WO2006101459A1

WO2006101459A1 - Microneedles

Info

Publication number: WO2006101459A1
Application number: PCT/SG2006/000069
Authority: WO
Inventors: Ciprian Iliescu; Francis Eng Hock Tay; Kwong Luck Tan
Original assignee: Agency For Science, Technology And Research
Priority date: 2005-03-23
Filing date: 2006-03-22
Publication date: 2006-09-28

Abstract

The present invention provides a microneedle comprising a microneedle body and a biodegradable microneedle tip. The tip may be coupled to or integral with the microneedle body. The microneedle may be porous or non-porous.

Description

Microneedles

Technical Field

The present invention relates to microneedles with biodegradable tips for transdermal drug delivery. Background of the Invention

The development of more sophisticated drugs has fed the growing need for more sophisticated methods of drug delivery. Conventional drug delivery techniques using pills and injections are often unsuitable for new protein- or DNA-based therapeutics, as well as other therapeutic compounds produced by modern biotechnology. An alternative drug delivery method involves drug administration across the skin (i.e. transdermal drug delivery). This approach avoids degradation of the medication in the gastrointestinal tract, as well as first-pass effects of the liver, which are commonly associated with oral delivery. It also eliminates the pain and inconvenience of intravenous injections. In addition, it offers the opportunity for continuous control of the delivery rate, unlike in conventional methods that deliver a large, discrete bolus.

Despite its many potential advantages, transdermal drug delivery is severely limited by the poor permeability of human skin. Most drugs do not permeate the skin at therapeutically relevant levels. A number of methods have been developed to increase the rate of transdermal transport but these have met with varied levels of success. Chemical enhancers can increase the permeability of skin to small molecules but they may also trigger skin irritation or other safety concerns that may limit their use. Iontophoresis employs an electric field to drive ionized molecules across skin by electrophoresis and non-ionized molecules by electro-osmosis. Despite concerns about skin irritation, iontophoresis may be useful in delivering selected peptides and small proteins. Recently, physical methods to temporarily increase skin permeability using electroporation and ultrasound have shown promise for delivery of both drugs and macromolecules. However, more research, in particular clinical studies, is needed to fully assess their potential impact.

Another proposed solution for transdermal drug delivery uses microneedle arrays. Microneedle arrays may be inserted into the skin and may create conduits for transport across the stratum corneum (the outer layer of skin that forms the primary transport barrier). Once a compound crosses the stratum corneum, it may be able to diffuse rapidly through the deeper tissue and be taken up by the underlying capillaries for systemic administration. Transdermal drug delivery using a microneedle array dramatically enhances the transport of molecules across skin (by up to 3 or 4 orders of magnitude). In addition, due to the lengths of the microneedles, which commonly range between about 100 and 150 μm, microneedle arrays are painless, since they do not reach nerves found in the deeper tissue. Figure 1 illustrates the working principle of microneedles for transdermal drug delivery.

Microneedles may be hollow or non-hollow. In operation, hollow microneedles puncture the skin and the microfluidic channel through the microneedles permits the delivery of the drug. Non-hollow microneedles puncture the skin and thereby generate microchannels in the skin. After a suitable time (commonly about 10 seconds to about 10 minutes) the microneedles are removed and the drug is applied to the skin. The drug will diffuse through the generated microchannels.

Microneedles may be produced using microfabrication technology. An advantage of this approach is that microfabrication readily produces micron-level structures in a way that can be easily scaled up for cheap and reproducible mass production. Microneedles with different shapes and profiles can be formed using an RIE (reactive ion etching) process.

A disadvantage with the use of microneedles is the breakage of microneedle tips during insertion into the skin. Commonly the microneedles are fabricated from silicon. Due to the fact that silicon is not a readily biodegradable material, residual parts of the broken microneedles in the skin can induce infections.

Object of the Invention

It is an object of the present invention to overcome or substantially ameliorate the above disadvantage. Summary of the Invention

In a first aspect of the invention there is provided a microneedle comprising:

- a microneedle body; and

- a biodegradable microneedle tip.

