WO2019186129A1

WO2019186129A1 - Microneedle platform for sensing and delivery

Info

Publication number: WO2019186129A1
Application number: PCT/GB2019/050846
Authority: WO
Inventors: Sanjiv Sharma; Owen GUY; Anthony E. G. Cass
Original assignee: Swansea University
Priority date: 2018-03-27
Filing date: 2019-03-26
Publication date: 2019-10-03
Also published as: GB2586738A; GB202015800D0; GB201804880D0; GB2586738B

Abstract

The invention concerns a dual function patch for delivering an agent into an individual and sensing an analyte typically associated with the delivery of, or effect of, said agent; and a method of delivering an agent into the skin and sensing an analyte typically associated with the delivery of, or effect of, said agent using said patch.

Description

Microneedle platform for Sensing and Delivery

Field of the Invention

Background of the Invention

Microneedles (MNs) have been investigated for a diversity of medical applications, including delivery of biopharmaceuticals, where delivery of bioactives to the skin has been the primary focus. MNs are micron-sized, needle-like projections, often organized in an array having a defined geometric pattern on a planar base and are an established technology that is currently being exploited for the targeted intra-epidermal and intradermal delivery of drugs and vaccines. Due to their microscopic dimensions Microneedle arrays (MN) are minimally invasive devices that by-pass the stratum corneum (SC) barrier, thus accessing the skin microcirculation and achieving systemic delivery by the transdermal route.

MNs have the inherent advantage of offering greater bioavailability of drugs to the systemic circulation. This is a direct consequence of the permeation of drugs past the SC barrier of the skin. Furthermore, this greater bioavailability is due to the fact that the drugs avoid any gastrointestinal and hepatic breakdown. Currently there are about 20 drugs that have been reportedly delivered transdermally. Attempts are being made to increase this number and for this various drug delivery strategies are being devised, these include coating the drugs with liposomes, dendrimers and nanoparticles to increase the absorption of the drug.

In addition to drug delivery, MNs have been utilised as biosensors. The skin interstitial fluid (ISF) represents a matrix of analytes such as metabolites, therapeutic drugs and disease biomarkers which may have important diagnostic and/or prognostic value. Microneedles, often in the form of wearable patches, allow this matrix to be accessed in a minimally invasive manner thereby facilitating detection of analytes of clinical significance.

We herein disclose a dual function delivery and sensing microneedle patch. Using such a patch permits the delivery of a therapeutic by the microneedles and measuring any consequent changes in analyte concentration in the skin ISF, thus permitting the tailored delivery of drugs, for example those that vary according to an individual’s response to same.

Statements of Invention

According to a first aspect of the invention there is provided a dual function patch for delivering at least one agent to an individual and for sensing an analyte under/in the vicinity of said patch, which analyte is typically associated with the delivery of, or effect of, said agent comprising:

- a base

- a plurality of microneedles attached to, or associated with, said base wherein at least one of said microneedles is a delivery microneedle provided with an agent delivery feature and either said delivery microneedle and/or at least one alternative microneedle is a sensing microneedle provided with a sensing feature for measuring voltage/current flow or resistance/impedance in situ that is indicative of at least one analyte in situ.

Ideally said patch is wearable and so adapted to be attached to the skin. As will be appreciated by those skilled in the art, this can be achieved in numerous ways such as, but not limited to, a skin adhesive layer or the like.

Reference herein to a base refers to a planar structure upon which the microneedles are mounted, or to which said microneedles are attached or with which said microneedles are associated. As will be appreciated by those skilled in the art, the base and microneedles may be manufactured from different materials. However, more preferably, the base is a structure from which the microneedles are manufactured wherein the microneedles form micro-protrusions from the surface of same. Techniques for the manufacture of same are known to those skilled in the art such as, but not limited to, injection moulding, hot embossing, laser micromachining, 3D printing and micromoulding.

In a preferred embodiment, said base and/or microneedles are formed of a polymeric substance selected from the group comprising: PMMA, polycarbonate, Acrylonitrile-Butadiene-Styrene ABS, Nylon PA, Polycarbonate PC, Polypropylene PP and Polystyrene GPPS.

In a preferred embodiment of the invention said microneedles or a selected number thereof are either solid or hollow.

