GB2478363A

GB2478363A - Microneedle patch and method of manufacture

Info

Publication number: GB2478363A
Application number: GB201003759A
Authority: GB
Inventors: Dewan Fazlul Hoque Chowdhury
Original assignee: NDM Technologies Ltd
Current assignee: NDM Technologies Ltd
Priority date: 2010-03-05
Filing date: 2010-03-05
Publication date: 2011-09-07
Also published as: GB201003759D0

Abstract

The substrate 4 of the patch 22 comprises a set of substantially rigid strips 24 carrying rows of microneedles 20. Each pair of adjacent strips 24 is connected by a flexible connection 28 so that the patch 22 can bend around the roller of an applicator. The microneedles 20, strips 24 and flexible connections 28 are preferably formed integrally in a single compression moulding operation. Spacer elements (30, fig 4) may be formed between the microneedles 20. The patch 40 may be manufactured by disposing a length of fine wire 42 (figs 5-6) so that it repeatedly crosses a substrate 46, then cutting the wire 42 at a predetermined distance from each crossing point to leave lengths of the wire 42 projecting from the substrate 46 as microneedles 44. A drug may be displaced from a chamber 60(figs 7-9) into a hollow microneedle 44 by deforming an elastic membrane 64 that forms a wall of the chamber 60.Alternatively, the drug may be displaced from the chamber 60 by causing a bubble of air to pass through a valve or filter in the wall of the chamber 60.

Description

TITLE

Manufacture of microneedle arrays

DESCRIPTION

Technical field

The invention relates to methods for the manufacture of arrays of microneedles for penetration of human or animal skin. The microneedle arrays may be used for delivering biologically active substances such as pharmaceuticals into the body, for withdrawing fluid samples from the body, or for physical treatment of the skin itself.

io The use of the microneedle arrays may be for medical or cosmetic purposes.

For simplicity, a substance delivered into the body by means of microneedle arrays manufactured in accordance with the present invention will be referred to as a "drug" and the subject of the procedure will be referred to as a "patient". The use of these terms is not intended to limit the scope of the specification to medical procedures or to human subjects.

Background

It is well known that, instead of delivering drugs into the body by a single hypodermic needle, they may be delivered by an array of microneedles, each needle being generally less than 1mm in diameter. The use of microneedles is relatively painless and allows the drug to be delivered over an extended area of the skin covered by the S.. array in a robust, consistent and reproducible manner. The microneedle arrays can be mounted in an applicator, which makes them suitable for semi-automated use by persons without medical training, such as patients themselves. S..

S

The microneedles may be hollow, with a central bore that provides a channel through :. * the skin for delivery of the drug from a reservoir into the body of the patient.

Alternatively, they may be solid (as opposed to hollow) and simply coated with the drug prior to use so that the drug is carried on the surface of the needles as they pierce the skin. As described in published international patent application WO 2008/125798, hollow microneedles may also be used to withdraw samples of interstitial fluid from a patient for analysis, the needles being connected to reservoirs at relatively low pressure to induce the flow of fluid out through the skin. The physical action of microneedles on the skin may also be used to affect the structure of the skin itself, for example to soften scar tissue or for cosmetic purposes. In such applications, solid microneedles would typically be used.

The microneedle array may be formed directly on the surface of a roller or, as described in the aforementioned patent application WO 2008/125798, it may be formed as a discrete patch that is applied to the belt of an applicator. As the io applicator is moved over the skin of a patient, the belt unwinds from a roller and brings the patch gradually into contact with the skin so that the needles are caused to penetrate as the roller passes over the patch. In order for the patch to adapt to the curvature of the roller, and bring one row of needles at a time into contact with the skin, the patch must be able to bend about an axis transverse to its direction of movement.

Because of the small size and precise specifications required of microneedle arrays, their manufacture is difficult and costly. Hollow microneedles have been constructed using chemical etching of silicon, microinjection moulding, and various other machining techniques. Generally speaking they are rather cumbersome and lengthy processes with high manufacture costs and requiring large capital equipment installations. It is an object of the present invention to provide improved and more * S. efficient manufacturing techniques for microneedle patches comprising arrays of ****** * hollow or solid microneedles. S* ** * S S * *

It is a further object to provide an improved reservoir arrangement for delivering a . : drug through a hollow needle after it has pierced the skin of a patient.

