Manufacture of high density microprojection arrays

Abstract

The present invention relates to devices and methods for manufacturing microprojection or microneedle arrays, in particular the manufacture of high density microprojection arrays by manufacturing a multilayered mold in which holes for forming the microprojections are made using lasers.

Description

MANUFACTURE OF HIGH DENSITY MICROPROJECTION ARRAYSCross-Reference to Related Application

[0001] This application claims priority to US Provisional Patent Application No. 63 / 674,828 filed on 24 July 2024.Background of the Invention

[0002] The present invention relates to devices and methods for manufacturing microprojection or microneedle arrays, in particular the manufacture of high density microprojection arrays by manufacturing a mold in which holes for forming the microprojections are made using lasers.Description of the Prior Art

[0003] In recent years, attempts have been made to devise new methods of delivering drugs and other bioactive materials, for vaccination and other purposes, which provide alternatives that are more convenient and / or enhanced in performance to the customary routes of administration such as intramuscular and intradermal injection. Limitations of intradermal injection include: cross -contamination through needle-stick injuries in health workers; injection phobia from a needle and syringe; and most importantly, as a result of its comparatively large scale and method of administration, the needle and syringe cannot target key cells in the outer skin layers. This is a serious limitation to many existing and emerging strategies for the prevention, treatment and monitoring of a range of untreatable diseases.

[0004] Patches including a number of projections thereon to allow bioactive material to be administered to a subject are an increasingly effective way of delivering therapeutic agents or biomarkers since there is minimal or no pain, little or no injury from the needle and highly reduced possibility of cross infection. The solid projections or needles on a patch can be made of multiple layers of drugs, macromolecules or nanoparticles alone or with structural excipient(s). These devices can be subsequently delivered to a desired target by the penetration of the projections or needles into the skin.

[0005] Recent developments in producing needle patches have focused on manufacturing techniques such as chemical vapour deposition, dopant diffusion, electron beam machining, wet and dry etching, laser cutting, masking, oxidation, photo-lithography, physical vapour deposition and scribing.

[0006] Previous systems have also focused on generating large and very sparsely packed projections. Such techniques often prove to be unsuccessful when making small and densely packed projections. No technologies are sufficiently capable of generating multiple layered needles from nanometer to millimeter scales. Moreover, these prior techniques are also proving ineffective at mass production of needle patches of suitable physical properties at an economic rate. As a result, the prior methods and devices for the delivery of material through the skin have exhibited limited success in transferring laboratory scale investigations to industrial scale production. The present invention provides devices and methods for large-scale commercial production of high density microprojection arrays (HD-MAPs) in an efficient and economical way.

[0007] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that the prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.Summary of the Present Invention

[0008] In one broad form an aspect of the present invention relates to methods for manufacturing a mold for making microprojection arrays by cutting a first plurality of holes of a first diameter, a second diameter and a first length into a stainless steel base plate, cutting a second plurality of holes of a third diameter, a fourth diameter and a second length into a stainless steel top plate, where the first diameter and second diameters are larger than the third and fourth diameter, cleaning the plates with a solution of 3: 1 mixture of sulfuric acid and 30% hydrogen peroxide, attaching the top plate to the base plate to form a stack, attaching one or more backing plates to the top plate of the stack and diffusion bonding the base plate, top plate and the one or more backing plates together to form the mold.

[0009] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the base plate and top plate are attached by laser welding

[0010] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the number of backing plates is two.

[0011] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the backing plates are attached to the stack by laser welding.

[0012] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where one or more weld pins are used to attach the backing plates to the stack.

[0013] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the number of weld pins is eight.

[0014] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the first diameter is from 150 to 170 pm and the second diameter is from 105 to 115 pm.

[0015] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the third diameter is from 55 to 65 pm and the fourth diameter is from 20 to 40 pm.

[0016] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the first length is from 310 to 330 pm.

[0017] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the second length is from 240 to 260 pm.

[0018] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the second length is from 190 to 210 pm.

[0019] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the second length is from 140 to 160 pm.

[0020] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the method adds a layer of silicon dioxide to the surface and into the holes of the mold by atomic layer deposition.

[0021] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the silicon dioxide layer is from 8 to 12 nm thick.

[0022] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the thickness of the backing plates is from 1450 to 1500 pm.

[0023] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the thickness of the backing plates is 1480 pm.

[0024] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the first and second plurality of holes are cut by a laser.

[0025] In another broad form an aspect of the present invention relates to molds for making microprojection arrays that have a stainless steel base plate having a plurality of cavities having a first diameter, a stainless steel top plate having a plurality of cavities having a second diameter wherein the second diameter is smaller than the first diameter, a first and second stainless steel backing plate; where the base plate is bonded to the top plate, the first backing plate is bonded to the top plate and the second backing plate is bonded to the first backing plate.