In a preferred embodiment, wherein the microneedles are solid, the selected microneedles are designed to be coated with a dissolvable or substantially dissolvable material which has the ability to pass into the surrounding environment under certain conditions, such as when said dissolvable material is in contact with an aqueous environment after penetrating the stratum corneum layer of the skin. Examples of dissolvable or substantially dissolvable materials are known in the art such as, but not limited to include polyvinyl alcohol (PVA), polyacrylates, polymers of ethylene-vinyl acetates, and other acyl substituted cellulose acetates, polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, polyethylene oxide, chlorosulphonate polyolefins, poly(vinyl imidazole), poly(valeric acid), poly butyric acid, poly lactides, polyglycolides, polyanhydrides, polyorthoesters, polysaccharides, gelatin, hydrogels and the like, mixtures, and copolymers thereof. Alternatively, said material is swellable such that when said material is in contact with an aqueous environment after penetrating the stratum corneum layer of the skin it absorbs moisture. As will be appreciated by those skilled in the art, as the dissolvable/swellable or substantially dissolvable material pass into the skin, it can also deliver any agent entrapped thereon or therein into the skin interstitial fluid (ISF). Accordingly, in a further preferred embodiment of the invention, said dissolvable/swellable or substantially dissolvable material further comprises at least one agent to be delivered into the skin and so released into the individual.

Alternatively, said microneedles or a selected number thereof are hollow. According to this preferred embodiment, the hollow microneedles are designed to have at least one aperture, so that said agent may be delivered through the aperture into the ISF.

In a preferred embodiment of the invention the hollow microneedles are fashioned to have a plurality of faces or sides such that a part of the microneedle, e.g. one of said faces or sides, has at least one aperture therein which is connected to an agent supply, and is used for agent delivery; and another of said faces or sides is solid and used for sensing purposes. Most ideally this latter type of microneedles is pyramidal, conical or of a shape that gives it a sharp tip ranging in 10-100 microns in diameter.

In yet a further preferred embodiment, delivery of agent is actuated by a stimulus. For example, the agents might be encapsulated in a reservoir coated with a metal layer (Au, Ag or Pt) which will corrode to release the entrapped drug in response to an electrical stimulus.

In yet a further preferred embodiment still, said base may further comprise at least one channel connected to said agent supply, which supply is positioned adjacent to at least one microneedle. Preferably a plurality of channels are provided adjacent to at least one microneedle, and ideally are connected to a pump for actively pumping a supply of agent through the channels. Preferably, said channel(s) has a diameter between about 0.20 to about 0.75 mm. More ideally, said channel has an aperture between 0.40 to 0.50 mm. In a preferred embodiment said agent(s) include(s) active agents intended for topical, local, and/or systemic delivery. Generally, any drug or active agent which can be effectively delivered trans-dermally can be delivered using the dual function patch of the present invention. Preferably, said agent(s) includes any conventional medicament, therapeutic or cosmetic agent, vaccine, protein, antibody, or biopharmaceutical.

Any suitable microneedle having the requisite features described herein, including the requisite length and diameter specifications can be used in accordance with the invention herein disclosed. In a preferred embodiment, the microneedles have a length of from about 1200 pm to about 100 pm. More preferably, the microneedles have a length of from about 1000 pm to about 400 pm. Most ideally, the microneedles have a length of from about 900 pm to about 500 pm.

In yet a further preferred embodiment of the invention said plurality of microneedles are provided or distributed in groups, typically arrays, wherein different groups or arrays have different functions. For example, at least one group or array is adapted to function as a drug delivery unit and at least one other group or array is adapted to function as a sensor unit. Alternatively, each group or array comprises a plurality of microneedles some of which are dedicated to drug delivery and others of which are dedicated to sensing. Alternatively, at least one group or array comprises microneedles with dual functionality i.e. they can both deliver drugs and sense the local environment.