The biodegradable microneedle tip may be coupled to the microneedle body. The shape of the microneedle may be such that it is capable of being inserted into the stratum corneum of a patient. The microneedle tip may be sharp. It may be attached to the microneedle body in such a manner that the tip or a portion thereof is capable of being separated from the microneedle body when inserted into the stratum corneum of the patient. The microneedle body may be non-fragile (e.g. resilient). It may be such that, when the microneedle is inserted into the stratum corneum of the patient, no part of the microneedle body separates therefrom. The microneedle body and the microneedle tip may, independently, be porous, or be non-porous, or have a channel, e.g. a fluid channel or a microfluidic channel, extending therethrough. If the microneedle body and the microneedle tip each have a channel (a microneedle body channel and a microneedle tip channel respectively) therethrough, said channels may communicate to form a continuous microneedle channel through the microneedle. Each or any of these channels may be a fluid channel, e.g. liquid channel. The internal surface of each channel (tip channel, body channel and/or microneedle channel) may be hydrophilic. It may be sufficiently hydrophilic that an aqueous fluid, e.g. water, is capable of entering, or passing through, the channel under capillary forces without the application of an external force. The internal surface may comprise a hydrophilic layer. The hydrophilic layer may be for example an oxide layer such as silicon dioxide. It may be between about 1 and about lOOnm thick, or between about 1 and 20 about nm thick or between about 5 and about IOnm thick. Thus the microneedle may have a microneedle channel therethrough. The microneedle may be suitable for administration of the fluid to the patient. The fluid channel may extend longitudinally through the microneedle body and the microneedle tip. The microneedle may comprise two ends, one end being the microneedle tip and the other being a fluid receiving end. The fluid channel may extend through the fluid receiving end. The fluid channel may be capable of transmitting a fluid from the fluid receiving end through the body to and through the channel in the tip, for example for administering and/or dispensing the fluid to a patient (e.g. for delivering the fluid to the skin of the patient). The fluid receiving end may be coupled to a fluid reservoir. The microneedle may be removably coupled to the fluid reservoir. The channel, if present, may be capable of transmitting a fluid from the reservoir through the body to and through the channel in the microneedle tip.

The microneedle may be capable of dispensing the fluid to the patient. It may be an elongate shape, for example needle-shaped, conical, pyramidal, acicular or some other shape. It may be sharp and/or pointed. The shape may be such that the microneedle is capable of being inserted into the stratum corneum of a patient. The microneedle may have a length of between about 50 and 150 microns, or between about 100 and 150 microns. It may be suitable for transdermal delivery of the fluid to the patient. It may be sufficiently long to be capable of penetrating the stratum corneum of the skin of the patient, and may be sufficiently short that it is incapable of penetrating to the dermis of the skin of the patient. It may be sufficiently long that, when fully inserted into the skin of the patient, the biodegradable tip is in the epidermis of the patient. It may be adapted for administration of the fluid, which may be a liquid or a gas, to the patient. The fluid may be a gas, a solution, a suspension, a dispersion, an emulsion or a microemulsion. The fluid may comprise a drug. The drug may be indicated for treating a condition, for example a disease, in the patient. The patient may be a vertebrate, and may be a mammal, for example a human.

The microneedle body may comprise a non-biodegradable material, or a material that is only slowly biodegradable. It may comprise a rigid material. It may comprise a non-fragile, or resilient, material. It may for example comprise silicon, stainless steel, silica, or some other material. It may comprise a semiconductor material or an electrically conductive material. The microneedle body may comprise an open porous structure through which the microneedle body channel passes, or it may have one or more discrete holes that form the microneedle body channel, or it may have no holes and/or no channel. It may have one or more cavities therein. The cavities may or may not constitute a channel. The microneedle body may be an elongated shape.

The biodegradable tip may be sharp, and may sufficiently sharp to penetrate an outer layer of skin (the stratum corneum) of the patient. It may be conical, pyramidal or some other sharp shape. The biodegradable tip may comprise any suitable rigid biodegradable material, for example porous silicon, or a rigid biodegradable polymer. It may comprise a semiconductor or an electrically conductive material. The biodegradable tip is coupled to the microneedle body. It may be attached to, joined to, coformed with, integral with or coupled in some other manner to the microneedle body. It may comprise a material that is sufficiently rigid as to be capable of penetrating the stratum corneum of the patient.

In an embodiment there is provided a microneedle for administration of a fluid to a patient comprising:

— a microneedle body having a microneedle body channel therethrough, and

- a biodegradable microneedle tip which defines an aperture proximate the end of said tip and which has a microneedle tip channel therethrough which communicates with said aperture, said tip being coupled to the microneedle body, wherein the microneedle tip channel communicates with the microneedle body channel to form a continuous microneedle channel through the microneedle for the administration of the fluid to the patient.

The microneedle body channel may comprise a single channel through the body. The microneedle tip channel may comprise a single channel through the tip, or it may comprise a series of interconnected channels. Thus the tip may optionally comprise an open porous structure through which the tip channel passes. In use, fluid in the microneedle body channel may communicate with fluid in the microneedle tip channel.

Thus fluid which enters the microneedle body channel may pass into the microneedle tip channel, and pass through and out of the tip. The continuous microneedle channel may enable fluid to pass through the microneedle into a patient when the tip, or the microneedle, is inserted into the skin of the patient.

In another embodiment there is provided a microneedle comprising:

- a microneedle body having no fluid channel therethrough; and - a biodegradable microneedle tip attached to the microneedle body.

The shape of the microneedle may be such that it is capable of being inserted into the stratum corneum of a patient. The microneedle body may be hollow or non-hollow. The biodegradable tip may be porous or non-porous.

In another embodiment there is provided a microneedle comprising: - a microneedle body; and

- a biodegradable microneedle tip integral with the microneedle body.

In a second aspect of the invention there is provided a microneedle array comprising a base having a first side and a second side, and a plurality of microneedles according to the first aspect of the invention, said microneedles extending from the first side of the base.