* Summary of the invention

The invention provides a microneedle patch comprising an array of microneedles on a substrate, wherein the substrate comprises a set of transverse strips; each strip carries one or more rows of microneedles; and adjacent strips are connected to one another by a flexible connection. The strips are typically substantially rigid, to a degree sufficient to provide a secure base for the microneedles to be pressed against the skin, while the flexible connections between them permit the patch to bend about an axis parallel to the length of the strips and to follow the curvature of an applicator roller.

The strips will normally be elongated in a direction that is transverse to the intended direction of movement of the patch on the applicator, and parallel to the axis about which the patch has to bend; but the word "strip" simply refers to elements of the substrate that can pivot with respect to one another and should not be taken to imply any particular dimensions or proportions of those elements.

The flexible connections may comprise any structure that allows relative angular movement between the adjacent strips. In particular, the connections may be provided by a flexible membrane to which the respective strips are attached; or by thinner parts of the substrate that are integral with the strips; or by a mechanical linkage.

Spacer elements may be provided on the substrate between the microneedles, the height of the spacer elements above the substrate being at least half the height of the microneedles above the substrate. This arrangement allows microneedles to be manufactured at a larger size than required, which is easier to achieve, and the spacer elements reduce their effective size to the desired length.

* .** The spacer elements may be substantially rigid, their height being less than the height S.....

* of the microneedles such that tips of the microneedles extend beyond the spacer * 25 elements. Such rigid spacer elements may be formed integrally with the substrate. *.*

S

Alternatively, the spacer elements may be substantially compressible, their height . : being at least equal to the height of the microneedles. Such compressible spacer * : elements provide support and protection for the microneedles during transport and storage but retract under pressure from the skin during use. They may be formed as a layer of material that is pierced by the microneedles.

The invention further provides a method of manufacturing a microneedle patch comprising the processes of: compression moulding a block of material to form an array of microneedles on a substrate, wherein the substrate comprises a set of substantially rigid transverse strips, each strip carrying one or more rows of microneedles; and forming a flexible connection in the substrate between each pair of adjacent strips.

The invention provides a method of manufacturing a second type of microneedle patch comprising the steps of: disposing a length of fine wire so that it repeatedly crosses a substrate; and cutting the wire on a first side of the substrate at a predetermined distance from each crossing point to leave a length of wire projecting from the substrate as a microneedle. Because fine wire -particularly hollow wire -is commercially available, this method avoids many of the difficulties encountered in the prior art with forming the microscopic structures of needles -particularly hollow needles.

The step of cutting the wire may involve cutting the wire at an oblique angle to the length of the wire, in order to create a sharp point of the microneedle. For most applications, the wire on a second side of the substrate is cut at each crossing point substantially flush with the substrate.

In a preferred form of the method, the substrate comprises at least one row of holes S. formed therethrough, and the step of disposing the length of wire so that it repeatedly * crosses the substrate comprises threading the length of wire through the row of holes * :* 25 from alternate sides of the substrate. *

In an alternative form of the method, the substrate comprises a plurality of strips, each : . strip being formed in two halves; and the step of disposing the length of wire so that it repeatedly crosses the substrate comprises arranging the length of wire in a sinuous pattern across a first half of a strip, then engaging a second half of the strip with the first half to trap the wire between the two halves.

The invention provides a third type of microneedle patch comprising: a hollow microneedle having a bore in fluid communication with a drug chamber; and an elastic membrane defining one wall of the drug chamber, which can be deformed by external pressure to reduce the volume of the drug chamber. This has the advantage that mechanical means or a convenient fluid can be used to apply the pressure to the membrane and thereby displace drug from the chamber through the needle, with no risk of contamination or dilution of the drug.

Means for exerting pressure on the membrane may comprise a compressible reservoir in the patch, which contains a fluid; and a sealed and substantially incompressible io conduit leading from the reservoir to a surface of the elastic membrane that is adjacent to but outside the drug chamber. With this arrangement, the pressure of the patch against the skin of a patient can be used to automatically force fluid from the reservoir and thereby displace drug from the chamber. Alternatively, a protrusion on the applicator can apply pressure to the membrane when the patch is brought into contact is with the skin.