[0026] In another broad form an aspect of the present invention relates to molds for making microprojection arrays that have a stainless steel base plate having a plurality of holes having a length and a first diameter and a second diameter, a stainless steel top plate having a plurality of holes having a length having a third and a fourth diameter wherein the first and second diameter is larger than the third and fourth diameter, a first and second stainless steel backingplate where the base plate is bonded to the top plate, the first backing plate is bonded to the top plate and the second backing plate is bonded to the first backing plate.

[0027] In one embodiment the present invention relates to molds for making microprojection arrays where the holes in the base plate having a length of 290 to 310 pm and the first diameter of from 150 to 170 pm and the second diameter is from 105 to 115 pm.

[0028] In one embodiment the present invention relates to molds for making microprojection arrays where holes in the top plate having a length of 240 to 260 pm and the third diameter is from 55 to 65 pm and the fourth diameter is from 20 to 40 pm.

[0029] In one embodiment the present invention relates to molds for making microprojection arrays where holes in the top plate having a length of 190 to 210 pm and the third diameter is from 55 to 65 pm and the fourth diameter is from 20 to 40 pm.

[0030] In one embodiment the present invention relates to molds for making microprojection arrays where holes in the top plate having a length of 140 to 160 pm and the third diameter is from 55 to 65 pm and the fourth diameter is from 20 to 40 pm.

[0031] In another broad form an aspect of the present invention relates to microprojection arrays having a cylindrical tapering base section having length of from 290 to 310 pm, a first diameter of from 150 to 170 pm and a second diameter is from 105 to 115 pm and a cylindrical tapering top section having a length of 240 to 260 pm, a third diameter of from 55 to 65 pm and a fourth diameter of from 20 to 40 pm; where the top section is positioned on the base section creating a step of from 15 to 35 pm in width.

[0032] In another broad form an aspect of the present invention relates to microprojection arrays having a cylindrical tapering base section having length of from 290 to 310 pm, a first diameter of from 150 to 170 pm and a second diameter is from 105 to 115 pm; and a cylindrical tapering top section having a length of 190 to 210 pm, a third diameter of from 55 to 65 pm and a fourth diameter of from 20 to 40 pm; where the top section is positioned on the base section creating a step of from 15 to 35 pm in width.

[0033] In another broad form an aspect of the present invention relates to microprojection arrays having a cylindrical tapering base section having length of from 140 to 160 pm, a first diameter of from 150 to 170 pm and a second diameter is from 105 to 115 pm, a cylindrical tapering top section having a length of 240 to 260 pm, a third diameter of from 55 to 65 pm and a fourth diameter of from 20 to 40 pm; wherein the top section is positioned on the base section creating a step of from 15 to 35 pm in width.

[0034] In another broad form an aspect of the present invention relates to methods for manufacturing a mold for making microprojection arrays by cutting holes of predetermined width and length into two or more plates with a laser each plate having two sides, cleaning the plates, coating each side of the plates with chrome to produce chromed plates, coating each side of the chromed plate with gold and diffusion bonding the plates together to produce a microprojection array mold.

[0035] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where there are one-three plates.

[0036] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the plates are cleaned with isopropyl alcohol.

[0037] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the plates are further cleaned by treating the plates with a 3: 1 mixture of sulfuric acid and 30% hydrogen peroxide.

[0038] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the plates are coated with chrome to a thickness of from 5 to 15 nm.

[0039] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the chromed plates are coated with gold to a thickness of from 190 to 210 nm.

[0040] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the chrome is coated onto the plate using an e-beam evaporator.

[0041] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the gold is coated onto the chromed plate using an e- beam evaporator.

[0042] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the plates are bonded together at about 625°C.

[0043] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where a carbide sheet is placed between the top surface of one plate and the bottom surface of another plate prior to diffusion bonding the plates together.

[0044] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays by laser welding a matrix backing to the diffusion bonded plates.

[0045] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays by adding a backing plate to the matrix plate.

[0046] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the laser is a UV laser.

[0047] In one embodiment the present invention relates to methods for manufacturing a mold for making microprojection arrays where the laser welding is performed by a YAG laser.

[0048] In another broad form an aspect of the present invention relates to methods for manufacturing a microprojection arrays having a plurality of microprojections by making a mold by cutting a plurality of holes of predetermined width and length into two or more plates with a laser each plate having two sides, cleaning the plates, coating each side of the plates with chrome to produce chromed plates, coating each side of the chromed plate with gold, diffusion bonding the plates together to produce a microprojection array mold and injecting apolymer into the mold to produce a microprojection array having a plurality of microproj ections .

[0049] In one embodiment the present invention relates to methods for manufacturing a microprojection arrays having a plurality of microprojections where the polymer is a liquid crystal polymer.

[0050] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections having two or more plates having a plurality of holes therein of a predetermined length and width.

[0051] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections where the number of plates is three.

[0052] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections where the plates are a base plate, a middle plate and a tip plate.

[0053] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections where the base plate is from 250 to 350 pm thick.

[0054] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections where the middle plate is from 125 to 175 pm thick.