Each of the microneedles may comprise a microneedle body and a biodegradable microneedle tip wherein said biodegradable microneedle tip is coupled to or integral with said microneedle body. The base may have holes therein, or may have no holes. If the base has holes, each hole may communicate from the first side of the base to the second side of the base. If the microneedles each have a microneedle channel therethrough, the holes may communicate with the microneedle channels to form array channels, each of which extends from the second side of the base to the tip of a microneedle so as to allow a fluid to pass from the second side of the base through the array channels and out of the tip of a microneedle. The holes may communicate with a fluid receiving end of the microneedle channels to form the array channels. The array channels may be capable of transmitting fluid pass from the second side of the base through the array channels and out of the tip of the microneedles into the skin of a patient when inserted into the stratum corneum of the patient. Thus the microneedle array may be suitable for administration of a fluid to a patient.

The microneedle array may be capable of forming a plurality of microchannels in the skin of a patient into which the microneedle array is inserted. The microneedle array may have array channels as described above, or may have no array channels.

In an embodiment there is provided a microneedle array for administration of a fluid to a patient, comprising:

- a base having a plurality of holes therein, each hole communicating from a first side of the base to a second side of the base; and

- a plurality of microneedles according to the first aspect of the invention, said microneedles extending from the first side of the base and said microneedles having microneedle channels extending therethrough; wherein each of the holes has one of the microneedles associated therewith, the microneedle channel of said microneedle being in communication with the hole such that, in use, fluid entering the hole from the second side of the base passes through the microneedle channel and exits the tip of the microneedle in order to administer the fluid to the patient. Each hole together with the microneedle channel in communication therewith may constitute an array channel which communicates from the second side of the base to the tip of a microneedle of the array. Each array channel may be a continuous array channel. It may be a fluid channel. It may be a microfluidic channel.

The base may be flat. It may be planar. It may be rigid or flexible. It may comprise the same material as the bodies of the microneedles or it may comprise a different material. The microneedles may be attached to or integral with the first side of the base. In another embodiment, the array comprises:

- a base having a plurality of holes therein, each hole communicating from a first side of the base to a second side of the base; and - a plurality of microneedles extending from the first side of the base, each of said microneedles comprising a microneedle body having a microneedle body channel therethrough, and a biodegradable tip which defines an aperture proximate the end of said tip and which has a microneedle tip channel therethrough which communicates with said aperture, said tip being coupled to the microneedle body, wherein the microneedle tip channel communicates with the microneedle body channel to form a continuous microneedle channel through the microneedle; wherein each of the holes has one of the microneedles associated therewith, the continuous microneedle channel of said microneedle being in communication with the hole such that, in use, fluid entering the hole from the second side of the base passes through continuous microneedle channel and the tip and exits the aperture in order to administer the fluid to the patient.

In another embodiment, the array comprises: - a base having a plurality of holes therein, each hole communicating from a first side of the base to a second side of the base; and

- a plurality of microneedles integral with, and extending from, the first side of the base, each of said microneedles comprising a microneedle body having a microneedle body channel therethrough, and a biodegradable tip which defines an aperture proximate the end of said tip and which has a microneedle tip channel therethrough which communicates with said aperture, said tip being integral with the microneedle body, wherein the microneedle tip channel communicates with the microneedle body channel to form a continuous microneedle channel through the microneedle; wherein each of the holes has one of the microneedle associated therewith, the continuous microneedle channel of said microneedle being in communication with the hole such that, in use, fluid entering the hole from the second side of the base passes through continuous microneedle channel and exits the tip of the microneedle in order to administer the fluid to the patient. In another embodiment, the array comprises a base having a first side and a second side, and a plurality of microneedles extending from the first side of the base, each of said microneedles comprising a microneedle body having no continuous channel therethrough and a biodegradable microneedle tip attached to the microneedle body, whereby the shape of the microneedle is such that it is capable of being inserted into the stratum corneum of a patient. The microneedle body may be hollow or non-hollow. The biodegradable tip may be porous or non-porous.

In another embodiment there is provided a microneedle array comprising a base having a first side and a second side, and a plurality of microneedles extending from the first side of the base, each of said microneedles comprising a microneedle body and a biodegradable microneedle tip integral with the microneedle body. The microneedles may be integral with the base.