In yet a further preferred embodiment, wherein a microneedle is a sensing microneedle, said sensing microneedle comprises an external conductive layer, more ideally, a plurality of these microneedles when positioned together or adjacent each other act as a single sensing unit or electrode, wherein the outer conducting layer of the group of electrodes acts as the working electrode of an electrochemical (bio)sensor. More preferably, the sensing microneedle(s) or sensing unit comprise an electrical connection by which the microneedle(s) or sensing unit receive(s) an electrical signal and, further, a processor is provided to process sensing signal(s) from said microneedle(s) or sensing unit and to generate a sensor output signal. Most preferably still, at least one of the microneedles or at least one group thereof is arranged to form a counter electrode. Yet more preferably, at least one of the microneedles or at least one group thereof is arranged to form a reference electrode.

In yet a further preferred embodiment, at least one sensing electrode is functionalized i.e. adapted to detect the presence of a particular analyte, and it is adapted to produce a voltage signal indicative of the presence of said analyte. The reference and counter electrodes are typically not functionalized, i.e. adapted to detect the presence of a particular analyte, or in certain embodiments, at least a part of the reference electrode may be functionalized but in a way that is different from the sensing electrode. For example, functionalisation may involve modification of a silver electrode to a silver/silver chloride by drop coating a solution of saturated ferric chloride thereon.

The determination, detection and/or quantitation of said analyte in the patch vicinity is sensed by the sensing microneedle(s). These include metabolites for examples, glucose, lactate and ketones or drugs such as theophylline or antibiotics such as penicillin or biomarkers for disease such as CDK4 proteins for skin cancer. This analyte could be, for example, an analyte specific for a particular disorder such as, but not limited to, a chronic metabolic disorder, such as blood insulin, proinsulin or C-peptide (diabetes); a marker of another disease, including acute diseases, such as cardiac disease e.g. cardiac troponin- or NT-ProBNP, a marker of thyroid function e.g. , thyroid stimulating hormone (TSH), a tumour marker, and a marker of an infectious agent and the like. Other examples of markers with increased detection levels in ISF include Carbonyl reductase (NAPDFI) 1 , creatine kinase B-type, protein S100-A4, alcohol dehydrogenase (NADP+), serine protease inhibitor Kazal-type 5, ribonuclease inhibitor, phosphatidylethanolamine-binding protein 1 , ubiquitin- like modifier-activating enzyme 1 , type IV collagenase, Sushi von Willebrand Factor A EGF and pentraxin domain-containing protein 1 , metalloproteinase inhibitor 2, neuroblast differentiation associated protein AFINAK, Insulin-like growth factor binding protein 6, Laminin subunit gamma-1 , Immunoglobulin superfamily containing leucine-rich repeat protein, cystatin-C, basement membrane specific heparan sulfate proteoglycan core protein, moesin, gelsolin, vasorin.

The microneedle(s) are, ideally, functionalized in different ways to allow multi- analytes sensing. Thus, at least two electrodes or groups/arrays of microneedles are adapted to detect the presence of different analytes. Further, at least two microneedles or groups/arrays of microneedles are functionalized in the same way.

In a preferred embodiment said processor is arranged to generate a sensor output signal that is an average of the signals from at least two electrodes.

In a preferred embodiment, at least three microneedles or groups/arrays of microneedles are functionalized in the same way, this provides for the added advantage of redundancy whereby at least one the three signals from the three microneedles or groups/arrays of microneedles can be ignored or disregarded.

Preferably, said processor is adapted to identify a signal from at least two of the at least three electrodes as being most similar to each other and probably more accurate to the true value of the analyte being measured and to then use these two signals to generate an output signal.

The processor is adapted to store a sequence of electrode signals and to analyse these signals.

Most preferably, at least one of the microneedles or microneedle groups/arrays is adapted to release a known quantity/concentration of analyte which is then used for the internal calibration of the sensor output i.e. to determine the relationship between voltage/current and concentration of the analyte. The processor is adapted to analyse the output signals and detect the occurrence of a predetermined change in the signals over time. In a preferred embodiment, said patch comprises several groups/arrays or subgroups/subarrays monolithically integrated on the same patch to enable the delivery of a number of agents and also sensing of analytes in the vicinity of the patch in response to the delivery of the different agents. This sensing may be undertaken either in a continuous monitoring mode or in a point of care mode which involves single or multiple point measurements.