The invention further provides a related type of microneedle patch comprising: a hollow microneedle having a bore in fluid communication with a drug chamber; an air filter defining one wall of the drug chamber; and means for supplying air through the filter into the drug chamber to displace a drug from the chamber into the bore of the microneedle. I... * *

The drawing S.....

* Figure 1 is a schematic view to illustrate the compression moulding of a solid micro- *. : 25 needle patch according to a first aspect of the invention.

Figure 2 is a plan view of a solid microneedle patch according to the first aspect of the invention.

: : Figure 3 is a longitudinal side view of the microneedle patch of Figure 2.

*: Figure 4 is a transverse side view of an alternative solid microneedle patch according to the first aspect of the invention.

Figure 5 is a side view, in cross-section, of a hollow microneedle patch during a process of manufacture according to a second aspect of the invention.

Figure 6 is a side view, in cross-section, of the hollow microneedle patch of Figure 5 at a later stage in the process of manufacture.

Figure 7 is a side view, in cross-section, of an alternative hollow microneedle patch according to the second aspect of the invention.

Figures 8 and 9 are side views, in cross-section, to illustrate the use of a compressible reservoir to deliver a drug to a hollow needle in accordance with a third aspect of the invention.

According to a first aspect of the invention, a patch comprising an array of microneedles is formed by a compression moulding technique. The microneedles must be robust and sharp enough to pierce the skin of a patient but the patch must be flexible enough to adapt to the curvature of a roller. In accordance with the invention the microneedle array is formed from a block of biocompatible, medical grade polymer. As shown in Figure 1, the polymer block 2 is bonded to a flexible substrate 4 using a layer of permanent adhesive. The substrate 4 may be, for example, a sheet of polyurethane or silicone. Its lower surface 6 may be provided with an adhesive backing (not shown) via which the patch can be adhered to the belt or roller of an applicator device, the adhesive backing being protected by a peelable layer until the patch is ready for insertion into the device.

A compression moulding tool 8 may be formed from a durable material in a known manner, for example by machining with an ultra-fine diamond cutting tool. As illustrated, the tool 8 has an array of narrow, conical indentations 10 in its lower * surface 12, which are complementary to the shape of the desired array of microneedles. The tool 8 is applied to the polymer block under high pressure and * typically also at elevated temperatures in order to mould the polymer to the desired shape.

* : The microneedles 20 are typically arranged on the patch 22 in a rectangular grid as shown in Figure 2 and, in particular, they are arranged in rows 24. The rows 24 are transverse to the intended direction of movement 26 of the patch 22 around the roller of a microneedle applicator (not shown) as it is applied to the skin of a patient. In other words, the length of the rows will be generally parallel to the axis of the roller.

In order for the patch 22 to be sufficiently flexible to curve about that axis, it may be cut along lines 28 between the rows of microneedles 20. The cut lines 28 may penetrate fully through the thickness of the polymer block 2 or they may stop just short of the flexible substrate 4 in order to score the block 2 and leave adjacent rows 24 connected by a thin, flexible film of polymer.

In an alternative embodiment of the invention (not illustrated) the flexible connection between adjacent strips could be a hinge or other mechanical linkage permitting pivotal movement between them.

Preferably, the compression moulding tool 8 includes thin, blade-like projections (not shown in Figure 1) that form the cut lines 28 at the same time as forming the microneedles 20, whereby the entire microneedle patch can be produced in a single compression operation. Alternatively there could be a first compression stage of manufacture that leads to formation of the microneedles 20 followed by a second stage of manufacture that cuts the array into strips 24, whilst retaining the strips 24 adhered to the substrate 4.

This manufacturing technique allows a high density of microneedles 20 to be produced along each strip 24, and further allows each strip to be thinner than 2mm, * *** possibly down to a thickness of few hundred microns.

**.*** * The block 2 could comprise a composite material that leads to the formation of a porous microneedle structure, which would be able to be loaded with a greater :. quantity of the drug for delivery to the patient. During the compression moulding * process, the higher compressional force transmitted to the base of the needle will lead * * to a more densely packed structure towards the base, and the lower compressional force transmitted to the tip of the needle (due to the shorter distance of travel of the compression tool) will lead to a less densely packed, and therefore more porous, structure towards the tip. This may lead to the production of what are essentially hollow microneedles with numerous outlet bores towards the tip.