In a third aspect of the invention there is provided a process for making a microneedle array, said process comprising: - providing a precursor array comprising:

• a base having a first side and a second side; and

• a plurality of microneedle precursors extending from the first side of the base,

- providing a protecting substance to the first side of the base, such that a tip portion of each microneedle precursor distal to the base is exposed (i.e. not coated by, protected by or in contact with the protecting substance) and the remainder of each microneedle precursor and the first side of the base are coated by (i.e. protected by or in contact with) the protecting substance; and

- converting each exposed tip portion into a biodegradable tip. The microneedle precursors may be attached to or integral with the first side of the base. The base and the microneedle precursors may, independently, comprise a semiconductor material, or may comprise an electrically conducting material. They may comprise the same material or different materials. They each may comprise a non-biodegradable material, or a material that is only slowly biodegradable when inserted into the skin of a patient. The base and the microneedle precursors may comprise silicon, for example single crystal silicon. The process may convert the microneedle precursors into microneedles according to the first aspect of the invention. The microneedles may have the same shape as the microneedle precursors, or may have a different shape. The tip portions may have the same shape as the biodegradable tips, or they may have a different shape. The step of providing the protecting substance may comprise:

- applying the protecting substance to the first side of the base and to the microneedle precursors so that the first side and the microneedle precursors are completely covered by the protecting substance, and

- removing the protecting substance from the tip portion of each microneedle precursor distal to the base, i.e. exposing said tip portions.

The step of removing the protecting substance from the tip portions may comprise:

- applying a coating substance to the protecting substance so that the protecting substance covering the first side and the microneedle precursors is completely coated by the coating substance, - removing a portion of the coating substance so as to expose the protecting substance in contact with the tip portions, and

- subjecting the exposed protecting substance to conditions sufficient to remove the protecting substance from the tip portions (i.e. to expose the tip portions), but not sufficient to remove the coating substance.

After the step of subjecting the exposed protecting substance, i.e. after exposing the tip portions, the coating substance may be removed, for example by dissolving the coating substance in a suitable solvent.

The protecting substance may be for example silicon nitride. It may be applied using chemical vapour deposition (CVD), for example low pressure CVD (LPCVD). The coating substance may be a photoresist, and may be a positive photoresist, for example AZ9620. The coating substance may be applied by spin coating. The step of removing the coating substance may comprise reflowing the coating substance and/or exposing the coating substance to a plasma, for example an oxygen plasma, and may comprise plasma etching. The conditions sufficient to remove the protecting substance may comprise using a dry reactive ion etching process, for example in trifluoromethane/oxygen.

The step of converting the exposed tip portions into a biodegradable tip may comprise an anodisation process. The process may additionally comprise removing the protecting substance after converting the exposed tip portions into biodegradable tips. The process may be capable of making a microneedle array according to the invention.

In an embodiment there is provided a process for making a microneedle array, said process comprising:

- providing a precursor array comprising: • a base having a first side and a second side; and

- applying a protecting substance to the first side of the base and to the microneedle precursors so that the first side and the microneedle precursors are completely covered by the protecting substance,

- applying a coating substance to the protecting substance so that the protecting substance covering the first side and the microneedle precursors is completely coated by the coating substance, - removing a portion of the coating substance so as to expose the protecting substance in contact with the tip portions,

- subjecting the exposed protecting substance to conditions sufficient to remove the protecting substance from the tip portions (i.e. to expose the tip portions), but not sufficient to remove the coating substance; and

- converting each exposed tip portion into a biodegradable tip.

In another embodiment there is provided there is provided a process for making a microneedle array, said process comprising:

- providing a precursor array comprising: • a base having a plurality of holes therein, each hole communicating from a first side of the base to a second side of the base; and

• a plurality of microneedle precursors extending from the first side of the base, each of said microneedle precursors having a microneedle body channel extending at least partially therethrough, wherein each hole has a microneedle precursor associated therewith, the microneedle body channel of which is in communication with the hole;

- converting each exposed tip portion into a biodegradable tip which defines an aperture proximate the end of said tip and which has a microneedle tip channel therethrough which communicates with said aperture, such that the microneedle tip channel communicates with the microneedle body channel and the hole to form an array channel through the array for the administration of the fluid to the patient. In another embodiment, the process comprises:

- applying a protecting substance to the first side of the base and to the microneedle precursors so that the first side and the microneedle precursors are completely covered by the protecting substance;

- applying a coating substance to the protecting substance so that the protecting substance covering the first side and the microneedle precursors is completely coated by the coating substance;

- removing a portion of the coating substance so as to expose the protecting substance in contact with the tip portions;

- subjecting the exposed protecting substance to conditions sufficient to remove the protecting substance from the tip portions (i.e. to expose the tip portions), but not sufficient to remove the coating substance;

- providing a precursor array comprising:

• a silicon base having a plurality of holes therein, each hole communicating from a first side of the base to a second side of the base; and • a plurality of silicon microneedles extending from the first side of the base, each of said silicon microneedles having a microneedle body channel extending at least partially therethrough, wherein each hole has a silicon microneedle associated therewith, the microneedle body fluid channel of which is in communication with the hole; - applying a silicon nitride layer to the first side of the base and to the silicon microneedles so that the first side and the silicon microneedles are completely covered by the silicon nitride layer; - applying a photoresist to the silicon nitride layer so that the silicon nitride layer covering the first side and the silicon microneedles is completely coated by the photoresist;

- removing a portion of the photoresist so as to expose the silicon nitride layer in contact with the tip portions;

- subjecting the exposed silicon nitride layer to a dry REE process in order to remove it from the tip portions (i.e. to expose the tip portions);

- removing the photoresist from the silicon nitride layer; and

- converting each exposed tip portion into a porous silicon tip by an anodisation process, whereby the porous silicon tip defines an aperture proximate the end of said tip and whereby said tip has a microneedle tip channel therethrough, such that the microneedle tip channel communicates with the microneedle body fluid channel and the hole to form an array channel through the array for the administration of the fluid to the patient. The invention also provides a microneedle array when made by the process of the third aspect of the invention.