According to a further aspect of the invention there is provided a method for delivering at least one agent to an individual and for sensing an analyte associated with the delivery of, or effect of, said agent comprising:

providing a dual function patch comprising a base to which there is attached, or associated with, at least one microneedle adapted for the delivery of an agent and either said delivery microneedle and/or at least one alternative microneedle is adapted for sensing voltage/current flow or resistance/ impedance in situ which voltage/current flow or resistance/ impedance is indicative of at least one analyte in situ ;

attaching said patch to the skin of an individual whereby said agent is delivered into said skin;

sensing, continuously or periodically, voltage/current flow or resistance/ impedance via said sensing microneedle(s);

processing said voltage/current flow or resistance/ impedance to determine the amount of said analyte whereby the amount of voltage/current or changes in resistance/ impedance, respectively, is indicative of the amount of a selected analyte.

In a preferred embodiment said method further includes the step of providing said patch with at least one calibration microneedle adapted for the delivery of a known amount of a selected analyte whereby the delivery of said known amount of said selected analyte generates a voltage/current that can be used to calibrate the patch. For example, the calibration microneedle(s) release(s) a known amount of chemical species (such as glucose) and a measurement is made of the resultant changes in current/voltage or resistance/ impedance and this data is used for the internal standardisation/calibration of the sensor.

Preferred features of each aspect of the invention may be as described in connection with any of the other aspects.

Throughout the description and claims of this specification, the words “comprise” and“contain” and variations of the words, for example“comprising” and“comprises”, mean“including but not limited to” and do not exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

All references, including any patent or patent application, cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. Further, no admission is made that any of the prior art constitutes part of the common general knowledge in the art.

Other features of the present invention will become apparent from the following examples. Generally speaking, the invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including the accompanying claims and drawings). Thus, features, integers, characteristics, compounds or chemical moieties described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith.

Moreover, unless stated otherwise, any feature disclosed herein may be replaced by an alternative feature serving the same or a similar purpose.

The Invention will now be described by way of example only with reference to the Examples below and to the following Figures wherein: Figure 1 shows a side sectional diagrammatic view of a solid microneedle patch of the invention;

Figure 2 shows a side sectional diagrammatic view of an alternative hollow microneedle patch of the invention;

Figure 3 shows a Scanning Electron Microscopy image of a part of the embodiment shown in figure 2;

Figure 4 shows a side sectional diagrammatic view of a further embodiment of a microneedle patch comprising channels in the base for delivery of agent;

Figure 5 shows a step by step of an example process for the manufacture of a patch according to the invention using an injection moulding technique;

Figure 6 shows a step by step of another example process for the manufacture of a patch according to the invention using laser ablation to obtain hollow microneedles;

Figure 7 shows a scanning electron microscopy images of microneedles obtained by laser ablation.

Figure 8 shows a scanning electron microscopy image Showing SEM images of microneedle arrays according to the invention using different materials a) Arrays fabricated by photolithography of SU-8 100 photoresist b) Arrays made by casting PDMS moulds with SU-8 50 photoresist followed by UV cross linking and c) Arrays fabricated using injection moulding of polycarbonate.

Figure 9 shows Western blot analysis showing amount of CDK4 proteins extracted by insertion of microneedle array structures into the skin. Here C1 and C2 represent conditions in which the microneedle arrays were gently tapped into the skin 3-4 times and then rinsed with 50ul PBS and microneedle arrays left in the skin sample for 5 minutes under moderate thumb pressure followed by rinsing with PBS, respectively. As evident from the Western blot, there is evidence of CDK4 delivery into the skin.

Referring to the figures and, firstly, to figure 1 there is shown a side sectional diagrammatic view of an exemplar dual function patch: delivery and sensing, according to an embodiment of the invention. It can be seen that the patch comprises a base 1 which is typically, but not exclusively, made from a polymeric material and from which a plurality of solid microneedles 2 are fashioned. In this particular embodiment, the microneedles are formed as projections from the base 1 and thus are made from the same material. As will be appreciated, alternative arrangements are envisaged such as where the base and microneedles are manufactured from different materials (not shown) and joined there together. In either case, one or more of said microneedles is/are made from a conducting material.

According to the invention, at least one of the solid microneedles (that or those that are conducting) function(s) as a sensing microneedle for sensing voltage/current or resistance/ impedance in situ which is indicative of an analyte and so serves for the detection of an analyte in situ when inserted into the skin of an individual.