One difficulty in the process of forming microneedles by moulding is that it can be difficult to fabricate sufficiently rigid and sharp microneedles of sufficiently short length. For example, a minimum practicable length of moulded needle may be 1mm but in order to avoid the pain receptors in the patients skin it may be desirable to provide microneedles 20 no more than 0.25mm long. Figure 4 illustrates a possible solution to this problem, namely to occupy part of the length of the microneedles 20 by spacers 30 placed between the microneedles so that the upper surfaces of the spacers 30 form an effective surface 32 of the patch 22, beyond which the tips 34 of io the microneedles protrude by the desired distance. The spacers 30 may be formed with the microneedles 20, integrally from the same bock of polymer 2 in the compression moulding process. Alternatively, they may be discrete elements laid as strips of flexible (but not too compressible) material between the rows 24 of microneedles, or laid transversely to the rows 23 between the columns of microneedles 20. A final and preferred option is to form all the spacers 30 from a sheet of material of the desired thickness, which is pressed over the array of microneedles 20 and penetrated by them.

According to a second aspect of the invention, an array of microneedles is formed in a patch by configuring a length of wire to cross a substrate repeatedly and then cutting the wire to an appropriate size and shape at each crossing point. The wire may be produced from inert metals such as gold, platinum, silver, stainless steel; from medically acceptable polymers; or from suitable alternative materials. The wire is * preferably hollow so as to form hollow needles. Stainless steel wires for example can be obtained commercially with a bore of lOOjim and walls of 50p.m thickness, thus having a total diameter of 200 pm.

* * Figure 5 is a cross-section through a microneedle patch 40 threaded with hollow * : wire 42 at an early stage in the manufacturing process according to the invention.

Figure 6 shows the same cross-section after formation of hollow microneedles 44 from the wire 42. The Figures show what will eventually be a row of microneedles 42 along a single strip of the patch 40, similar to the strips 24 shown in Figure 2. A substrate 46 of the patch 40 is formed from a layer of biocompatible, medical grade polymer, which is pierced at regular intervals along the strip by small holes 48. In the manufacturing process according to the invention, the hollow wire 42 is disposed in the patch in a sinuous arrangement so that it passes alternately up and down through the holes 48 along the row. The configuration of the wire 42 comprises substantially straight sections 50 that pass through the holes and are perpendicular to the substrate 46, successive straight sections 50 being interconnected by curved sections 52 above and below the substrate 46.

This sinuous configuration of wire 42 may be created by threading an end of the wire alternately up and down through the holes 48 in the manner of stitching. The process can be automated with a pin on one side of the substrate 46 to guide the wire 42 through the holes 48; and a crimp type mechanism on the other side of the substrate 46 to catch the wire and pull it through. The curved sections 52 of the wire may be supported, e.g. by rollers, to hold the straight sections 50 in place. A continuous supply of the wire will be delivered from a roll as the leading end of the wire 42 moves along the strip.

Alternatively, the sinuous configuration of wire 42 may be created without the need for such a stitching mechanism if each strip of the substrate 46 in formed from two halves. The sinuous pattern of wire 42 may then be laid down on one half of the strip as a single layer before the other half of the strip is placed over it to clamp the arrangement in place. The two halves may be sealed together using radio-frequency *0*S* * welding, sonic welding, heat sealing, or just using adhesive. If the substrate 46 is of * 25 polymer construction then a curing process would seal the two halves permanently.

*:. Each half of the strip may have a set of half-cylindrical grooves, in which the wires 42 are laid and which between them form the holes 48. Alternatively, the material of the * two half strips may be sufficiently flexible to grip the wire 42 between the halves * without crushing it and without the need for special grooves in which the wire must be located.

-10 -During or after disposal of the wire 42 in the substrate 46 in the described configuration, glue or another filling material 54 is applied around the lengths of wire where they pass through the holes 48 in order to seal around the wires 42 and to hold them in place. Each straight section 50 of the wire 42 can then be cut above and below the substrate 46 to form discrete microneedles of the desired length and shape.