In a fourth aspect of the invention there is provided a fluid administration apparatus for administration of a fluid to a patient, comprising:

- a microneedle array according to the invention; and - a fluid reservoir coupled to the second side of the base of the array and capable of holding the fluid; wherein the microneedle array comprises array channels, each of which extends from the second side of the base to the tip of a microneedle, said array channels being capable of transmitting the fluid into the skin of a patient when inserted into the stratum corneum of the patient. Said transmitting may comprise passing the fluid from the second side of the base through the array channels and out of the tip of a microneedles of the array.

The array channels may be capable of transmitting the fluid into the sMn of the patient without application of external pressure. In use, the transmitting may proceed due to capillary forces. The fluid may diffuse from the tips of the microneedles of the array into the skin of the patient.

In a fifth aspect of the invention there is provided a method for administering a fluid to a patient, comprising:

- applying a fluid administration apparatus according to the invention to the skin of the patient; and - passing the fluid from the fluid reservoir through the array channels of the apparatus into the skin of the patient.

The array may be applied to the skin of the patient such that at least some of the microneedles penetrate through the stratum corneum of the skin of the patient, and may be such that the biodegradable tips are within the epidermis of the skin of the patient. The step of applying the apparatus may comprise inserting the microneedles of the apparatus into the skin of the patient, or into a region of the skin of the patient. The fluid may be passed from the reservoir, through the array channels, out of the tips of the microneedles of the apparatus and into the epidermis. The fluid may be passed through the array channels and into the epidermis without application of pressure to the fluid.

The invention also provides a microneedle according to the invention, a microneedle array according to the invention or a fluid administration apparatus according to the invention when used for administering a fluid to a patient.

In a sixth aspect of the invention there is provided a method for administering a fluid to a patient, said method comprising:

- applying a microneedle array according to the invention to a region of the skin of the patient, thereby creating microchannels in said region;

- withdrawing the microneedle array from the skin of the patient; and

- applying the fluid to at least a portion of the region of the skin; whereby the fluid penetrates the microchannels and enters the skin of the patient.

The microneedle array may or may not have array channels. The method may comprise leaving the array in the region of the skin for a period of time. The period may be at least about 5 seconds, or at least about 10 seconds, and may be between about 5 seconds and about 30 minutes, or between about 10 seconds and 10 minutes. In a seventh aspect of the invention there is provided a method for administering a fluid to a patient, said method comprising:

- applying a microneedle array according to the invention to a region of the skin of the patient such that the microneedles of the array penetrate the skin of the patient, said microneedle array comprising array channels, each of which extends from the second side of the base to the tip of a microneedle, said array channels being capable of transmitting the fluid into the skin of a patient when inserted into the stratum corneum of the patient; and

- applying the fluid to the second side of the base of the microneedle array; thereby allowing the fluid to pass through the fluid administration channels of the array and into the skin of the patient.

In an eighth aspect of the invention there is provided a method for treating a condition in a patient comprising administering a fluid to the patient using a fluid administration apparatus or a microneedle array according to the invention, said fluid being indicated for the treatment of the condition. The administering may be according to the fifth, sixth or seventh aspect of the invention. The fluid may be provided in a single administration, or it may be administered in a plurality of discrete administrations, or it may be administered continuously. In an embodiment, the administering uses a fluid administration apparatus according to the invention. If the fluid is administered in a plurality of discrete administrations, the array of the apparatus may be left embedded in the skin of the patient, and may not be removed between discrete administrations. If the fluid is administered continuously, the array of the apparatus should be left embedded in the skin of the patient, and should not be removed until the continuous administration is complete. In some embodiments the administering does not comprise application of pressure to the fluid.

Brief Description of the Drawings

A preferred form of the present invention will now be described by way of example with reference to the accompanying drawings wherein: Figure 1 is a diagram showing a microneedle array according to the present invention inserted into the skin of a patient, illustrating how the array can create channels into the skin for drug delivery;

Figure 2 shows SEM (scanning electron micrograph) images of a microneedle and of a microneedle array according to the present invention; Figure 3 is a diagrammatic representation of a fabrication process for a microneedle according to the present invention, wherein the process consists of two steps: an isotropic etching process (Figure 3a) followed by an anisotropic process (Figure 3b);

Figure 4 shows two electron micrographs of microneedles according to the present invention, produced by the process shown in Fig. 3, showing the mask still in place; Figure 5 is a diagrammatic illustration of microneedles showing the forces acting upon a microneedle during insertion into a patient;

Figure 6 is an SEM picture of a "broken" tip of a microneedle made by a conventional fabrication process; Figure 7 is a diagrammatic representation of different types of microneedles: a) isotropic profile, b) ramp, c) and d) isotropic plus anisotropic profile, and e) and f) hollow microneedles;

Figure 8 illustrates the main steps of a process for fabricating microneedles with biodegradable tips according to the present invention; and

Figure 9 shows SEM images of a microneedle with porous tip according to the present invention.

