is performed with closed loop feedback provided by an optical detection mechanism on the underside of the plate opposite to that upon which the laser energy is applied, and the laser drilling controller adjusts the energy profile used for laser drilling for control of hole size. In some preferred examples, the apertures have side walls which are tapered with an angle of greater than or equal to 10° to the longitudinal axis, and the drilling is performed in a plurality of steps. In some preferred examples, during the drilling, the laser spot is defocussed to achieve a funnel to a certain depth and then refocussed to a smaller spot size to provide the exit opening, whereby the aperture is funnel shaped. In some preferred examples, percussion drilling is performed during the second stage to provide the exit opening.

[0072] In some preferred examples, the laser drilling is performed using an Ultra Short Pulse (USP) laser system providing pulse widths in the low picosecond (less than lOps) or femtosecond range operating in the Green or UV wavelength range.

[0073] We also describe an aerosol generator aperture plate comprising liquid supply cavities on an inlet side and aerosol-forming apertures on an outlet side, at least some of said apertures being in fluid communication with said cavities, and the aperture plate having characteristics of being manufactured in a method of any example described herein.

[0074] DETAILED DESCRIPTION OF THE INVENTION

[0075] Brief Description of the Drawings

[0076] The invention will be more clearly understood from the following description of some embodiments thereof, given by way of example only with reference to the accompanying drawings in which:

[0077] Fig. l is a diagrammatic side view of a first stage of aperture plate manufacture, in which resist columns are used to achieve steep reservoir cavity side walls,

[0078] Fig. 2 shows the plate after a laser drilling second stage following cavity manufacturing steps of Fig. 1,

[0079] Figs. 3 and 4 show a plate after completion of a second stage which involves laser drilling in the blind bases of the cavities to provide aerosol forming apertures which may be cylindrical in shape as in Fig. 3, or tapered or conical in shape as in Fig. 4, Fig. 5 is a plan view showing a number of liquid supply cavities in an aperture plate manufactured according to Figs. 3 and 4, illustrating particularly an arrangement and pitch of the liquid supply cavities,

[0080] Fig. 6(a) is a cross-sectional view showing part of a plate after a first stage in this case also with a planar lower surface but with different cavities, and Figs. 6(b) and (c) show this part of the plate after laser drilling of cylindrical and conical apertures respectively,

[0081] Fig 7 is a plan view diagram showing a distribution of cavities formed by etching in a plate, and of laser-drilled aerosol-forming apertures in the bases of these cavities,

[0082] Fig. 8 is a diagrammatic sectional view across an alternative cavity after first stage manufacture and before aperture drilling, and a plan view of distribution of such cavities in a full aperture plate,

[0083] Fig. 9 is an SEM showing liquid supply cavities in an aperture plate manufactured with first stage etching; Fig. 10 is an SEM with higher resolution sufficient to show the aerosol forming apertures within the liquid supply cavities of Fig. 9; Fig. 11 is an SEM with further magnification showing the apertures in more detail; Fig. 12 is an SEM with sufficient magnification to show a single aperture in detail in top (liquid supply side) plan, Fig. 13 is an SEM showing an underneath plan view of five apertures in the aerosol exit side below an individual cavity,

[0084] Figs. 14(a) to (k) inclusive are diagrammatic vertical sections through alternative cavities arising from first stage manufacture in various embodiments,

[0085] Fig. 15 is a diagrammatic side view showing a first stage of a method of aperture plate manufacture, in which there is electroforming according to the known electroforming processes, but the plating is continued so that there are no apertures on peaks of resist,

[0086] Fig. 16 shows the completion of a second stage of the method of Fig. 15, after laser drilling in the valleys,

[0087] Fig. 17(a) is a cross-sectional view across a plate during first stage manufacture, Fig. 17(b) shows this plate after laser drilling in the second stage to provide cylindrical apertures, and Fig. 17(c) is a similar view in this case showing laser drilling second stage with conical or tapered apertures,

[0088] Fig. 18(a) is a cross-sectional view showing part of a plate after a first stage in this case with a planar lower surface, and Figs. 18(b) and (c) show this part of the plate after laser drilling of cylindrical and conical apertures respectively,

[0089] Fig. 19 is an SEM showing a full aperture plate,

[0090] Fig. 20 is an SEM with 200x magnification of part of the aperture plate with cavities having diameters in the region of 160 pm,

[0091] Fig. 21 is an SEM showing a cut-away section of a single recess, with lOOOx magnification, and superimposed annotation to illustrate recess depth at three positions, and

[0092] Figs. 22 to 24 are plots showing performance of aperture plates of the invention.

[0093] Detailed Description of the Embodiments

[0094] We describe aperture plates (or “vibrating membranes”) for atomisers, especially for nebulizer applications, and their manufacture. The invention is particularly suited to nebulizers because it is especially effective at providing aperture plates which output consistent aerosol droplets with a size and flow rate to suit the particular medication being aerosolized for access to the patient’s lungs. Indeed, as described below the invention particularly allows versatility in choice of configuration of a reservoir layer and of apertures to suit the intended application, such as administration of medication by way of aerosol to a child’s lungs. However, the method may be applied to manufacture of aperture plates for other applications such as humidification, spray coating, spray cooling, spin-spray deposition of thin films, spray drying, mass spectrometry, liquid fuel injection, inkjet printing, 3D prototyping, soft robotic actuation or moisture removal.

[0095] In this specification aperture plates are described, having a body of material, which is in most embodiments integral, and it has in inlet surface with liquid supply cavities for receiving a liquid to be aerosolized and an outlet surface for delivery of aerosol, there being multiple aerosol-forming apertures with openings in the outlet surface for each cavity. These apertures extend from the bases of the reservoir cavities. It is preferred for a range of applications such as nebulizer applications that there are multiple apertures, preferably up to 300. The direction from liquid supply to aerosol delivery is referred to as the longitudinal direction, and across the plate it lateral.

[0096] Advantageously in the various manufacturing methods described there is a first stage to provide blind recesses which will become liquid supply reservoir cavities in a desired shape and arrangement using manufacturing techniques which are simple to control, and which are well established. The lateral and longitudinal dimensions, the recess wall shapes, the pitch of the recesses, and therefore the total number of liquid supply cavities possible per unit area, may be easily adapted through simple changes to tooling and / or process parameters and makes for a very versatile architecture for addressing future unmet needs. The blind recesses may be arranged in a hexagonal arrangement of equilateral triangles (801 in Fig. 7) or rectangular or other regular arrangement with centre-to-centre separations.

[0097] In a second stage of manufacture, there is laser drilling within the blind recesses to provide aerosol forming apertures, so that the recesses become liquid supply cavities leading to multiple aerosol forming apertures leading to the outlet surface. Laser drilling is well known, even for nebulizer aperture plate manufacture, as described in detail in US7316067 (The Technology Partnership). The combination of the two stages together achieves aperture plate manufacturing in a manner which is well controlled to achieve the micron-level dimensions required and uses a combination of established technologies. Also, in this invention because the laser drilling is through the blind bases of recesses the depth to be drilled is small and so a single laser drilling stage (one set of laser drilling parameters) will often be sufficient.