[0055] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections where the tip plate is from 90 to 110 pm thick.

[0056] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections where the base plate is about 300 pm thick.

[0057] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections where the middle plate is about 152 pm thick.

[0058] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections where the tip plate is about 100 pm thick.

[0059] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections by adding a vented backing plate.

[0060] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections where the vented backing plate is from 1450 to 1500 pm thick.

[0061] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections where the vented backing plate is about 1480 pm thick.

[0062] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections by adding a second backing plate.

[0063] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections where the second backing plate is from 1450 to 1500 pm thick.

[0064] In one embodiment the present invention relates to devices for manufacturing microprojection arrays having a plurality of microprojections where the second backing plate is about 1480 pm thick.

[0065] In another broad form an aspect of the present invention relates to methods for manufacturing a microprojection array having a plurality of microprojections by cutting a first plurality of holes of a first diameter, a second diameter and a first length into a stainless steel base plate, cutting a second plurality of holes of a third diameter, a fourth diameter and a second length into a stainless steel top plate, where the first diameter and second diameters are largerthan the third and fourth diameter, cleaning the plates with a solution of 3: 1 mixture of sulfuric acid and 30% hydrogen peroxide, attaching the top plate to the base plate to form a stack, attaching one or more backing plates to the top plate of the stack; diffusion bonding the base plate, top plate and the one or more backing plates together to form the mold and injecting a polymer into the mold to produce a microprojection array having a plurality of microproj ections .

[0066] In one embodiment the present invention relates to methods for manufacturing a microprojection array having a plurality of microprojections where the polymer is a liquid crystal polymer.

[0067] It will be appreciated that the broad forms of the invention and their respective features can be used in conjunction, interchangeably and / or independently, and reference to separate broad forms is not intended to be limiting.Brief Description of the Drawings

[0068] Various examples and embodiments of the present invention will now be described with reference to the accompanying drawings, in which: -

[0069] Figure 1 is a schematic of the steps utilized in one embodiment of the manufacture of a high density microprojection array.

[0070] Figure 2A is a schematic diagram of one of the plates used to produce the mold for making the MAPs; and Figure 2B is a magnified section of the plate showing the detail of the holes’ dimensions and positions in the plate.

[0071] Figure 3 is a schematic representation of one cavity in the mold for producing microprojections in a high density microprojection array delineating the dimensions of various parts of the mold where the mold is made from a base plate, top plate and two backing plates (one vented and the other unvented).

[0072] Figure 4 is a schematic representation of one cavity in the stack for producing microprojections in a high density microprojection array delineating the dimensions and variances of the top plate and base plate of the stack.

[0073] Figures 5A-D are scanning electron microscopy (SEM) pictures of the microprojections of the microprojection arrays manufactured from the molds made by the methods of the present invention.

[0074] Figure 6A is a schematic representation of one of the microprojections from the high density microprojection array manufactured by a mold that was made by a method using a three-tiered stack (tip plate, middle plate and base plate; Figure 6B is a schematic representation of one of the microprojections from the high density microprojection array manufactured by a mold that was made by a method using a two-tiered stack where the base is about 300 pm and the top about 250 pm in length; Figure 6C is a schematic representation of one of the microprojections from the high density microprojection array manufactured by a mold that was made by a method using a two-tiered stack where the base is about 300 pm and the top about 200 pm in length; and Figure 6D is a schematic representation of one of the microprojections from the high density microprojection array manufactured by a mold that was made by a method using a two-tiered stack where the base is about 300 pm and the top about 150 pm in length.

[0075] Figure 7A is a scanning electron microscopy (SEM) picture of the microprojections of the microprojection arrays manufactured from the molds made by the two-tiers method of the present invention where the where the base is about 300 pm and the top about 250 pm in length; Figure 7B is a scanning electron microscopy (SEM) picture of the microprojections of the microprojection arrays manufactured from the molds made by the two-tiers method of the present invention where the where the base is about 300 pm and the top about 200 pm in length; and Figure 7C is a scanning electron microscopy (SEM) picture of the microprojections of the microprojection arrays manufactured from the molds made by the two-tiers method of the present invention where the where the base is about 300 pm and the top about 150 pm in length.

[0076] Figure 8 is a schematic of the steps utilized in an alternative embodiment of the manufacture of a high density microprojection mold.

[0077] Figure 9 is a photograph of the 3 plates that comprise the three-tiered stack: base plate, middle plate and tip plate.

[0078] Figure 10 is a schematic of one cavity that forms the microprojections from the high density microprojection array delineating the dimensions of various parts of the mold where the mold is made from a base plate, middle / top and two backing plates (one vented and the other unvented).

[0079] Figure 11 is a photograph of a three -plate stack in a jig.

[0080] Figure 12 is a scanning electron microscopy (SEM) picture of the microprojections of the microprojection arrays manufactured from the molds made by the three-tiers method of the present invention.