Detailed Description of the Preferred Embodiments The present invention provides a fabricated microneedle array, e.g. a silicon microneedle array, with biodegradable tips made, for example, of porous silicon. Any broken tips from the microneedles of the array can remain in the body safely after removal of the array, and will be dissolved by the body, commonly within 2 to 3 weeks. In the context of the present specification, the term "biodegradable" refers to materials that are capable of being converted to a soluble form(s) (i.e. dissolved) by the activity of a biological material. The soluble form(s) may be non-toxic to a subject into which the microneedles are inserted. The conversion may or may not be attended by a chemical conversion, e.g. oxidation, of the biodegradable material. For example a biodegradable material may be one that biodegrades and/or is soluble in a biological fluid of a subject to which the biodegradable material is exposed, e.g. in which the biodegradable material is located. The biological fluid may be blood. The subject may be human or non-human. The conversion may be rapid or may be slow.

The inventors have used standard microfabrication techniques to etch arrays of micron-sized microneedles in silicon which may be used as precursor arrays in the present invention. In one example, microneedle arrays were fabricated according to the present using isotropic DRIE (deep reactive ion etching) process using SFβ/Ch gases. The fabrication process was optimized for an aspect ratio of 3:1 (height: width of the structure base). The results are presented in Figure 2a and Figure 2b, which show SEM images with a) a microneedle and b) an array of microneedles.

To enable easy penetration into the skin, it is preferable to have microneedles with high aspect ratio. The aspect ratio may be between about 10:1 and 2:1, or may be greater than about 10:1 or less than about 2:1. It may between about 10:1 and 3:1, 10:1 and 5:1, 5:1 and 2:1, 3:1 and 2:1 or 4:1 and 5:2, and may be about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 9:2, 4:1, 7:2, 3:1, 5:2 or 2:1. To achieve a high aspect ratio of the microneedles, a combination of isotropic and anisotropic profiles was fabricated. The fabrication process consists of two steps: an isotropic etching process (Figure 3a) followed by an anisotropic process (Figure 3b). Figure 4 presents the results of fabrication of such microneedles (the photoresist mask used for deep RIE process was not removed). In this fabrication process, an isotropic etching process was conducted as described above. Following this, an anisotropic etching process in plasma was performed. For the anisotropic process, a classical Bosch process in a deep RIE ICP (Inductive Coupling Plasma) was used. This process consists of two steps: etching and passivation. The etching step may for example use SFβ while for the passivation step C₄F₈ may be used. The alternation of these steps generates an anisotropic profile. A problem with conventional microneedles relates to the breakage of the tips of the needles during application. In many cases, the applied force is not perfectly perpendicular to the skin surface and so application of the microneedle array can cause the breaking of the microneedles. Figure 5 illustrates how the component of the force in the z-direction (F_z) does not cause a problem during the insertion of the microneedles into a patient, but the component F_x in the lateral direction (the x-direction) can easily break the top part of the tip. Hitherto, microneedles have been made from non-biodegradable materials such as silicon. Consequently, residual parts of broken microneedles in the skin could induce infections. Figure 6 shows an SEM picture of a "broken" tip of such a microneedle. The present invention provides a solution to this problem. The inventors have fabricated silicon microneedle arrays with biodegradable needle tips made of a biodegradable material such as porous silicon. Hence, the broken tips can remain in the body safely after removal of the microneedles, and will be dissolved by the body, commonly within 2 to 3 weeks. Depending on the nature of the tip, the broken portion may dissolve in the patient's body within between about 1 day and 1 month, or between about 1 week and 1 month, 2 weeks and 1 month, 1 day and 1 week, 1 and 3 days, 1 and 4 weeks, 1 and 2 weeks, 2 and 3 weeks, 3 and 4 weeks or 2 and 4 weeks, and may dissolve within about 1, 2, 3, 4, 5, 6 or 7 days, or about 1, 2, 3 or 4 weeks or within about 1 month. There is therefore disclosed herein microneedles with tips made from a biodegradable material such as porous silicon, wherein the tips may be breakable. Accordingly there is disclosed herein microneedles whereby the tips are such that, if the tips break during or after insertion into the skin of a patient, said tips do not cause infections in the patient There is also disclosed arrays of such microneedles. A representative microneedle array for transdermal drug delivery according to the present invention comprises of 25-200 silicon microneedles of 100-150 μm tall on a silicon die disposed at a distance of typically 100-500 μm, however larger or smaller arrays may be used. The microneedle profile may be generated using an isotropic reactive ion etching (RIE) process (Figure 7a), a cryogenic RIE process (black silicon method - Figure 7b), or a combination of isotropic and anisotropic RIE processes (Figure 7c and Figure 7d). Thus the microneedles may have straight (i.e. approximately parallel) sides, as shown in Figs. 7c, 7d and 7f, or may have sloped sides (i.e. the microneedles may be tapered), as shown in Figs. 7a, 7b and 7e. In addition, hollow microneedles can be generated as presented in Figure 7e and Figure 7f. These illustrate how the microneedle may comprise a continuous microneedle channel which extends through the microneedles from a fluid receiving end of the microneedle opposite the tip (in Figs. 7e and 7f at the bottom end of the figure) to the tip (in Figs. 7e and 7f at the top end of the figure). This channel enables fluid to pass through the microneedle from the fluid receiving end to the tip, and out of the tip. Characteristic of these microneedles is that the tip (the most susceptible part to be broken during application) is made from a biodegradable material, for example porous silicon.