[0098] Our prior published PCT specification W02013 / 186031 (Stamford Devices Limited) describes reservoir aperture plates having inlet liquid supply cavities, and the bases of the cavities have multiple aerosol-forming apertures. Both the cavities and the apertures are formed by electrodeposition around resist columns. However, in this invention the apertures are provided in a particularly simple manner, by forming the cavities first and then laser drilling the apertures in the bases of the cavities. Also, we describe preferred aperture plate structures for improved aerosolization of liquid medicines for access to the lower regions of the lungs, especially of children.

[0099] Referring again to manufacture of the blind recesses, while many different blind shapes are possible, it is preferred that the base of the blind cavity that is formed has a significant portion that is within a distance from the starting plate outlet surface which is no more than a desired maximum length of aerosol-forming aperture. That allows drilling of multiple aerosol-forming apertures to have a small length deviance arising from distance from the base of the blind cavity to the outlet surface. In some preferred examples the maximum aperture length is 12 pm, and so there is an adequate blind recess surface area that is less than 12 pm from the outlet surface so that the desired number of apertures per cavity can be drilled at the desired aperture pitch. The apertures have in preferred examples an outlet diameter in the outlet surface in the range of 0.5 pm to 10.0 pm, but preferably 1.0 pm to 5 pm.

[0100] In general, it is preferred for nebulizer use that the cavities have round inlet surface openings (round in plan view from the liquid supply side) and the number of apertures per cavity is in the range of 2 to 300. Also, it is preferred that the variance in length of the apertures be no more than 50%, the flatter the profile of the base of the cavity the smaller the variance. In general, it is preferred that the base of the blind recess formed in the first stage be flat enough so that apertures can be drilled to the maximum desired aperture length (preferably 12 pm) over an area that is encompassed by at least 50% of the diameter of the recess at the inlet surface.

[0101] In various examples the first stage may be performed by manufacturing techniques which fall into one of the following categories:

[0102] (a) Adding material such as by electroforming / electrodeposition or 3D Printing,

[0103] (b) Removal of material such as by wet or dry etching.

[0104] (c) Manipulating the material such as by embossing, punching / stamping or rolling.

[0105] Additive Techniques for the First Stage: Electrodeposition / Electroforming with Resist Pillars

[0106] Fig. 1 shows a diagrammatic side view of a first stage of aperture plate manufacture in an electrodeposition additive method. There is electrodeposition of a base layer of metal 105 on a mandrel 103, followed by electrodeposition of metal 101 around cylindrical pillars 104 of resist to form blind recesses for liquid supply reservoir cavities 102. The liquid supply cavities have a cylindrical shape (circular in the inlet surface) of desired dimensions, in a method using resist column and deposition steps generally as described in our published patent specification No. WO20 13 / 186031 (Stamford Devices Limited), the entire contents of which are herein incorporated by reference. However, in the present invention there is no need for selective electrodeposition in the lower layer, as apertures are not formed in it by the electrodeposition. The pitch (A) of the cavities 102 is 270 pm, and in general it is preferably in the range of 40 pm to 500 pm, more preferably 100 pm to 500 pm, more preferably 150 pm to 400 pm, more preferably 200 pm to 300 pm.

[0107] The cavity 102 diameter (B) is 160 pm, and more generally is preferably in the range of 40 pm to 400 pm, more preferably 120 pm to 300 pm, more preferably 150 pm to 200 pm.

[0108] The dimension C (cavity depth) is 40 pm, preferably in the range of 10 pm to 100 pm, more preferably 20 pm to 70 pm, more preferably 30 pm to 60 pm.

[0109] The blind base layer 105 has a thickness (D) of 6 pm, and in general it preferably has a thickness in the range of 3 pm to 12 pm, preferably 3 pm to 8 pm, more preferably 4 pm to 7 pm. This defines the length of the apertures which will be drilled.

[0110] The overall plate thickness (C+D) is preferably in the range of 13 pm to 112 pm, more preferably about 46 pm.

[0111] The aperture 106 outlet diameter (E) is in a preferred example 3 pm, and more generally it is preferred that it is in the range of 0.5 pm to 5.0 pm, more preferably 1.0 pm to 4.0 pm, and more preferably in the range of 1.5 pm to 4.5 pm.

[0112] Other important parameters are as follows.

[0113] Number of apertures per cavity: 2 to 300 preferably 5 to 300, more preferably 25 to 300, and in this example 214.

[0114] Number of reservoirs per mm2: 1 to 25, preferably 2 to 16, more preferably 7 to 12, and in this example 10.

[0115] Aperture plate diameter when flat (before being domed if it is domed): 3 mm to 8 mm, preferably 4 mm to 6 mm, and in this example 5 mm.

[0116] These parameter ranges have been found to be particularly effective for providing an aperture plate for a nebulizer to vibrate at the typical nebulizer drive frequencies such as 128 kHz to provide a good flow rate of well in excess of 0.1 mL / min and an average VMD of less than 6 pm. In many cases the flow rate is over 1.0 mL / min, as described in more detail below. It should be noted that while the techniques used here involve some techniques which are similar to those of WO2013 / 186031 an important difference is that there is no need for a first stage mask and etching to provide the aerosol-forming apertures. It is only necessary to provide a planar part 105 without apertures, as these are provided by laser drilling in the second stage. This simplifies the electrodeposition steps. Electrodeposition is very advantageously employed to achieve the blind recesses, especially with steep side walls, and laser drilling is very advantageously employed for the apertures in the blind bases of the recesses. It is also envisaged that the lower part 105 may be provided separately as a foil, and the cavities formed by electrodeposition on the film.

[0117] In more detail, there is first electroplating of the thin uniform thickness planar layer 105 onto the mandrel 103. Thereafter the pillars 104 of photoresist are applied to the metallised mandrel in a hexagonal or rectangular arrangement. Thereafter there is electroplating onto the metallised mandrel thereby providing a plate of material 100 with recesses 102, formed by electroplating in the regions between the non-conductive resist islands 104, and the recesses coincide with the peaks of the resist pillars 104 thereby providing a plate of material 100 with recesses 102 separated by plated material 101. In most examples the plating is only to the top of the resist columns. However, if an overhang is required in the cavity (as shown in Fig. 14 (a) the resist columns may be overplated to form the overhangs.

[0118] As shown in Fig. 2 there is then laser drilling of tapered aerosol-forming apertures 106 in the bases of the recesses, the layer 105.

[0119] Fig. 3 shows another example, a plate 300 having liquid supply cavities 301 with side walls which are curved and very close (within 10°) of longitudinal and having a flat blind base with laser-drilled cylindrically shaped aerosol forming apertures 302. Such cavities can be readily manufactured using resist columns or pillars which are tapered to achieve the desired negative cavity shape.

[0120] Fig. 4 shows a plate 310 having a similar first stage manufacture, but in this case the cavities 311 are drilled in their bases to provide conical or tapered aerosol-forming apertures 312. The configuration of cavity in these examples is best achieved in the first stage by photo-defined electrodeposition.