[0081] Figure 13 is a photograph of one embodiment of a molded high density microprojection array.Detailed Description of the Preferred Embodiments

[0082] The present invention relates to devices and methods for manufacturing microprojection or microneedle arrays, in particular the manufacture of high density microprojection arrays by manufacturing a multilayered mold in which holes for forming the microprojections are made using lasers. One embodiment for the method of making the microprojection molds of the present invention is shown in Figure 1. The process begins by designing a microprojection array with predetermined density, length, width and geometric design of the microprojections. Once the design of the microprojection array is determined a mold to manufacture the design can be constructed using one or more plates which are then laser etched to provide the appropriate density, length, width and geometric design of the microprojections in the microprojection array. A laser is used to drill holes into the one or more plates that will provide the cavities for the microprojections of the microprojection array. The number of plates into which holes are drilled can be between one and three plates depending on the desired microprojection size and shape. The plates are then piranha cleaned (solution of sulfuric acid and hydrogen peroxide), and the drilled plates are then assembled with backing plates. One or more backing plates may be used and the plates can either be vented or unvented. The plates are laser welded utilizing a plurality of weld and then the plates are diffusion bonded together to provide the mold. A coating of silicon dioxide may be applied to the mold using atomic layer deposition to improve moldability of the microprojections. The injection moldingcavity size may be fine-tuned and the mold is prepared for injection molding in which the cavities of the molds are filled with liquid crystal polymers.

[0083] In one embodiment of the present invention two plates other than the backing plates are used to develop the mold. The first plate is a base plate and the second plate is a top plate. These two plates will provide the cavities / holes into which the polymer is injected to make the microprojection array. The holes are laser drilled and the holes in the base plate have a larger diameter than those in the top plate. Figure 2A is a schematic diagram of one of the plates used to produce the mold for making the MAPs; Figure 2B is a magnified section of the plate showing the detail of the holes’ dimensions and positions in the plate. The base and top plates may be made of stainless steel including SS316. The mold may optionally include a one or more backing plates which can be vented or unvented. In one embodiment two unvented backing plates are used. The backing plates are made of stainless steel including but not limited to SS304. The process can be used to make molds that produce microprojection arrays that vary in size, shape and density depending on the thickness of the base and top plate and the positioning and diameter of the holes within the plates. In one embodiment the base plate is from 290 to 310 pm thick and the top plate from 240 to 260 pm thick. Based upon the design, holes are cut into the base and top plates by a UV laser which is adjusted to produce different holes sized and tapers. In one embodiment the mold defines multiple microprojections cavities that are comprised of two sections: 1) a base plate that has cavities which are 160 ± 10 pm in diameter at the bottom of the base plate and 110 + 5 pm at diameter at the top of the base plate and where the length of the cavity is about 300 + 10 pm in length; 2) a top plate that has cavities which are 60 + 5 pm in diameter at the bottom of the top plate and 30 + 10 pm in diameter at the top of the top plate and where the length of the cavity is 150 +10 pm in length (Figure 4). The plates are stacked in such a way that the cavities in the base plate align with those in the top plate to produce a two-tiered cavity (Figure 5). This two-tiered cavity will produce a microprojection that tapers to a plateau or step of 25 + 10 pm which then tapers to a tip of 30 + 10 pm. The plates are inspected for quality and are cleaned and sonicated with isopropyl alcohol and acetone. The plates are then treated with a piranha solution which is a 3: 1 mixture of sulfuric acid and 30% hydrogen peroxide. The solution may be mixed before application or directly applied to the material, applying the sulfuric acid first, followed by the peroxide. This treatment is then followed by rinsing the plates with de-ionized water and blow drying themwith nitrogen. The next step in the process is for the plates to be diffusion bonded together. The plates are stacked according to base plate on top of which is placed the top plate. The plates are aligned by using alignment holes in the two plates and the alignment is checked by a zeta microscope. The number of alignment holes may vary depending on the process, but includes but is not limited to from 4 to 16 holes that are aligned and kept aligned by putting a weld pin in place in the holes. In one embodiment the number of weld pins and holes is 8. A sheet or block of carbide, molybdenum or ceramic is placed between the plates. Titanium jigs are placed within an overall carriage which is placed into an EVG bonder and sheets or blocks are placed between the top and bottom surfaces of each of the plates. The plates are bonded together by exposing them to a temperature of about 1040°C. Figure 4 is a schematic of a mold with the base plate, a top plate, a vented backing and a backing layer. Alternatively the vented backing may be an unvented layer.