The cutting may be done by laser or with a blade, provided that the wire is not crushed so as to close the bore in the process. The cuts can be made singly or preferably along the whole row in one operation. As indicated by the lower cut lines 56 in Figure 5, the wire 42 below the substrate 46 is preferably cut flush with the io base of the substrate. When the system is used for diagnostics applications, the wire 42 may instead be extended below the substrate so as to provide fluid communication with a diagnostic sensor. As indicated by the upper cut lines 58 in Figure 5, the wire 42 above the substrate 46 may be cut obliquely to form a sharp point on each microneedle 44 that will assist with piercing the skin, as seen in Figure 6. Alternatively, the upper cuts 58 may also be made parallel to the substrate, as seen in Figure 7.

In order to ensure that the hollow wire 42 remains straight for at least the length that is required, during the application of the wire to the substrate 46 and prior to the wire being cut to size, guide slots or stabilizing plates (not illustrated) may be placed on top of the substrate 46. The top surface of such stabilizing plates could also serve as a guide for the cutting of the wire 42. Such stabilizing plates will typically be removed * before the end of the manufacturing process. However, if they are sufficiently p.....

* flexible and compressible, they may be left in place to support the microneedles 44 and protect their tips during transport and storage of the patch 40. In use, the pressure of the patch 40 against the patient's skin will cause the compressible plate to retract from the tips of the microneedles 44, allowing the tips to penetrate the skin. S.. S

* : In the above schematic the bottom part of the wire is shown to be flush with the lower part of the reservoir base. This is firstly to enable the cutting of the wire, and secondly to enable a chamber to be built up around each of the microneedles, as shown in the schematics below (cross section across the front of a single row of microneedles on a strip).

It will be understood that the entire patch 40 will comprise a stack of strips as just described, arranged side by side. The strips may be attached to a common flexible membrane or they may be attached directly to one another (or pre-formed in partial contact with one another) so as to allow some flexibility between adjacent strips.

Thereby, the entire patch 40 will be able to curve about the surface of a roller that has an axis parallel to the length of the strips.

Figure 7 shows how the hollow microneedles 44 may be interfaced with chambers 60 formed in the patch 40. As shown, one chamber 60 is formed around the bottom of each microneedle. Alternatively, multiple microneedles could be interfaced with a single, larger chamber. Chambers 60 can be created using injection moulding means such as conventional injection moulding, or micro-injection moulding, or also by compression moulding or using machining techniques. These may be produced from a number of materials including plastics, ceramics, metals, or a combination thereof.

The chambers 60 are formed within a body 62, which can be built up by applying an additional layer of material that is pre-cut and moulded or machined to the desired shape, to give the desired cavity structure and volume, for example a conical chamber 60 as shown beneath each needle 44. The chambers 60 are sealed at their lower end by a membrane 64. They may be in fluid communication with each other via conduits 66 through the chamber body 62 or via conduits (not illustrated) between *S..

* the lower membrane 64 and the chamber body 62. The chambers 60 and conduits 66 ****** * 25 may be in communication with a larger reservoir 70 for storing a drug for delivery to the patient or for receiving fluid samples withdrawn from the patient.

S S..

S

: Microneedle patches with such chambers 60 may be pre-filled with a drug during manufacture. Alternatively, in order to provide flexibility and avoid possible * S. 551 * 30 deterioration during storage, means may be provided for loading the chambers 60 with a drug at the point of use. The patch may therefore be provided with a port for entry of the drug, which may be a standard connector such as a LuerLok® or Luer- -12 -Slip® mechanism, or simply a septum that self-seals after being punctured by the syringe of a needle. The entry port will be in fluid communication via conduits 66 with all of the drug chambers 60, allowing them to be filled without any need to expose the microneedles 44 to the surroundings. The microneedles 44 may thus be sterilized and protected by a lid or cap until the patch is applied to the applicator for use.

The lower membrane 64 may be a solid material or it may be a flexible material that is plastic but not elastic, In the case of using a solid material the chambers 60 will io need to be pressurized in order to expel the contents of the chambers 60 via the microneedles. In the case of the lower membrane being flexible, i.e., it can be compressed but not stretched, then the lower membrane can be depressed by manual or other means such that the contents of the reservoir 70 are compressed and expelled.

For example, if the patch with hollow microneedles is loaded on to an applicator then insertion of the needles into the skin followed by compression of the reservoir 70 will lead to the expulsion of the contents through the tips of the microneedles 44.