Further, the microneedles are coated with a dissolvable or substantially dissolvable material 3, whereupon insertion into the skin and more particularly the aqueous environment of the interstitial fluid (ISF), said material dissolves. Preferably, as will be appreciated, the material further contains an agent entrapped therein such that upon dissolving of the material the entrapped agent is released into the ISF. In an alternative the microneedles may be coated with a swellable material from which agent is released as the swellable material absorbs moisture. It follows from the afore that the patch is capable of the dual function of delivering an agent and sensing an analyte within the skin. Although not shown, a single patch can be provided with more than one material e.g. a first material including a first agent and a second material including a second agent wherein said first and second material may be the same or different. This arrangement permits the rapid delivery of agent(s) and the subsequent assessment - in terms of analyte presence - whereby the effects of such agent(s) can be monitored for the purpose of determining functionality of said agent, amount of agent needed to produce a certain response and the tailoring of agent delivery based upon a desired physiological response.

Referring to figure 2, an alternative embodiment of the dual function patch is shown as a side sectional diagrammatic view. The patch comprises hollow microneedles. In this embodiment, the patch comprises a main polymeric base 10 comprising an array of hollow microneedles 11 that are associated therewith. In this arrangement, microneedle 11 comprises a solid portion 12 continuous with base 10 and an inner channel 13 which opens at aperture 14, thus creating a hollow structure. The aperture 14 is in fluid communication with a supply or reservoir of agent 15, via the inner channel 13. This supply 15 may comprise a matrix such as a hydrogel that facilitates the controlled release of drug/therapeutic.

As is conventional with microneedles, there is a tip 11 which is necessary to ensure penetration of the stratum corneum and insertion of the needle(s) into the skin. It is therefore preferred that aperture 14 is not located at the tip of the needle thus effectively reducing its sharpness. In a preferred arrangement, the microneedles are shaped as a multi-sided pyramid with, in this embodiment, a diameter in the range of 5 to 50 microns and a height that is approximately equal to the width of its base, both of which are approximately 0.7mm or 700 microns, although the exact size and shape will vary depending on the application of the microneedle. In this embodiment, the aperture 14 is located on at least one face of the microneedle. This can best be seen from figure 3.

Further, to facilitate the delivery of agent, the patch may comprise a network of microchannel(s) 16 that connect with a port 18 which, in turn, is adapted to be connected to an external syringe/pump for pumping agent into the patch. Additionally, in terms of functioning as a sensor, at least one or more microneedle(s) is/are made from/coated with a conducting material/coating so that alone or together with adjacent microneedles, it/they can form a single electrode.

Depending upon the analyte to be detected, the microneedle(s) also is/are modified/functionalized to make it/them responsive to the presence of a particular analyte. This generally involves applying a substance to the surface of the microneedle(s) that will react with the analyte to produce a voltage/current or resistance/ impedance detectable by the electrode.

Typically, one or more of the microneedles is not functionalized and function(s) as a reference electrode and another one or more of the microneedles as a counter electrode.

A processor (not shown) is mounted on the back of the base 10, i.e. on the opposite side to the microneedles 11 , and each of the sensing electrodes, functionalized or otherwise, and reference electrode is connected to the processor. The processor is adapted to detect the voltage/current or resistance/ impedance of the sensing and reference electrodes and process these signals to generate an output signal representative of the presence/amount of the analyte to be detected. This processing may take place continuously or periodically. Further the processor may additionally, or alternatively, measure changes in parameters.

Referring to figure 4, there is shown an alternative patch according to an embodiment of the invention, the patch comprises a main polymeric base 10 made up of an array of microneedles 11 . In this figure, solid microneedles are shown although it is equally feasible to use hollow microneedles as disclosed herein. As shown, the base 10 further comprises at least one channel 19 which is/are positioned in between the microneedle projections or their bases. Channel 19 is/are connected to a supply or reservoir of agent as depicted in figure 2. This is further depicted in the microscopy image of figure 7, where, via laser ablation, several channels 19 have been created between the microneedles 11 . In this arrangement, once the microneedles have penetrated the skin, fluid agent flows through channel(s) 19 along the sides of the microneedles and so diffusing through the penetrated skin into the underlying ISF. This relatively simple arrangement can make use of the passive flow of agent although, alternatively, the patch may comprise a network of microchannel(s) 19 that connect to a port 18 which, in turn, is connected to a syringe/pump for pumping as a supply of agent through the patch as described with reference to figure 2.