[0084] As described above the method of manufacture of the molds permits the production of microprojection arrays of varying sizes, shapes and densities. In another embodiment of the methods of the present invention the top plate may also include cavities which are 60 ± 5 pm in diameter at the bottom of the top plate and 30 + 10 pm in diameter at the top of the top plate and where the length of the cavity is 250 +10 pm in length or 200 +10 pm in length. When the top plate cavity length is 250 +10 pm in length and is bound to a base plate where the length is 300 + 10 pm in length it will produce a cavity 550 + 20 pm in length and when the top plate cavity length is 200 +10 pm in length and is bound to a base plate where the length is 300 + 10 pm in length it will produce a cavity 500 + 20 pm in length. Figures 6B-D are schematics of the three two-tiered designs and Figures 7A-C are SEM scans of microprojections manufactured from the molds made by the two-tiered plates of the present invention.

[0085] In an alternate embodiment of the mold for the manufacture of high density microprojection arrays there are three layers that comprise the mold: the base plate, middle plate and tip plate. These plates may be made of stainless steel including SS316 and SS304 as well as tool steel. The mold may optionally include a vented backing and a backing layer which may also be made of stainless steel including but not limited to SS316E. Figure 8 is a schematic of the steps utilized in another embodiment of the manufacture of a high density microprojection array. In one embodiment the base plate is from 290 to 310 pm wide, themiddle plate is from 150 to 250 pm wide and the tip plate from 90 to 110 pm wide. Based upon the design, holes are cut into the three plates by a UV laser which is adjusted to produce different holes sized and tapers. Figure 9 is a photograph of the three plates. In one embodiment the mold defines multiple microprojections that are comprised of three sections: 1) a base that is 130 pm wide at the bottom and 110 pm at the top of the base and is about 300 pm in length; 2) a middle that is 60 pm wide at the bottom and 40 pm at the top of the middle and is about 150 pm in length; and 3) a tip that is 20 pm wide at the bottom and 10 pm at the top of the tip and is about 100 pm in length (Figure 10). The plates are inspected for quality and are cleaned and sonicated with isopropyl alcohol and acetone. The plates are then treated with a piranha solution which is a 3: 1 mixture of sulfuric acid and 30% hydrogen peroxide. The solution may be mixed before application or directly applied to the material, applying the sulfuric acid first, followed by the peroxide. This treatment is then followed by rinsing the plates with de-ionized water and blow drying them with nitrogen. The plates are then vacuum dried at about 200°C and then plasma cleaned. The plates are then coated with about lOnm (5-20 nm range) of chrome or titanium followed by the addition of about 200nm of gold within an e-beam evaporator (turret speed 20 rev / min and a deposition rate of 1.5A / sec. The plates are held within a laser cut jig and both sides of the plates are coated. The next step in the process is for the various plates to be diffusion bonded together. The plates are stacked according to base plate on top of which is the middle plate on top of which is the tip plate. The plates are aligned by using alignment holes in all three plates and the alignment is checked by a zeta microscope. The number of alignment holes may vary depending on the process, but usually includes but is not limited to from 4 to 16 holes that are aligned and kept aligned by putting a weld pin in place in the holes. A carbide sheet is placed between the layers of the plates. Titanium jigs are placed within an overall carriage which is placed into an EVG bonder and carbide sheets are placed between the top and bottom surfaces of each of the plates (Figure 11). The plates are bonded together by exposing them to a temperature of about 625°C (range of 300 to 650°C) (with a ramp speed of about 30°C / min step) for 6 hours at a pressure of 55kN under a vacuum (l x 10’3mbar). Final alignment of the plates is done by imaging on a zeta microscope.

[0086] The next step of the process optionally is to weld a matrix backing and a backing plate to the diffusion bonded plates. A backing plate is added to the diffusion bonded plate using alignment pins and weld pins which are welded in place by using a YAG laser (Energy = 300J).Once the mold is completed a grinder may be used to shape the final stack of plates also called a mold or insert. Figure 12 is an SEM scan of a microprojection manufactured by the three-tier method of the present invention.

[0087] In another embodiment the mold may consist of a single plate. In one embodiment the two sections are: 1) a base that is 130 pm wide at the bottom and 110 pm at the top of the base and is about 300 pm in length; and 2) a middle that is 60 pm wide at the bottom and 40 pm at the top of the middle and is about 150 pm in length.

[0088] The MAP design specifications utilizing a two plate (base plate and top plate) stack of different embodiments are shown in Table 1.Table 1 - MAP design specifications (two plate stack)

[0089] The MAP design specifications utilizing a three plate (base plate, middle plate and tip plate) stack of different embodiments are shown in Table 2.Table 2 - MAP design specifications (three plate stack)

[0090] The mold insert is used to manufacture the MAPs by taking the insert from stock and placing it into an injection moulding tool. Material is drawn from stock and conditioned over a required length of time prior to moulding activities. The insert is injected with polymer substances, such polymers include liquid crystal polymers. Quality of the moulded array is assessed during set-up and once the desirable array quality is confirmed either through optical or SEM assessment, the manufacture commences to the required batch size. MAPs are placed onto trays and then transported into Laminar Flow cabinet where they are prepared for packing and courier. Figure 13 shows one embodiment of a molded microprojection array made by the method of the present invention.