A third aspect of the invention relates to a mechanism for automatically delivering drugs from a reservoir 70 to the microneedles 44 when the microneedle patch is applied to the skin of a patient on a roller, or a belt wrapped around a roller. The reservoir 70 and needle may be configured on the patch 40 so that, as the flexible patch unwinds from the roller, the microneedle 44 contacts the skin of the patient first and the associated reservoir 70 is synchronized to contact the skin shortly afterwards. **I.

The reservoir 70 is compressible, so pressure on it as indicated by the bold arrow 72 *...sI * 25 causes the volume of the reservoir to shrink and forces fluid 73 to flow from the reservoir 70 through the rigid conduit 66, as indicated by the arrows 74, and to the * underside of the drug chamber 60. A resilient membrane 64 separates the conduit 66 * ** from the drug chamber 60 and pressure from the fluid 73 causes the membrane 64 to : *: bow upwards and displace a drug from the chamber 60 into the bore of the S.....

microneedle 44 and from there into the body of the patient.

-13 -As viewed in Figures 8 and 9, pressure is applied to the patch starting with the microneedle 44 on the left and moving towards the right, so that the fluid 73 is urged towards the right side of the reservoir 70. That is why the exit from the reservoir 70 to the conduit 66 is located at the right side. However, other configurations are possible in which the reservoir 70 has the shape of a simple dome or other convenient shape and its exit is located centrally. One reservoir 70 will typically be connected to supply fluid 73 to multiple microneedles 44 in the same strip of the patch 40.

Because of the intervening membrane 64 between the conduit 66 and the drug chamber 60, the fluid 73 from the reservoir 70 does not come into contact with the drug in the chamber 60 so any convenient fluid may be used without the risk that it will dilute the drug or be injected into the patient. The fluid 73 may be a liquid such as water or oil; or a gas such as air. In place of the resilient membrane 64, a valve or air filter could be provided that allows a bubble of air to pass through from the is conduit 66 to the chamber 60 and displace a known quantity of drug from there into the needle 44. The air filter may have a hydrophobic or lipophobic coating as appropriate to prevent respectively an aqueous or an oil-based drug formulation from passing through it in the reverse direction.

As an alternative to the compressible reservoir 70, mechanical means located within the applicator or on the belt to which the patch 40 is applied may be used to apply pressure beneath the membrane 64 after the microneedles have been inserted into the skin. * *

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S..... * S * ** * S * * S

S *5*

S * *S * . S * S

S..... * S

Claims

-14 -CLAIMS1. A microneedle patch comprising an array of microneedles on a substrate, wherein: the substrate comprises a set of transverse strips; each strip carries one or more rows of microneedles; and adjacent strips are connected to one another by a flexible connection.
2. A microneedle patch according to claim 1, wherein the strips are attached to a flexible membrane that provides the flexible connection between them.
3. A microneedle patch according to claim 1, wherein the substrate is an integral piece of a material that is thick enough to be substantially rigid in the areas forming the strips and thin enough to be flexible in the areas forming the connections between the strips.
4. A microneedle patch according to claim 1, wherein adjacent strips are hinged together by a mechanical linkage that provides the flexible connection between them.
5. A microneedle patch according to any of claims 2 to 4, wherein the microneedles are integral with the substrate.
6. A microneedle patch according to any of claims I to 5, further comprising * .** spacer elements on the substrate between the microneedles, the height of the spacer **S.elements above the substrate being at least half the height of the microneedles above *** S S. * 25 the substrate. *. *5 * . S * I
7. A microneedle patch according to claim 6, wherein the spacer elements are * ,* substantially rigid, and wherein the height of the spacer elements is less than the height of the microneedles such that tips of the microneedles extend beyond the * 30 spacer elements. -15-
8. A microneedle patch according to claim 7, wherein the spacer elements are integral with the substrate.
9. A microneedle patch according to claim 6, wherein the spacer elements are substantially compressible, and wherein the height of the spacer elements is at least equal to the height of the microneedles.
10. A microneedle patch according to claim 9, wherein the spacer elements comprise a layer of material that is pierced by the microneedles.
11. A method of manufacturing a microneedle patch comprising the processes of: compression moulding a block of material to form an array of microneedles on a substrate, wherein the substrate comprises a set of substantially rigid transverse strips, each strip carrying one or more rows of microneedles; and forming a flexible connection in the substrate between each pair of adjacent strips.
12. A method of manufacturing a microneedle patch according to claim 11, wherein the flexible connections are formed in the compression moulding process.
13. A method of manufacturing a microneedle patch according to claim 12, wherein the flexible connections are formed by cutting score lines in the substrate after the compression moulding process. S...S.....