[0121] Fig. 5 shows one preferred arrangement of cavities 306 in a portion of an aperture plate, having separations in the directions of arrows F and G at a 60° angle to each other in the range of 10 pm to 100 pm. It is notable in this approach that the cavities have side walls aligned with, or slightly tapered from, the longitudinal axis of the cavity. In general, this type of first stage is very suitable where a small angle, or none, to longitudinal is required. It is also particularly advantageous for achieving a sharply defined area of flat blind base of each cavity, to provide a desired area for the number and configuration of aerosol forming apertures to be drilled, and very consistent aperture length.

[0122] Subtraction Techniques for the First Stage: Etching

[0123] Subtraction techniques such as wet etching or dry etching can be performed for the first stage to achieve aperture plates with the parameters set out above with reference to Figs. 1 and 2.

[0124] Referring to Figs. 6(a), 6(b), and 6(c), and Fig. 7 a first stage comprises providing a plate 800 of metal such as 316L Stainless Steel or Hastelloy C276, the plate having an inlet, surface and an outlet surface, upper and lower respectively. Advantageously wet etching is particularly suited to steel, and so the material may be inexpensive.

[0125] Wet Etching, as described in more detail below, is performed with a masking layout to provide a plurality of blind recesses which will form the liquid supply cavities 801 with sloped side walls for the final produced aperture plate. Each blind recess 801 has a funnel-shaped curved sidewall 802 and a flat base 803, and the diameter (B) is as specified above with an etch depth such that the remaining material thickness at the base of the liquid supply cavity is between 3 pm and about 12 pm, parameter D above.

[0126] As shown in Figs. 6(b) and 6(c) the second stage can provide cylindrical apertures 805 or tapered (funnel shaped) apertures 806 respectively. Fig. 7 shows the overall layout of liquid supply cavities 801, being hexagonal in plan-view from the inlet side (equilateral or rectangular in other examples).

[0127] During the etching process, a resist is a photoresist when it chemically changes upon exposure to certain wavelengths and if applicable, a subsequent thermal baking step in such a way that the exposed and unexposed resist areas have a different dissolution rate in the developer solution, thus permitting the realisation of a structured photoresist mask. The photoresist material may be applied by spin coating, spray coating or dip coating the substrate. The resin of almost all positive and image reverse resists is a polymerized phenolic resin made of formaldehyde and phenol. The chain length of the resin molecule determines relevant properties of the photoresist. Negative resists cross-link after exposure and a subsequent baking step, while the unexposed part of the resist is dissolved in the developer. Some negative resists are also based on phenolic resin, with a (melamine) cross-linker.

[0128] Spin-coating is the most common coating technique for resists allowing for very smooth and homogeneous resist films. Spray coating allows the coating of almost arbitrary shaped and textured substrates but in order to attain a smooth and homogeneous resist film thickness as well as a good edge coverage of textures, an optimized resist composition with different solvents with low and high boiling points is required. Dip coating techniques are used for large, rectangular shaped substrates and the demand for a minimum resist consumption per coated area. For a homogeneous resist film thickness over the entire substrate, a certain solvent composition in the resist is required. Masking is performed using standard photolithographic methods by application, exposure and developing of the photoresist material onto the surface of the material which is required to be etched.

[0129] Wet etching is a material removal process that uses liquid chemicals or etchants to remove materials from a wafer. The specific layout is defined by the photoresist masks on the wafer. Materials that are not protected by this mask are etched away by liquid chemicals.

[0130] Dry etching is usually an anisotropic process in which the momentum of ion species accelerating towards the substrate in combination with a masking process is used to physically remove and etch the target materials. Dry etching requires an elevated softening point of the resist as well as steep sidewalls. Dry etching techniques such as Metal Anisotropic Reactive Ion etching and Oxidation (MARIO), Titanium Inductively coupled plasma Deep etch (TIDE) or Titanium Deep Reactive Ion Etching (Ti-DRIE) processes may be used (Aimi et. al. 2004,

[0024] ), (Parker et. al. 2005,

[0015] ), (Zhang et. al. 2004,

[0024] ), (Woo et. al. 2017,

[0023] ).

[0131] In one example of wet etching, spin coating of AZ40XT-11D™ (Merck Performance Materials) Chemically Amplified Photoresist is applied to a 50 pm thick sheet of 304 Stainless Steel using dynamic spin-coat dispense at 30 rpm to provide a 40 pm thick film. This was followed by a soft bake at 125 °C with proximity for 120 s at 1.27 mm, 120 s at 0.63 mm and 180 s contact. Exposure was carried out using a Suss MA-200™ aligner with a 20 pm proximity gap and 900 mJ / cm2nominal exposure dose. Post expose bake was completed at 105 °C with proximity for 10 at 1.3 mm, 10 s at 0.6 mm and 80 s contact. This was followed by development using AZ 300MIF™ (Merck Performance Materials), with 3 x 40 second puddles. Spray etching of the stainless steel was carried out using Ferric Chloride (FeC13) at a specific gravity of 1.292 with IMol Hydrochloric Acid (HC1) at a temperature of 50 °C for 4 minutes to create an etch depth in the exposed areas of 45 pm.

[0132] Alternative First Stage Manufacturing Processes

[0133] Alternative techniques can be performed for the first stage to achieve aperture plates with the parameters set out above with reference to Figs. 1 and 2.

[0134] In such other examples, an inlet layer is formed by hot embossing, electropolishing, moulding, inkjet, or 3D Printing or UV Nanoimprint Lithography. These processes have the potential of creating complex and intricate geometries down to the micron scale. The speed at which these processes can create a product are not taken into consideration. The process is not limited to a single step. If required, multiple processes can be used in conjunction to achieve the desired result. Hot embossing is a process which relies on increasing the temperature of a polymer sheet above its melting range followed by pressing a heated mould into the polymer generating pressure to fill the surface structures. In hot embossing, a mould is attached to one clamp, and the polymer material or substrate is attached to another clamp, both clamps are heated, one clamp is stationary while the other lowers slowly and gradually as the polymer slowly deforms around the mould. When it is lowered, the polymer is softened and forms into the shape of the mould. The process takes between 5 - 30 mins to complete. The applications of hot embossing can be found in optical devices such as compact discs, lenses, mirrors, optical benches, wave guides and switches (Omar 2013,

[0012] ) and (Becker & Heim, 1999, [3]). Common materials used in Hot Embossing are Polycarbonate (PC), Cyclic Olefin Copolymers (COC) and Polymethylmethacrylate (PMMA).

[0135] Micro injection is very similar to standard injection moulding, but on a micro-scale. Similar to standard injection moulding, polymer granules are fed into the hopper, are pushed along the barrel where they are softened and molten, and then injected into a mould under pressure where it solidifies (Surace, 2012,

[0021] ), (Omar 2013,

[0012] ) and (Scott, 2021,

[0020] ). Manufacture of the core may alternatively be by way of 3D printing.