Exemplar ways of making the patch according to the invention is shown in figure 5. In a first method (structure 1 ) a single block of material, ideally conducting material, is etched or cut using conventional techniques to yield a single structure whose main base 10 is integral with a number of projecting microneedles 11 . In this method the number and size of the base/microneedles are determined having regard to the etching/cutting process. In the alternative, a pair of moulds (structure 2 and 3) are fashioned; a first creating the outline of the projecting microneedles and a second for creating the base and inside of the microneedles whereby the positioning of curable material, ideally conducting material, between the two moulds (structure 4) results in the creation of a single structure (structure 5) whose main base 10 is integral with a number of projecting hollow microneedles 11 .

In figure 6 it is seen that a single patch made of a base 10 and a number of solid microneedles 11 can be further machined, in this case laser ablated, to drill/create channels 13 in the microneedles. Notably, the distal opening of these channels is deliberately positioned remote from the microneedle tip so that the sharpness of the tip is not compromised. Similarly, in figure 7 it can be seen that a single patch made of a base 10 and a number of solid or hollow, but usually solid, microneedles 11 can be further machined to create channels 19 at the base of the microneedles, ideally between individual microneedles. These channels 19 serve to administer fluid, containing effective/therapeutic agent, into the skin.

Although not shown the patch then has a processor attached to the rear - non- contact side thereof - which processor is adapted to communicate with each electrode and receive signals therefrom and also process these signals so as to create an output representative of the amount of analyte to be detected. In this way, the single patch can be used to deliver one or more selected agents, depending upon the application of same to the microneedles and/or the administering of same through or adjacent the microneedles, and to measure the presence/amount of analyte present under/in the vicinity of said patch. This information can be used to determine the state of the in-situ environment, the successful use of said agent or even the amount/dosage/delivery time(s) of said agent.

Usually, an adhesive layer of a conventional nature is applied to the side of the patch that makes contact with the skin, especially if it is the intention to wear the patch for any amount of time. In use, a patch according to the invention is applied to the skin and, passively or actively (via pumping), agent is delivered, and the processor measures the amount of analyte in situ and provides a reading thereof.

Claims

1. A dual function patch for delivering at least one agent to an individual and for sensing an analyte under/in the vicinity of said patch, which analyte is typically associated with the delivery of, or effect of, said agent comprising:

- a base; and

- a plurality of microneedles attached to, or associated with, said base, wherein at least one of said microneedles is a delivery microneedle provided with an agent delivery feature and either said delivery microneedle and/or at least one alternative microneedle is a sensing microneedle provided with a sensing feature for measuring voltage/current flow or resistance/impedance in situ that is indicative of at least one analyte in situ.

2. The patch according to claim 1 wherein the patch is adapted to be attached to the skin.

3. The patch according to any preceding claim wherein the base and microneedles may be manufactured from the same or different materials.

4. The patch according to any preceding claim wherein said base and/or microneedles are formed of a polymeric substance selected from the group comprising: polymethylmethacrylate (PMMA), polycarbonate, Acrylonitrile- Butadiene-Styrene (ABS), Nylon PA, Polypropylene (PP) and Polystyrene (GPPS).

5. The patch according to any preceding claim wherein the microneedles are solid and are designed to be coated with a swellable or dissolvable or substantially dissolvable material.

6. The patch according to claim 5 wherein the dissolvable or substantially dissolvable material is selected from the group comprising: polyvinyl alcohol (PVA), polyacrylates, polymers of ethylene-vinyl acetates, and other acyl substituted cellulose acetates, polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, polyethylene oxide, chlorosulphonate polyolefins, poly(vinyl imidazole), poly(valeric acid), poly butyric acid, poly lactides,

1 polyglycolides, polyanhydrides, polyorthoesters, polysaccharides, gelatin, hydrogels and the like, mixtures, and copolymers thereof.

7. The patch according to any one of claim 5 or 6 wherein said material further comprises at least one agent to be delivered into the skin.