Thus in one form the present invention provides microneedle for administration of a fluid to a patient comprising a microneedle body and a biodegradable tip coupled to (e.g. integral with) the microneedle body. The microneedle body may have a microneedle body channel therethrough. The biodegradable tip may define an aperture proximate the end of said tip and may have a microneedle tip channel therethrough which communicates with the aperture. The microneedle tip channel communicates with the microneedle body channel to form a continuous microneedle channel through the microneedle for the administration of the fluid to the patient. During said administration, the fluid may pass into a fluid receiving end of the microneedle channel (located at a fluid receiving end of the microneedle), through the microneedle channel to the tip, and may exit the microneedle through the aperture in the tip, said tip being at the opposite end of the microneedle to the fluid receiving end. The microneedle may be any suitable, preferably elongated, shape that allows it to be inserted into the skin of the patient. Some suitable shapes are shown in Fig.7, however other shapes may also be used.

The patient to which the microneedle may be applied may be a mammal, a marsupial, a fish, a bird or a reptile. The mammal may be a primate, e.g. a human or non- human primate or may be some other non-human mammal. The mammal may be selected from the group consisting of human, non-human primate, equine, porcine, murine, bovine, leporine, ovine, caprine, feline, ungulate, pachyderm and canine. The mammal may be selected from a human, horse, cow, bull, buffalo, sheep, dog, cat, goat, llama, rabbit, pig, elephant, and a camel, for example. The microneedle should be sufficiently long to penetrate through the stratum corneum to the epidermis of the patient. Consequently the length of the microneedle will depend on the nature of the patient, in particular the thickness of the stratum corneum and of the epidermis thereof. For a human patient, the microneedle may have a length of between 50 and 150 microns, or between about 50 and 100, 100 and 150 or 75 and 125 microns, and may have a length of about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 or 150 microns. The biodegradable tip of the microneedle may be between about 10 and 50 microns long, or between about 10 and 40, 10 and 30, 10 and 20, 20 and 50, 30 and 50 or 20 and 40 microns long, and may be about 10, 20, 30, 40 or 50 microns long. The tip may represent between about 10 and 50% of the length of the microneedle, or between about 10 and 40, 10 and 30, 10 and 20, 20 and 50, 30 and 50 or 20 and 40% of the length of the microneedle, and may be about 10, 20, 30, 40 or 50% of the length of the microneedle. The microneedle may have its largest cross-sectional area at the end remote from the tip. The largest cross-sectional area may be between about 0.005 and 0.5 mm², or between about 0.005 and 0.1, 0.005 and 0.05, 0.005 and 0.01, 0.01 and 0.5, 0.1 and 0.5, 0.01 and 0.01 or 0.01 and 0.05mm², and may be about 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4 or 0.5mm². The end of the biodegradable tip may be sufficiently sharp to enable the microneedle to penetrate the stratum corneum of the patient. In the case of a human patient, this may represent a tip width of less than about 10 microns, or less than about 7, 5 or 3 microns, and may be between about 1 and 10 microns, or between about 1 and 5, 1 and 2, 5 and 10, 2 and 8 or 3 and 7 microns, and may be about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 microns. In some embodiments the microneedle has a tip channel therethrough. The inner walls of the tip channel may be hydrophilic. The tip channel may have a hydrophilic layer at least partially coating the inner walls. The hydrophilic layer may be for example an oxide layer such as silicon dioxide. It may be between about 1 and about lOOnm thick, or between about 1 and 20 about nm, 5 and 10, 1 and 50, 1 and 20, 1 and 10, 10 and 100, 50 and 100, 10 and 50, 5 and 50, 50 and 30 or 5 and 20 nm thick, and may be for example about 1, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90 or lOOnm thick, or may be more than lOOnm thick. In use, if the microneedle has a microneedle channel, a fluid to be administered to the patient may pass through the microneedle (i.e. through the microneedle body and the biodegradable tip via the continuous microneedle channel) into the patient. It may pass without application of pressure to the fluid. It will therefore be clear that the walls of the microneedle body should ^■ be impermeable to the fluid, so that fluid entering the microneedle body can pass to the fluid tip and can not pass into the epidermis of the patient in which the microneedle body is located in use. The fluid tip may have one aperture (e.g. a hole, a pore, an opening etc.) or it may have more than one aperture, and may have many apertures, to allow the fluid to enter the epidermis into which the tip penetrates.