[0136] There are many 3D printing techniques, all with varying production speeds, feedstock material choices and resolution capabilities. Basic FDM (Fused Deposition Modelling) 3D printing adds layers on top of layers through a hot nozzle (called the extruder) of a set diameter to produce the 3D object (O'Neal, 2019,

[0013] ). Advanced printers using lasers on photosensitive materials, such as Multiphoton Lithography can have high resolution (-250 nm) and can produce parts down to the micrometre scale. (Prabhakaran, 2019,

[0016] ). Another manufacturing approach is Digital Light Processing (DLP) and Stereo Lithography (SLA), both methods used in 3D printing with resin baths, and both use UV light on photosensitive resin to harden it. In both printing methods, a platform is moved vertically as layer by layer is being solidified by the laser / projector. A DLP printer can print faster compared to SLA, therefore it has the ability to solidify an entire plane at a time, compared to SLA which is essentially drawing the objects layer by layer with a singular laser. The accuracy and resolution can also vary between the two processes. In DLP printing, square pixels are applied in a combination to solidify the resin which causes the 3D object to have steps around the edges. However, this process is being refined, and anti-aliasing techniques are being applied with a specific kind of DLP printing called CDLM DLP printing. The anti-aliasing function essentially smoothens the edges of the subject removing the steps. Any photopolymer can be used in either of these two processes, therefore theoretically if a photo-initiator is introduced into a polymer, it can be used as the resin for SLA / DLP printing (Waheed, 2016,

[0022] ). Nanoimprint Lithography (NIL) can create sub-micron features on a polymer surface such as a diaphragm. It creates an arrangement via deformation onto a resist material using a mould. There are many types of lithography, but two fundamental types are Thermal Nanoimprint Lithography (T-NIL) and UV Nanoimprint Lithography (UV-NIL) with both being capable of creating features as small as lOnm. The main differences between T-NIL and hot embossing are that hot embossing is slower and can work on larger mould structures. NIL applications mainly cover nanoelectronics, nano-optoelectronics, nanophotonic, nano-biology, optical components, etc. (Omar 2013,

[0012] ).

[0137] Table 1 is a summary comparison of key process parameters for some of the techniques described above.

[0138] Table 1. Comparison of replication processes

[0139] This invention utilises distinctly different processes to create the aperture plate. For the first stage of manufacture to create the liquid supply cavities, additive (e.g. Electroforming or 3D-Printing) subtractive (e.g. Etching, Electropolishing or Laser Micromachining), or material manipulation (e.g. punching, embossing, or rolling) techniques may be employed. Alternative dry etching techniques such as Metal Anisotropic Reactive Ion etching and Oxidation (MARIO) or Titanium Inductively coupled plasma Deep etch (TIDE) processes may be used (Zhan, 2004,

[0024] ), (Aimi, 2004 [1, 24]), (Parker, 2005,

[0015] ).

[0140] For the second stage of manufacture, laser drilling is used to create the aerosol forming apertures within the pre-formed liquid supply cavities. This second stage is discussed in more detail in the following section.

[0141] Second Stage Manufacturing - Laser Drilling

[0142] Laser drilling is performed in the bases of the blind recesses provided by the first stage to achieve the aerosol forming apertures with the parameters set out above with reference to Figs. 1 and 2.

[0143] Known approaches to laser drilling (Dbring, [5], [6], [7]), (Gruner, 2016,

[0010] ), (Forster, 2021, [9]), (Li, 2020,

[0011] ), (Raciukaitis, 2021,

[0017] ), (Schaeffer, 2012,

[0019] ), (Zhao, 2020,

[0025] ) of vibrating mesh aperture plates utilises laser-micro machining to create the apertures required for aerosol formation. Machining to create the required aperture shape suitable for effective and efficient aerosol production is achieved by controlled deflection of the laser beam using separate X and Y Galvanometers. Control of the shape, size and consistency of the resultant laser drilled holes is achieved by appropriate configuration, movement, and control of the laser beam at the surface of the material to be machined. In general, to generate an aperture with a tapered shape, either single step percussion drilling or multi-step drilling may be used. Importantly, because of this invention providing cavities with blind bases there is only a small thickness to drill through (1 pm to 20 pm, preferably in the range of 4 pm to 8 pm). This makes the laser drilling simpler.

[0144] Percussion Drilling is where the laser beam hits the material without any relative movement and typically the spot size of the laser largely determines the hole size. A small focal spot created by a short focal length lens can create a spot size of ~5pm. In this case, the hole entrance will be only slightly larger than spot size so typically, this is best suited to creating straight through holes with limited taper through thin layers the thickness of which is comparable with the spot size. This can present challenges in terms of creating an aperture shape which can create high output rates (efficiency) and low droplet sizes for deep lung penetration (efficiency).

[0145] Larger spot sizes (-15-20 pm) are often used with thicker substrates but create an inherent taper and tip processing effect to get a small exit diameter. Using this method in an open loop control system, it is difficult to control exit hole size due to laser stability and issues caused by variations in material properties and substrate geometrical features such as thickness and flatness. In this case, closed loop feedback in the form of an optical detection mechanism placed on the underside of the substrate opposite to that upon which the laser energy is applied can be used to adjust the energy profile used for laser drilling in order to improve control of hole size.

[0146] During multi-step drilling, the laser spot is defocussed to achieve a funnel to certain depth and then refocussed to a smaller spot size to get the exit hole. The resultant aperture shape is funnellike in nature with relatively large entrance (liquid) side and small exit (aerosol) side geometries.

[0147] The second stage may use percussion drilling with a small spot size to create cylindrical or tapered holes through the thinned section of the aperture plate in the base of the pre-formed cavities. In this way, using the arrangement of the liquid supply cavities (reservoir layer), the aperture plate consists of a plurality of through-hole aerosol-forming apertures in the base of each liquid supply cavity with multiple cavities distributed throughout each aperture plate. After formation of the cavities, laser drilling is performed through the thinned sections of these cavities to form small aerosol-forming apertures. Laser drilling is preferably performed according to the laser drilling processes described in US7316067 (The Technology Partnership). The drilling is through a relatively short axial dimension, and so irregularities in drilling are not a problem and the desired accuracy is still achieved.

[0148] Multibeam based laser drilling processes (e.g., Scanned Mask Imaging) may be used to blanket drill many holes simultaneously, permitting the parallel processing of many aperture plates, thus increasing throughput, and reducing cost even further. This technique comes with the added advantage that it is unnecessary to align the laser drilling of the exit holes with the premanufactured reservoirs. For targeted applications in the manufacture of vibrating mesh nebulisers, extremely high precision and high-speed laser drilling processes are required to ensure repeatability, quality, and throughput. Such demanding applications require careful selection of laser system architecture and processes to minimise excess heat generation during the laser drilling process. In this case Ultra Short Pulse (USP) laser systems with pulse widths in the low picosecond (less than lOps) or femtosecond range operating in the Green or UV wavelength range are most suitable. Laser drilled holes or aerosol forming apertures used in the manufacture of aperture plates for vibrating mesh nebulisers may be in the range from 0.5 pm to 20 pm in diameter, preferred in the range 1 pm to 10 pm, more preferred in the range 2 pm to 5 pm, for example 3.5 pm. Aerosol forming apertures may be at a pitch of 4 pm to 60 pm, preferred in the range of 8 pm to 20 pm and most preferred in the range of 12 pm to 16 pm, for example 14 pm in a rectangular or hexagonal or other regular pitch arrangement. The total possible number of aerosol-forming apertures per aperture plate is determined by the diameter and pitch of cavities during the first stage of manufacture coupled with the diameter and pitch of the aerosol forming apertures.