[0091] As previously described the molds of the present invention may be used to produce high density microprojection arrays in which the microprojections of the arrays have varying size, shape and density. In the methods described above, the microprojections made from the molds will provide one or more steps which can assist in ensuring more consistent depth of penetration in different biological subjects, despite variations in the tissue properties from subject to subject. During insertion of the projection, the step can impact on the dermal tissues, which typically present an increased resistance to penetration compared to tissues in outer layers of the skin (such as the viable epidermis, for example), thereby limiting further penetration of the projection. By providing projections with a suitably configured stepped effective profile, and using controlled application parameters, it is therefore possible to ensure that the tips of the projections extend into the dermis by a predetermined distance.

[0092] Additionally, the step can help create additional physical stimulus within the biological subject in use. As projections penetrate the skin and tissue during an impact application of a patch, the projections generate a pressure wave, which can assist in causing cell damage. This enhances the immunological response generated within the subject by acting as a “physical adjuvant”.

[0093] Finally, example projection is similar to projection but has a tapering conical support section. The overall effective profile of the projection is generally conical, but the step results in a rapid change in diameter in the transition between the base section and the top section in the two-tiered method and between the base and the middle and between the tip and the middle in the three-tiered approach.

[0094] The microprojections of the microprojection arrays manufactured by the methods of the present invention may be coated with various substances including but not limited to small chemical or biochemical compounds including antigens, ligands, drugs, metabolites, amino acids, sugars, lipids, saponins, and hormones; macromolecules such as complex carbohydrates, phospholipids, peptides, polypeptides, proteins, peptidomimetics, and nucleic acids (mRNA, DNA, siRNA); or other organic (carbon containing) or inorganic molecules; and particulate matter including whole cells, bacteria, viruses, virus-like particles, cell membranes, dendrimers and liposomes or combinations thereof. Substances may also include contrast enhancing reagents or surface modifying materials. Some of the substances utilized for delivery by the microprojections include antigens (protein or nucleic acid) from pathogenic organisms which include, but are not limited to, viruses, bacteria, fungi, parasites, algae and protozoa and amoebae. In some cases a vaccine adjuvant may be necessary to enhance the vaccine's ability to induce protection against infection. Adjuvants help activate the immune system, allowing the antigens-pathogens components that elicit an immune response in vaccines to induce longterm protective immunity. Adjuvants include but are not limited to pathogen components such as monophosphoryl lipid A (which has been combined with alum to produce AS04), poly(I:C) (which is a synthetic double stranded RNA), CpG DNA adjuvants (which are short segments of DNA) and emulsions such as MF59 which is an oil in water emulsion that include squalene and AS03 which is D,L-alpha-tocopherol (Vitamin E), an emulsifier, polysorbate 80 and squalene. Other adjuvants include particulate adjuvants such as alum, virosomes and cytokines. Excipients or other additives which include but are not limited to cyclodextrins, amino acids, reducing agents carbohydrates and proteins and combinations thereof. Excipients include but are not limited to Histidine, Sodium acetate, Sodium chloride, Sodium citrate, Sodium phosphate, Sodium sulfate, Sodium succinate, Gelatin, Hydrolysed Gelatin, Protamine sulfate, Arginine, Aspartic acid (sodium salt), Glutamic acid, Glycine, Isoleucine, Lactic acid, Lysine, Maleic acid, Malic acid (sodium salt), Methionine, Urea, EDTA, Magnesium chloride, Benzalkonium chloride, Brij 35, Poloxamer 188 (Pluronic F- 68), Polysorbate 20, Polysorbate 80, Sodium docusate, Triton X-100, Lactose, Sucrose, Trehalose, Glycerol, Mannitol, Sorbitol, Gamma-Cyclodextrin, 2-OH propyl b-CD, Sulfobutyl ether beta-cyclodextrin, Carboxymethyl cellulose, Dextran sulfate, Dextran 40, PEG-3350,Sodium Hyaluronate, Sodium thioglycolate, Cysteine, and Glutathione and combinations thereof.

[0095] Within this disclosure, any indication that a feature is optional is intended provide adequate support (e.g., under 35 U.S.C. 112 or Art. 83 and 84 of EPC) for claims that include closed or exclusive or negative language with reference to the optional feature. Exclusive language specifically excludes the particular recited feature from including any additional subject matter. For example, if it is indicated that A can be drug X, such language is intended to provide support for a claim that explicitly specifies that A consists of X alone, or that A does not include any other drugs besides X. "Negative" language explicitly excludes the optional feature itself from the scope of the claims. For example, if it is indicated that element A can include X, such language is intended to provide support for a claim that explicitly specifies that A does not include X. Non-limiting examples of exclusive or negative terms include "only," "solely," "consisting of," "consisting essentially of," "alone," "without", "in the absence of (e.g., other items of the same type, structure and / or function)" "excluding," "not including", "not", "cannot," or any combination and / or variation of such language.