* 25
14. A method of manufacturing a microneedle patch according to any of claims 11 to 13, wherein the compression moulding process further includes forming ** substantially rigid spacers between adjacent pairs of microneedles, the height of the : * spacers above the substrate being less than the height of the microneedles above the substrate. *..*

* S 30
15. A method of manufacturing a microneedle patch according to any of claims 11 to 13, further comprising, after the compression moulding process, applying a layer of -16 -substantially compressible material to the substrate so that the layer is pierced by the microneedles.
16. A method of manufacturing a microneedle patch comprising the steps of: disposing a length of fine wire so that it repeatedly crosses a substrate; and cutting the wire on a first side of the substrate at a predetermined distance from each crossing point to leave a length of wire projecting from the substrate as a microneedle.
17. A method of manufacturing a microneedle patch according to claim 16, wherein the step of cutting the wire involves cutting the wire at an oblique angle to the length of the wire.
18. A method of manufacturing a microneedle patch according to claim 16 or claim 17, further comprising the step of cutting the wire on a second side of the substrate at each crossing point substantially flush with the substrate.
19. A method of manufacturing a microneedle patch according to any of claims 16 to 18, wherein the substrate comprises at least one row of holes formed therethrough, and wherein the step of disposing the length of wire so that it repeatedly crosses the substrate comprises threading the length of wire through the row of holes from alternate sides of the substrate. * **
20. A method of manufacturing a microneedle patch according to any of claims 16 S.....

* 25 to 18, wherein the substrate comprises a plurality of strips, each strip being formed in two halves, and wherein the step of disposing the length of wire so that it repeatedly crosses the substrate comprises arranging the length of wire in a sinuous pattern * across a first half of a strip, then engaging a second half of the strip with the first half to trap the wire between the two halves.

*I. S* -17 -
21. A method of manufacturing a microneedle patch according to claim 20, wherein at least one of the half strips has an engagement face with a set of grooves across the face for defining the crossing positions of the wire.
22. A method of manufacturing a microneedle patch according to any of claims 16 to 21, comprising the further step of sealing between the wire and the substrate at each crossing.
23. A method of manufacturing a microneedle patch according to any of claims 16 io to 22, wherein the wire is hollow.
24. A method of manufacturing a microneedle patch according to claim 23, comprising the further step of attaching a structured layer to the second side of the substrate to form chambers in fluid communication with the hollow microneedles.
25. A microneedle patch comprising: a hollow microneedle having a bore in fluid communication with a drug chamber; and an elastic membrane defining one wall of the drug chamber, which can be deformed by external pressure to reduce the volume of the drug chamber.
26. A microneedle patch according to claim 25, further comprising: *.** * a compressible reservoir in the patch, which contains a fluid; and S..a sealed and substantially incompressible conduit leading from the reservoir to S.....* 25 the elastic membrane, whereby pressure exerted on the reservoir can be transmitted along the conduit by the fluid to exert pressure on the elastic membrane. S.. *

* **
27. A microneedle patch according to claim 26, wherein the conduit opens into the :.: reservoir at an end of the reservoir that is remote from the microneedle.

*S.*SS *
28. An applicator for a microneedle patch according to claim 25, comprising a protrusion that is arranged to exert pressure on the elastic membrane of the drug -18-chamber when the applicator is used to bring the microneedles of the patch into contact with the skin of a patient.
29. A microneedle patch comprising: a hollow microneedle having a bore in fluid communication with a drug chamber; an air filter defining one wall of the drug chamber; and means for supplying air through the filter into the drug chamber to displace a drug from the chamber into the bore of the microneedle.
30. A microneedle patch according to claim 29, wherein the air filter is perforated by pores, which allow air to pass through but which are coated to prevent at least certain drug formulations from passing through.
31. A microneedle patch substantially as described herein with reference to any of Figures 2 to 9. * * *... *S..... * S S. S. * . . * S S.. * *S * . S SS. *SS.. S*S * .