[0149] We have illustrated the completion of the second stage of this method, after laser drilling in the cavities to provide aerosol forming apertures The lowest plane within the cavities provides the location for the laser drilling process to form the aerosol forming apertures. Apertures may be cylindrical or tapered, as illustrated, or other shape appropriate for the generation of droplet sizes suitable for pulmonary drug delivery, specifically those with a Mass Median Aerodynamic Diameter ranging from 1 pm to 5 pm.

[0150] In one example shown in Figs. 6 and 7 and 11, through-hole apertures 805 or 806 are drilled, from the base of a wet chemically etched blind recess 801 to the outlet side surface. Fig. 7 shows the overall layout of liquid supply cavities 801, being hexagonal in plan-view from the inlet side (equilateral or rectangular in other examples).

[0151] Fig. 8 shows a full aperture plate 900 with an arrangement of cavities 901, each having a diameter of 150 pm and a depth of 45 pm at its deepest point in a plate material having a thickness of 50 pm, thereby providing a remaining axial length of 5 pm from the lowest point on the cavity to the planar surface underneath. In this case the cavities have shallow funnel shapes with an angle to horizontal (the general plane of the aperture plate) of about 45°, and the preferred manufacturing processes for this configuration are chemical etching.

[0152] Example referring to SEM Images Fig. 9 is an SEM showing an example of an aperture plate manufactured with First Stage wet etching. The diameter of each cavity is about 150 pm, and there are 180 cavities in the aperture plate. There are 5 apertures in each cavity, arranged to form a square of sides about 60 pm and one in the geometrical centre. The overall plate diameter is 5.0 mm. Fig. 10 is an SEM with 250 x magnification, sufficient to show the apertures within the cavities. Fig. 11 is an SEM with further magnification, 2500x, showing the apertures in more detail, particularly separation of about 61 pm in the vertical and horizontal directions as shown and 44 pm diagonally. Fig. 12 is an SEM with further magnification at lOOOOx showing an individual aperture having a diameter of 13 pm in its inlet side and this narrows to 4.1 pm on its outlet side. Fig. 13 is an SEM at a magnification of lOOOx showing an underneath plan view of five apertures in the aerosol exit side below an individual cavity, showing the 4.1 pm outlet openings.

[0153] In this example, liquid supply cavities were etched by anisotropic wet chemical etching into a 50 pm sheet of 1.4404 (316L) Stainless Steel. A photomask of materials (oxides) resistant to the etchant (hydrochloric acid) was used to define the etching pattern for the cavities. The bases of the reservoirs were laser drilled to create the aerosol forming apertures. A major benefit of etching for the first stage is that the material may be a steel, which is less expensive than metals such as Pd and Ni.

[0154] Further Examples of Cavities Produced with Different First Stage Techniques

[0155] Figs. 14(a) to (k) inclusive show that many shapes of liquid supply cavity are possible, and the method of performing the first stage is chosen to suit. These examples are:

[0156] Fig. 14(a), cavity 1150, cylindrical with an overhang rim 1151,

[0157] Fig. 14(b), cavity 1152, convex walls, flat blind base, and an overhang rim 1153,

[0158] Fig. 14(c), cavity 1156 with a fully curved shape in the general form of a sphere and having an overhang rim 1157,

[0159] Fig. 14(d), cavity 1158 with cylindrical side wall but with a funnel shaped blind base 1159, Fig. 14(e), cavity 1160 with a cylindrical side wall, a flat blind base 1161, and rounded corner around the base,

[0160] Fig. 14(f), cavity 1162 with tapered side wall and flat blind base 1163,

[0161] Fig. 14(g), cavity 1164 with tapered side wall and funnel shaped blind base 1165,

[0162] Fig. 14(h), cavity 1166 with a tapered side wall and a narrower blind base,

[0163] Fig. 14(i), cavity 1168 with a tapered (frustum shaped) side wall and a flat blind base 1169, Fig. 14(j), cavity 1170 with a tapered side wall which has an inlet opening which is curved in a funnel shape, and this cavity having a flat blind base 1171, Fig. 14(k), cavity 1174 with a tapered side wall and a widening mouth 1175.

[0164] The Fig. 14 drawings show a variety of cross-sectional profiles, and the particular technology chosen to provide the cavities is chosen to suit. Where there is a requirement for side walls with an angle to longitudinal axis of the cavity less than 20° (1158, 1160), additive (material addition) techniques are particularly suitable (for example electroplating with photo-defined resist pillars). Where there is a requirement for more tapered or curved (funnel-shaped) side walls ((angle to longitudinal axis of the cavity greater than 20°) (1162, 1164, 1166, 1168, 1170, 1174), especially with a shallow angle (more than 40° with respect to the longitudinal axis)) then subtractive (material removal) techniques (for example etching) or material manipulation (for example embossing, punching / stamping or rolling) can be used advantageously. Etching is a mature technology compatible with high-volume, low-cost manufacturing and would therefore be appropriate to use where the design is particularly cost sensitive.

[0165] Additional Alternative Manufacturing Approaches

[0166] Additive Techniques for the First Stage: Electroforming / Electrodeposition with Shallow Resist Islands

[0167] Fig. 15 shows a first stage of a method of aperture plate manufacture, in which there is electroforming which is akin initially to the known electroforming processes, but the plating is continued so that there are no apertures on peaks of resist. The electroforming is performed as described in US6235177 (Aerogen Ltd.), the contents of which are incorporated herein by reference. There is electroplating onto a mandrel 1507 which has islands 1508 of resist, thereby providing a plate of material 1501 with hills 1502 and recesses 1503 on the inlet side and hills 1505 and recesses 1504 on the outlet side. The hills 1502 and 1505 are formed by electroplating in the regions between the non-conductive resist islands, and the valleys 1503 and 1504 coincide with the peaks of the resist islands. The depth of the recesses and of the hills depend on the slopes of the resist islands. A major difference from the prior art, however, is that the electrodeposition does not stop at a time when the peaks of the resist islands are still exposed. Instead, the deposition continues until the resist islands are completely covered, with the recesses 1503 and 1504 coinciding with the peaks of the islands. The plating continues until the thickness above the resist islands matches a desired depth of the blind bases of the liquid supply cavities 1503.

[0168] The electrodeposition only provides the recesses 1503 over the islands, and so when the resist 1508 is removed there are the outlet side recesses 1504. The exact time for stopping electrodeposition is not as critical, all that matters is that there is a desired depth of material at the recesses 1503, which is in the range as set out with reference to Figs. 1 and 2 for the aperture lengths. Also, the width of the recess 1503 is chosen according to the height of the resist islands 1508. If the resist islands 1508 are very wide and shallow, then the recesses 1503 will likewise be shallow, providing more space for aerosol-forming apertures. In these diagrams for clarity, we show only one laser-drilled aperture per recess / cavity, but there are multiple apertures.