[0096] Similarly, referents such as "a," "an," "said," or "the," are intended to support both single and / or plural occurrences unless the context indicates otherwise. For example "a dog" is intended to include support for one dog, no more than one dog, at least one dog, a plurality of dogs, etc. Non-limiting examples of qualifying terms that indicate singularity include "a single", "one," "alone", "only one," "not more than one", etc. Non-limiting examples of qualifying terms that indicate (potential or actual) plurality include "at least one," "one or more," "more than one," "two or more," "a multiplicity," "a plurality," "any combination of," "any permutation of," "any one or more of," etc. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.

[0097] Where ranges are given herein, the endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of theinvention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0098] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

[0099] While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that the various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

[0100] Further advantages of the present immunological compositions and adjuvants of the present invention can be achieved by those skilled in the art based upon the embodiments described herein and are thus specifically within the scope of the present invention.

[0101] Throughout this specification and claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers or steps but not the exclusion of any other integer or group of integers. As used herein and unless otherwise stated, the term "approximately" means ±20%.

[0102] It will of course be realised that whilst the above has been given by way of an illustrative example of this invention, all such and other modifications and variations hereto, as would be apparent to persons skilled in the art, are deemed to fall within the broad scope and ambit of this invention as is herein set forth.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:1) A method for manufacturing a mold for making microprojection arrays comprising: cutting a first plurality of holes of a first diameter, a second diameter and a first length into a stainless steel base plate; cutting a second plurality of holes of a third diameter, a fourth diameter and a second length into a stainless steel top plate, wherein the first diameter and second diameters are larger than the third and fourth diameter; cleaning the plates with a solution of 3: 1 mixture of sulfuric acid and 30% hydrogen peroxide; attaching the top plate to the base plate to form a stack; attaching one or more backing plates to the top plate of the stack; and diffusion bonding the base plate, top plate and the one or more backing plates together to form the mold.2) The method of claim 1 wherein the base plate and top plate are attached by laser welding.3) The method of claim 2 wherein the number of backing plates is two.4) The method of claim 1 wherein the backing plates are attached to the stack by laser welding.5) The method of claim 5 wherein one or more weld pins are used to attach the backing plates to the stack.6) The method of claim 5 wherein the number of weld pins is eight.7) The method of claim 1 wherein the first diameter is from 150 to 170 pm and the second diameter is from 105 to 115 pm.8) The method of claim 1 wherein the third diameter is from 55 to 65 pm and the fourth diameter is from 20 to 40 pm.9) The method of claim 1 wherein the first length is from 310 to 330 pm.10) The method of claim 1 wherein the second length is from 240 to 260 pm.1 l)The method of claim 1 wherein the second length is from 190 to 210 pm.12)The method of claim 1 wherein the second length is from 140 to 160 pm.13) The method of claim 1 further comprising adding a layer of silicon dioxide to the surface and into the holes of the mold by atomic layer deposition.14) The method of claim 13 wherein the silicon dioxide layer is from 8 to 12 nm thick.15)The method of claim 1 wherein the thickness of the backing plates is from 1450 to 1500 pm.16) The method of claim 15 wherein the thickness of the backing plates is 1480 pm.17) The method of claim 1 wherein the first and second plurality of holes are cut by a laser.18) A mold for making microprojection arrays comprising: a stainless steel base plate having a plurality of cavities having a first diameter; a stainless steel top plate having a plurality of cavities having a second diameter wherein the second diameter is smaller than the first diameter; and a first and second stainless steel backing plate; wherein the base plate is bonded to the top plate, the first backing plate is bonded to the top plate and the second backing plate is bonded to the first backing plate.19) A mold for making microprojection arrays comprising: a stainless steel base plate having a plurality of holes having a length and a first diameter and a second diameter; a stainless steel top plate having a plurality of holes having a length having a third and a fourth diameter wherein the first and second diameter is larger than the third and fourth diameter; and a first and second stainless steel backing plate; wherein the base plate is bonded to the top plate, the first backing plate is bonded to the top plate and the second backing plate is bonded to the first backing plate.20) The mold of claim 19 wherein the holes in the base plate having a length of 290 to 310 pm and the first diameter of from 150 to 170 pm and the second diameter is from 105 to 115 pm.21) The mold of claim 20 wherein holes in the top plate having a length of 240 to 260 pm and the third diameter is from 55 to 65 pm and the fourth diameter is from 20 to 40 pm.22) The mold of claim 20 wherein holes in the top plate having a length of 190 to 210 pm and the third diameter is from 55 to 65 pm and the fourth diameter is from 20 to 40 pm.23)The mold of claim 20 wherein holes in the top plate having a length of 140 to 160 pm and the third diameter is from 55 to 65 pm and the fourth diameter is from 20 to 40 pm.24) A