8. The patch according to any one of claims 1-4 wherein the microneedles are hollow and are designed to have at least one aperture so that an agent may be delivered through the aperture into the skin.

9. The patch according to claim 8 wherein hollow microneedles are fashioned to have a plurality of faces or sides such that a part thereof has at least one aperture therein, connected to an agent supply, and is used for agent delivery and another of said faces or sides is solid and used for sensing purposes.

10. The patch according to any preceding claim wherein said base may further comprise at least one channel connected to an agent supply, which supply is positioned adjacent to at least one microneedle, whereby once the microneedles have penetrated the skin, fluid agent flows through said channel(s) along the sides of the microneedles and so into the penetrated skin.

1 1. The patch according to claim 10 comprising a plurality of channels connected to a pump for actively pumping a supply of agent through the channels.

12. The patch according to any one of claims 10 or 1 1 wherein said channel(s) has an aperture diameter between about 0.20 to about 0.75 mm.

13. The patch according to any one of claims 9-12 wherein said microneedles are pyramidal or conical.

14. The patch according to any preceding claim wherein the microneedles have a length of from about 500 pm to about 900 pm.

2

15. The patch according to any preceding claim wherein said plurality of microneedles are provided or distributed in groups or arrays wherein different groups or arrays have different functions.

16. The patch according to claim 15 wherein at least one group or array is adapted to function as a drug delivery unit and at least one other group or array is adapted to function as a sensor unit.

17. The patch according to any one of claims 15 or 16 wherein at least one group or array comprises microneedles with dual functionality.

18. The patch according to any preceding claim, wherein said microneedle comprises an external conductive layer so that it can function as a sensing microneedle.

19. The patch according to claims 16-18 wherein a plurality of said microneedles are positioned together or adjacent each other to act as a single unit or electrode, wherein the outer conducting layer of the group of electrodes acts as the working electrode of an electrochemical (bio)sensor.

20. The patch according to any one of claims 1-19 wherein the sensing microneedle(s) or sensing unit, comprise an electrical connection by which the microneedle(s) or sensing unit receive(s) an electrical signal and, further, a processor is provided to process sensing signal(s) from said microneedle(s) or sensing unit and to generate a sensor output signal.

21. The patch according to any one of the preceding claims wherein at least one of the microneedles is adapted to be a reference electrode and/or at least one of the microneedles is adapted to be a counter electrode.

22. The patch according to any one of the preceding clams wherein at least one sensing microneedle or sensing unit is functionalized or adapted to detect the presence of a particular analyte and is adapted to produce a voltage signal indicative of the presence of said analyte.

3

23. The patch according to claim 22 wherein the microneedle(s) are functionalized to allow multi-analyte sensing.

24. The patch according to any one of claims 20-23 wherein said processor is arranged to generate a sensor output signal that is an average of the signals from at least two electrodes.

25. The patch according to any one of claims 22-24 wherein at least three microneedles or groups/arrays of microneedles are functionalized in the same way.

26. The patch according to claim 25 wherein said processor is adapted to identify a signal from at least two of the at least three electrodes.

27. The patch according to any preceding claim wherein at least one of the microneedles or microneedle groups/arrays is adapted to release a known quantity/concentration of analyte which is then used for the internal calibration of the sensor output.

28. The patch according to any preceding claim wherein the patch comprises several groups/arrays or subgroups/subarrays integrated on the same patch to enable the delivery of a number of agents and also the sensing of analytes in the vicinity of the patch in response to the delivery of the different agents.

29. A method for delivering at least one agent to an individual and for sensing an analyte associated with the delivery of, or effect of, said agent comprising:

providing a dual function patch comprising a base to which there is attached, or associated with, at least one microneedle adapted for the delivery of an agent and either said delivery microneedle and/or at least one alternative microneedle is adapted for sensing voltage/current flow or resistance/impedance in situ which voltage/current flow or resistance/impedance is indicative of at least one analyte in sit ,

4 sensing, continuously or periodically, voltage/current flow or resistance/ impedance via said sensing microneedle(s); and

30. The method according to claim 29 wherein the method further includes the step of providing said patch with at least one calibration microneedle adapted for the delivery of a known amount of a selected analyte whereby the delivery of said known amount of said selected analyte generates a voltage/current that can be used to calibrate the patch.

5