[0169] This first stage manufacturing approach benefits from using well established technology, but the cavities are funnel shaped with angles to the longitudinal axis and therefore less area for drilling suitable apertures in the second stage. It is therefore more suited for a funnel cavity shape with a number of apertures per cavity towards the lower end of the range.

[0170] In this example and also other examples the aperture plates are constructed of materials having a high strength for use being vibrated at frequencies in the region of 128 kHz and which are resistant to corrosion in the expected use environment. One particular material that provides such characteristics is a palladium nickel alloy. One particularly useful palladium nickel alloy comprises about 90% palladium and about 10% nickel. Aperture plates constructed of such a palladium nickel alloy have enhanced corrosion resistance. In this instance, alternative materials for constructing the aperture plates of the invention may include noble metals like platinum or gold or alloys thereof.

[0171] On the other hand, in less demanding applications which expose aperture plates to less corrosive media, alternative materials may be used to improve process control, increase product yield, and reduce cost. In this case, alternative materials for constructing the aperture plates of the invention may include Nickel or Tin or Copper or Silver or Cobalt or alloys thereof. The metal is deposited from a solution onto a conductive mandrel by an electrolytic process. The metal is electroplated onto an accurately made mandrel that has the inverse contour, dimensions, and surface finish desired on the finished aperture plate. When the desired thickness of deposited metal has been attained, the aperture plate is separated from the mandrel. The mandrels that may be utilized to produce the aperture plates of the invention may comprise a conductive surface having a plurality of spaced apart nonconductive islands. In this way, when the mandrel is placed into the solution and current is applied to the mandrel, the metal material in the solution is deposited onto the mandrel.

[0172] Fig. 16 shows this part of an aperture plate 1550 which has also been formed by electroforming in the first stage and shows it after completion of the second stage of laser drilling, showing aerosol- forming apertures 1560 in recesses 1553 and 1554 on the inlet and outlet sides respectively. There are raised portions 1552 between the recesses 1553. Laser drilling in this layout of recesses and through such a thin layer is simple to achieve. These aperture parameters are applicable to all embodiments of the invention.

[0173] In the example shown in Fig. 16, the dimensions are:

[0174] Depth of inlet side recess (liquid supply cavity), 30 pm.

[0175] Diameter of the cavity (from one peak 1502 to the other), 120 pm

[0176] Axial (inlet side to outlet side dimension) length of the narrowest locations coinciding with alignment of the recesses, and length of the apertures, 5 pm.

[0177] Depth of outlet side recesses, 15 pm.

[0178] Thickness of the aperture plate at its deepest locations, 50 pm.

[0179] Diameter of the apertures 1560 at the outlet side, 3.5 pm

[0180] These dimensions may be different by simple manufacturing step control of parameters in order to achieve the desired cavity and aperture configurations. This diagram shows only one aperture per cavity but there may be multiple apertures drilled into each recess, close enough together so that their lengths are similar. It will be clear that this method is particularly suited to applications where the side walls of the cavities are at a large angle to the longitudinal axis (vertical as viewed in these drawings), such as greater than 40°. For the electroforming cavity manufacture approach, the major parameters which may be controlled to achieve the desired configuration are: number, height, width, and distribution of resist islands 1508, and time for electrodeposition, thereby setting the height of the recesses (cavity blind bases).

[0181] Choice of parameters achieves the dimensions of the cavities, and the profile of the cavity blind bases, thereby setting the desired geometry for drilling of the apertures to the required number and distribution per cavity.

[0182] Metal Forming / Manipulation for the First Stage:

[0183] Alternatively, the starting plate of material may be manipulated to form the cavities by embossing, stamping (Rhim et. al. 2005,

[0018] ), or rolling of planar sheet material to create the desired shape of the liquid supply cavities.

[0184] Fig. 17(a) is a diagrammatic side view showing a first stage of another method of aperture plate manufacture using a metal manipulation or forming process such as stamping, embossing or rolling, casting or moulding. There are peaks in a material 1650 on the inlet side and the outlet side, 1651 and 1652 respectively. Similarly, there are valleys in the inlet side and the outlet side, 1653 and 1654 respectively.

[0185] Figs. 17(b) and (c) show the plate after laser drilling for the second stage, in one case cylindrical apertures 1660, and in the other tapered apertures 1670. In this example there is only one aperture per cavity, however in other examples multiple apertures are laser drilled in each cavity.

[0186] Stamping is a fabrication process that presses a workpiece, such as a metal strip, between a die set assembly into a predetermined shape. Stamping presses and stamping dies are tools used in the stamping process. The die set assembly can perform various operations on the work piece, such as cutting and forming operations like punching, drawing, bending, flanging and hemming. Stamping processes have been deployed in manufacturing processes for mass- producing parts at low cost. Embossing differs from stamping in that embossing uses male and female dies so that features may be formed on both sides of the material as in Fig. 17(a) whereas stamping only uses a male die such that features are formed on one side only as in Figs. 18(a). During a rolling process, the material is manipulated by the rolling action of a roller having projections which reflect the arrangement of the cavities and thus roll the desired shape of the cavities into a flat section of material that is fed between the rollers.

[0187] For stamping, embossing or rolling, the preferred materials are highly corrosion resistant and biocompatible metals such as austenitic stainless steels (e.g. 304 or 316L), Nickel or Nickel Molybdenum-Chromium alloys (e.g. Hastelloy C276), Titanium or Titanium alloys (e.g., Ti-6A1- 4V, Austenitic or Martensitic Nickel-Titanium), or Cobalt alloys, SS Nitronic 60, BioDur, ASTMF1586 and others and the pressures applied are preferably in the range of 0.1 to 5.0 Tons - more typically less than 2.0 Tons for the typical thickness materials being used for the mesh material of vibrating mesh nebulisers and atomisers.

[0188] Fig. 18(a) is a diagrammatic side view showing a first stage of an alternative embodiment, manufactured using stamping for the first stage. There are peaks 1701 and valleys 1702 formed in a material 1700 on the inlet side while the outlet side remains flat and un-formed.

[0189] Fig. 18(b) and (c) shows the completion of a second stage of this method, after laser drilling in the valleys 1702, to provide a plurality of apertures 1710 which may be cylindrical or conical or tapered (1712) as indicated in Figs 18(b) and 18(c) respectively. In one example, a suitable stamping system for manufacturing high tolerance part is described in EP1536931B1. A manufacturing system includes one or a progression of stamping stations for supporting a punch or die. The stamping stations include a structure for guiding the punch in substantial alignment with the die with tight tolerances. The system includes a press for providing the stamping stations with the necessary force to perform the particular stamping operation. In one aspect, the system is designed to minimize the number of moving components involved in the support structure in guiding the punch to the die. In another aspect, the system includes a locating sub-plate having indexing features for precisely aligning the progression of stamping stations relative to each other. The locating sub-plate and its indexing features have exacting tolerances and submicron surface finishes. In a further aspect of the present invention, the system includes an interface system for coupling the force of the press with the punch but structurally decoupling the press from the punch. The interface system also allows isolation of each stamping station so that operation at one station does not affect operation at another station.