microprojection array comprising:a cylindrical tapering base section having length of from 290 to 310 pm, a first diameter of from 150 to 170 pm and a second diameter is from 105 to 115 pm; and a cylindrical tapering top section having a length of 240 to 260 pm, a third diameter of from 55 to 65 pm and a fourth diameter of from 20 to 40 pm; wherein the top section is positioned on the base section creating a step of from 15 to 35 pm in width.25) A microprojection array comprising: a cylindrical tapering base section having length of from 290 to 310 pm, a first diameter of from 150 to 170 pm and a second diameter is from 105 to 115 pm; and a cylindrical tapering top section having a length of 190 to 210 pm, a third diameter of from 55 to 65 pm and a fourth diameter of from 20 to 40 pm; wherein the top section is positioned on the base section creating a step of from 15 to 35 pm in width.26) A microprojection array comprising: a cylindrical tapering base section having length of from 140 to 160 pm, a first diameter of from 150 to 170 pm and a second diameter is from 105 to 115 pm; and a cylindrical tapering top section having a length of 240 to 260 pm, a third diameter of from 55 to 65 pm and a fourth diameter of from 20 to 40 pm; wherein the top section is positioned on the base section creating a step of from 15 to 35 pm in width.27) A method for manufacturing a mold for making microprojection arrays comprising: cutting holes of predetermined width and length into two or more plates with a laser each plate having two sides; cleaning the plates; coating each side of the plates with chrome to produce chromed plates; coating each side of the chromed plate with gold; and diffusion bonding the plates together to produce a microprojection array mold.28) The method of claim 27 wherein there are one to three plates.29) The method of claim 27 wherein the plates are cleaned with isopropyl alcohol.30) The method of claim 29 wherein the plates are further cleaned by treating the plates with a 3: 1 mixture of sulfuric acid and 30% hydrogen peroxide.31)The method of claim 27 wherein the plates are coated with chrome to a thickness of from 5 to 15 nm.32) The method of claim 27 wherein the chromed plates are coated with gold to a thickness of from 190 to 210 nm.33) The method of claim 27 wherein the chrome is coated onto the plate using an e-beam evaporator.34) The method of claim 27 wherein the gold is coated onto the chromed plate using an e-beam evaporator.35) The method of claim 27 wherein the plates are bonded together at about 625°C.36) The method of claim 27 wherein a carbide sheet is placed between the top surface of one plate and the bottom surface of another plate prior to diffusion bonding the plates together.37) The method of claim 27 further comprising laser welding a matrix backing to the diffusion bonded plates.38) The method of claim 37 further comprising adding a backing plate to the matrix plate.39) The method of claim 27 wherein the laser is a UV laser.40) The method of claim 37 wherein the laser welding is performed by a YAG laser.41) A method for manufacturing a microprojection array having a plurality of microprojections comprising: making a mold by cutting a plurality of holes of predetermined width and length into two or more plates with a laser each plate having two sides; cleaning the plates; coating each side of the plates with chrome to produce chromed plates; coating each side of the chromed plate with gold; diffusion bonding the plates together to produce a microprojection array mold; and injecting a polymer into the mold to produce a microprojection array having a plurality of microprojections.42) The method of claim 41 wherein the polymer is a liquid crystal polymer.43) A device for manufacturing microprojection arrays having a plurality of microprojections comprising two or more plates having a plurality of holes therein of a predetermined length and width.44) The device of claim 43 wherein the number of plates is three.45) The device of claim 44 wherein the plates are a base plate, a middle plate and a tip plate.46) The device of claim 44 wherein the base plate is from 250 to 350 pm thick.47)The device of claim 44 wherein the middle plate is from 125 to 175 pm thick.48) The device of claim 44 wherein the tip plate is from 90 to 110 pm thick.49) The device of claim 44 wherein the base plate is about 300 pm thick.50) The device of claim 44 wherein the middle plate is about 152 pm thick.51)The device of claim 44 wherein the tip plate is about 100 pm thick.52) The device of claim 43 further comprising a vented backing plate.53)The device of claim 52 wherein the vented backing plate is from 1450 to 1500 pm thick.54) The device of claim 53 wherein the vented backing plate is about 1480 pm thick.55) The device of claim 52 further comprising a second backing plate.56) The device of claim 55 wherein the second backing plate is from 1450 to 1500 pm thick.57) The device of claim 56 wherein the second backing plate is about 1480 pm thick.58) A method for manufacturing a microprojection array having a plurality of microprojections comprising: cutting a first plurality of holes of a first diameter, a second diameter and a first length into a stainless steel base plate; cutting a second plurality of holes of a third diameter, a fourth diameter and a second length into a stainless steel top plate, wherein the first diameter and second diameters are larger than the third and fourth diameter; cleaning the plates with a solution of 3: 1 mixture of sulfuric acid and 30% hydrogen peroxide; attaching the top plate to the base plate to form a stack; attaching one or more backing plates to the top plate of the stack; diffusion bonding the base plate, top plate and the one or more backing plates together to form the mold; and injecting a polymer into the mold to produce a microprojection array having a plurality of microprojections.59) The method of claim 58 wherein the polymer is a liquid crystal polymer.

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