[0190] Preferred Characteristics of Aperture Plates for Nebulizer Use

[0191] Images of aperture plates produced according to the method of first stage wet etching and second stage laser drilling are shown in Fig. 19 to 21, to give further examples of the invention. Fig. 19 is an SEM with only 30x magnification showing a full aperture plate 1800 with reservoir cavities 1801. In this case there are 193 reservoir cavities, and their diameters are about 160 pm. There are 214 apertures drilled in each cavity, and their inlet diameters are about 5 pm and their pitch is about 10 pm. There are 214 x 193= 41,302 apertures in the whole aperture plate 1800.

[0192] Fig. 20 is an SEM with 200x magnification of part of the aperture plate 1800 with the cavities 1801 shown in more detail and individual diameters illustrated for some of them, having diameters in the region of 160 pm, and showing the 214 aerosol-forming apertures 1802 per cavity.

[0193] Fig. 21 is an SEM showing a cut-away section of a single recess formed in a plate by wet etching, with lOOOx magnification. A line across the inlet surface is superimposed, where the lateral dimension is 157 pm, very close to the centre. Measurements are taken vertically down from this virtual line to the bottom surface of the blind recess, showing cavity depths in the region of 31 to 35 pm, across over a large portion of the area in plan of the cavity. This shows that there is good consistency in the lengths of the apertures which will be drilled, and that there is a consistency to within 4 pm over an area defined by more than 50% of the inlet surface diameter. The base of the recess is that part which is drilled in the second stage to provide the aerosol forming apertures. The base is defined here as the surface of the recess / cavity which is no more than the maximum aperture length from the outlet surface. It is preferred that it is between 50% and 100% of the maximum diameter of the cavity. For example, for a cavity maximum diameter (typically the inlet opening) of 160 pm, a minimum of 50% of that diameter (80 pm) has a material thickness (longitudinal dimension to the outlet surface) not exceeding 12 pm.

[0194] For a vibrating mesh nebuliser to operate in an optimum manner, the aperture plate is preferred to behave as a shallow shell and not a membrane. For a typical plate diameter of between 3 mm and 10 mm (e.g. 5 mm) and a radius of curvature of between 4 mm and 10 mm (e.g. 6 mm), the plate thickness should be at least 30 pm; otherwise, it will start to behave more like a membrane than a shallow shell. This limits the maximum volume that may be removed from the plate to ensure that the plate continues to operate as a shallow shell.

[0195] Test Results

[0196] Referring to Figs. 22 and 23 these are individual value plots showing the performance of a number of aperture plates as set out in the table below, when driven at 128 kHz with a 0.9% saline solution liquid. A plot of VMD vs. flow rate is given in Fig. 24. This demonstrates the high flow rate possible with such architecture for, which significantly reduces the treatment time for patients and increases the likelihood of compliance greatly. For example, with conventional nebulisers exhibiting flow rates typically approximately 0.50 ml / min, a typical 2.5 ml dose of bronchodilator would take 5 minutes to deliver. Using this technology and assuming an achievable flow rate of 2 ml / min or greater, the same 2.5 ml dose would only take 1.25 minutes to deliver which is much more convenient for the patient and will increase compliance and reduce the risk of hospitalisation greatly thus reducing the burden on the healthcare system while ensuring the patient is appropriately and satisfactorily treated.

[0197] Advantages

[0198] The invention utilises a hybrid approach and scalable, high yield, low-cost manufacturing methods for generating diverse meshes for use in vibrating mesh nebulisers. The techniques described capitalise on the advantageous benefits of each process to create versatile geometries compatible with nebulising solutions with complex and challenging physicochemical properties in a cost- effective and scalable product. Furthermore, raw materials used for the mesh are low cost, readily available to extremely tight tolerances and compatible with both the first and second stage processes.

[0199] By using more efficient techniques to eliminate laser machining of large volumes of material as is the case for conventional machining of aperture plates, laser drilling of apertures only needs to be carried out through a length equal only to the axial dimension from the base of the cavity to the outlet surface of the plate. This enables the creation of very small exit holes in the range 1-5 pm consistently, repeatably with high throughput, low cost, and high quality.

[0200] Components of embodiments can be employed in other embodiments in a manner as would be understood by a person of ordinary skill in the art. The invention is not limited to the embodiments described but may be varied in construction and detail. For example, while we have described that the liquid supply cavities are preferably provided to have circular inlet openings (in the first, liquid supply, surface), in some examples they may be a different shape, such as oval. Different shapes may be achieved by applicable masking for either of the material addition or subtraction first stage approaches.

Claims

Claims1. A method of manufacturing an aperture plate (100, 300, 900, 1800) for vibration to provide an aerosol, the method comprising: in a first stage forming recesses (102) each having a circular inlet opening and a blind base, said recesses being provided in a first surface of a plate of a material also having an opposed second surface, and in a second stage laser drilling a plurality of aerosol forming apertures (106) in the base of each of the recesses, to form said recesses into liquid supply cavities in the first surface which are in fluid communication with a plurality of the drilled apertures which extend to the second surface.

2. A method as claimed in claim 1, wherein pitch (A) of the cavities (102, 301, 801) is in the range of 40 pm to 500 pm.

3. A method as claimed in claim 2, wherein pitch (A) of the cavities (102, 301, 801) is in the range of 150 pm to 400 pm.

4. A method as claimed in any preceding claim, wherein the cavity (102) diameter (B) is in the range of 40 pm to 400 pm.

5. A method as claimed in claim 4, wherein the cavity (102) diameter (B) is in the range of 120 pm to 300 pm.

6. A method as claimed in claim 5, wherein the cavity (102) diameter (B) is in the range of 150 pm to 200 pm.

7. A method as claimed in any preceding claim, wherein the cavity depth is in the range of 10 pm to 100 pm.

8. A method as claimed in claim 7, wherein the cavity depth is in the range of 20 pm to 70 pm.

9. A method as claimed in claim 8, wherein the cavity depth is in the range of 30 pm to 60 pm.

10. A method as claimed in any preceding claim, wherein the apertures are drilled in the recess bases at locations whereby the apertures have a length in the range of 3 pm to 12 pm.

11. A method as claimed in claim 10, wherein the apertures are drilled in the recess bases at locations whereby a majority of the apertures have a length in the range of 3 pm to 8 pm, optionally 4 pm to 7 pm.

12. A method as claimed in any preceding claim, wherein at least a majority of the blind recesses each have a central lower surface circumvented by a circle defined by half of the recess opening diameter, in which said lower surface is no more than 12 pm from the second surface.

13. A method as claimed in any preceding claim, wherein the plate thickness is in the range of 13 pm to 112 pm.

14. A method as claimed in any preceding claim, wherein the outlet diameter of the apertures (E) is in the range of 0.5 pm to 5.0 pm.

15. A method as claimed in claim 14, wherein the outlet diameter (E) of the apertures is in the range of 1.0 pm to 4.0 pm.

16. A method as claimed in any preceding claim, wherein the number of apertures (105, 312, 805) drilled per cavity is in the range of 2 to 300.

17. A method as claimed in claim 16, wherein the number of apertures drilled per cavity is in the range of 5 to 300.

18. A method as claimed in claim 17, wherein the number of apertures drilled per cavity is in the range of 25 to 300.

19. A method as claimed in any preceding claim, wherein the aperture plate diameter when flat is in the range of 3 mm to 8 mm.

20. A method as claimed in claim 19, wherein the aperture plate diameter when flat is in the range of 4 mm to 7 mm.

21. A method as claimed in any preceding claim, wherein the first stage is performed by providing a plate with a planar first surface and forming the blind recesses (802) by selectively removing material from said first surface in a material subtraction step.

22. A method as claimed in claim 21, wherein the material subtraction is performed by chemical etching with use of a photolithographic mask.

23. A method as claimed in claim 22, wherein the etching comprises wet etching.

24. A method as claimed in claim 22 or claim 23, wherein the material of the plate comprises steel, preferably Hastelloy or stainless steel.

25. A method as claimed in any of claims 21 to 24, wherein the cavities have funnel shaped side walls.

26. A method as claimed in any of claims 1 to 20, wherein the first stage is performed by material addition (101).

27. A method as claimed in claim 26, wherein the first stage is performed by electrodeposition.

28. A method as claimed in claim 26 or claim 27, wherein the blind recesses (102) are formed by material addition to have a plurality of recesses having side walls which are at an angle of no more than 20° with respect to a longitudinal axis between the first surface and the second surface.

29. A method as claimed in claim 28, wherein the electrodeposition is around pillars (104) of resist, said pillars providing a shape for the recess (102).

30. A method as claimed in claim 29, wherein the electrodeposition does not extend over the tops of the resist pillars (104).

31. A method as claimed in claim 29, wherein the electrodeposition extends over the tops of at least some of the resist pillars (104) to provide an inwardly extending rim (1151) around an opening of each cavity.

32. A method as claimed in any of claims 27 to 31, wherein the materials which are deposited are selected from one or more of palladium, platinum, gold, nickel, silver, cobalt, copper or alloys thereof.

33. A method as claimed in any preceding claim, wherein the second stage comprises parallel laser drilling.

34. A method as claimed in claim 33, wherein the second stage is performed for at least some recesses by multibeam laser drilling to drill apertures simultaneously.

35. A method as claimed in claim 34, wherein the multibeam laser drilling comprises scanned mask imaging.

36. A method of any preceding claim, wherein the apertures have side walls which are tapered with an angle of more then 10° to an aperture longitudinal axis, and percussion laser drilling is performed with closed loop feedback provided by an optical detection mechanism on an underside of the plate opposite to that upon which the laser energy is applied, and the laser drilling controller adjusts the energy profile used for laser drilling for control of hole size.

37. A method as claimed in any preceding claim, wherein percussion drilling is performed during the second stage.

38. A method as claimed in any preceding claim, wherein the laser drilling is performed using an Ultra Short Pulse (USP) laser system.

39. An aerosol generator aperture plate (800) comprising liquid supply cavities (801) with circular openings in an inlet surface and aerosol-forming apertures in an outlet surface, said apertures being in fluid communication with said cavities, wherein: the cavities (801) have characteristics of being formed by etching blind recesses in a plate, and the apertures (806) have characteristics of being laser drilled through bases of the recesses.

40. An aperture plate as claimed in claim 39, wherein the cavities have characteristics of being formed by chemical wet etching.

41. An aperture plate as claimed in claim 39 or claim 40, wherein the aperture plate is of steel material, preferably Hastelloy or stainless steel.

42. An aerosol generator aperture plate (100) comprising liquid supply cavities (102) in an inlet surface and aerosol-forming apertures (106) in an outlet surface, at least some of said apertures being in fluid communication with said cavities, wherein: the cavities have characteristics of being formed by electrodeposition around resist pillars (104) conforming to the cavities, and the apertures (106) have characteristics of being formed by laser drilling.

43. An aerosol generator aperture plate as claimed in any of claims 39 to 42, wherein pitch (A) of the cavities (102) is in the range of 40 pm to 500 pm.

44. An aerosol generator aperture plate as claimed in any of claims 39 to 43, wherein pitch (A) of the cavities (102) is in the range of 150 pm to 400 pm.

45. An aerosol generator aperture plate as claimed in any of claims 39 to 44, wherein the cavity (102) diameter (B) is in the range of 40 pm to 400 pm.

46. An aerosol generator aperture plate as claimed in any of claims 39 to 45, wherein the cavity (102) diameter (B) is in the range of 120 pm to 300 pm.

47. An aerosol generator aperture plate as claimed in any of claims 39 to 46, wherein the cavity (102) diameter (B) is in the range of 150 pm to 200 pm.

48. An aerosol generator aperture plate as claimed in any of claims 39 to 47, wherein the cavity depth is in the range of 10 pm to 100 pm.

49. An aerosol generator aperture plate as claimed in any of claims 39 to 48, wherein the cavity depth is in the range of 20 pm to 70 pm.

50. An aerosol generator aperture plate as claimed in any of claims 39 to 49, wherein the cavity depth is in the range of 30 pm to 60 pm.

51. An aerosol generator aperture plate as claimed in any of claims 39 to 50, wherein the apertures have a length in the range of 3 pm to 12 pm, optionally 3 pm to 8 pm.

52. An aerosol generator aperture plate as claimed in any of claims 39 to 51, wherein at least a majority of the cavities each have a central lower surface circumvented by a circle defined by half of the cavity opening diameter, in which said lower surface is no more than 12 pm from the second surface.

53. An aerosol generator aperture plate as claimed in any of claims 39 to 51, wherein the plate thickness is in the range of 13 pm to 112 pm.

54. An aerosol generator aperture plate as claimed in any of claims 39 to 53, wherein the aperture (106) outlet diameter (E) is in the range of 0.5 pm to 5.0 pm, optionally 1.0 pm to 4.0 pm.

55. An aerosol generator aperture plate as claimed in any of claims 39 to 54, wherein the number of apertures per cavity is in the range of 2 to 300.

56. An aerosol generator aperture plate as claimed in any of claims 39 to 54, wherein the number of apertures per cavity is in the range of 25 to 300.

57. An aerosol generator aperture plate as claimed in any of claims 39 to 56, wherein the aperture plate diameter when flat is in the range of 3 mm to 8 mm, optionally 4 mm to 7 mm.

58. An aerosol generator comprising an aperture plate of any of claims 39 to 57, a support for the aperture plate, and a vibration generator for causing vibration of the aperture plate.

59. A nebulizer comprising an aerosol generator of claim 58, a drive for delivering power to activate the vibration generator, and a means of delivering liquid to the cavities of the aperture plate.

Images