Alternatively, the microneedle may be used to provide a microchannel in the skin of the patient through which the fluid may be administered to the patient. Thus a microneedle array may be applied to the skin such that the microneedles of the array penetrate a region of the skin. For this method of administering the fluid, it is not important whether the array has array channels, or whether the microneedles have microneedle channels. Commonly the array will be left in the skin for a period of time before withdrawing it and applying the fluid to at least a portion of the skin of the patient The period may be at least about 5 seconds, or at least about 10, 20, 30, 40, 50 or 60 seconds, and may be between about 5 seconds and about 30 minutes, or between about 10 seconds and 10 minutes or between about 5 seconds and 10 minutes, 5 seconds and 1 minute, 1 and 30 minutes, 5 and 30 minutes, 10 and 30 minutes, 10 seconds and 1 minute or 1 and 10 minutes. The period may be about 5, 10, 15, 20, 25, 30, 40 or 50 minutes or about 1, 2, 3, 4, 5, 10, 15, 20, 25 or 30 minutes, or may be more than 30 minutes.

Insertion of the array into the skin of the patient may be painless, or largely painless, to the patient.

A plurality of microneedles may be assembled or formed on a base to provide a microneedle array. The array may therefore comprise a base having a first and a second side, and a plurality of microneedles extending from the first side. The microneedles in the array may extend substantially orthogonally from the base thereof. In one form of the invention the array may comprise a base having a plurality of holes, and a plurality of microneedles extending from a first side of the base such that each hole in the base communicates from the first side of the base to a second side of the base and communicates with the continuous microneedle channel of one of the microneedles. In use, fluid entering a hole from the second side of the base passes through continuous microneedle channel with which it communicates, and exits the aperture of the tip of the microneedle through which the continuous microneedle channel passes, in order to administer the fluid to the patient.

The number of microneedles in an array according to the invention may depend on the nature of the patient. Thus for a larger patient (e.g. an elephant) a larger array may be used. An array (e.g. for a human patient) may have between about 10 and 500 microneedles, or may have more than 500 microneedles, e.g. about 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000. It may have between about 10 and 200, 10 and 100, 10 and 50, 50 and 500, 100 and 500, 200 and 500, 50 and 200 or 100 and 200, and may have about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 microneedles. The distance between each microneedles in an array may be between about 50 and 500 microns, and may be between about 50 and 200, 50 and 100, 100 and 500, 300 and 500, 100 and 400 or 100 and 300 microns, and may be about 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 microns, or may be less than 50 microns or more than 500 microns. The microneedles may be arranged in the array in a regular or an irregular fashion. They may be arranged in an orthogonal arrangement, a rectangular arrangement, a triangular arrangement, a linear arrangement or some other arrangement. Each microneedle in the array may be between about 50 and 150 microns in length. If a rectangular or orthogonal arrangement us used, each side of the array may, independently, have between about 2 and 200 microneedle, or between about 2 and 100, 2 and 50, 2 and 10, 10 and 200, 20 and 200, 50 and 200, 100 and 200, 10 and 100, 10 and 50, 10 and 20 or 20 and 50 microneedles, and may have about 2, 3, 4, 5, 6, 7, 8, 9, 01, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 microneedle. The microneedles in an array may be all the same length or they may be different lengths. The mean length of the microneedles in an array may be between about 50 and 150 microns, or between about 50 and 100, 100 and 150 or 75 and 125 microns, and may be about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 or 150 microns.

The microneedle array of the invention may be incorporated into a fluid administration apparatus, wherein the apparatus comprises an array coupled to a fluid reservoir capable of holding the fluid, such that, in use, under the influence of capillary force, the fluid can pass through the array, and into the skin of a patient to which the apparatus is applied and diffuse into the skin. In such an apparatus, the array should be such that it has array channels which extend from the second side of the base through the base and the microneedles to allow passage of a fluid through the array. The array may be sealed to the reservoir such that the fluid can not exit the reservoir except through continuous array channels. Thus the fluid administration array of the invention may be coupled to a fluid reservoir capable of holding the fluid. The administration of the fluid to the patient may be for the treatment of a condition, e.g. a disease, in the patient. The disease may be for example diabetes, HIV or cancer. The administration may be for the purpose of vaccination.

The microneedle array of the present invention may be made from a precursor array comprising a base having a first side and a second side and a plurality of microneedle precursors extending from the first side of the base. The microneedle precursors may extend substantially orthogonally from the base thereof. The precursor array may have a similar overall shape to the array of the present invention. Thus in one form of the invention the precursor array comprises a base having a plurality of holes therein, each hole communicating from a first side of the base to a second side of the base. In one embodiment of the invention, the base and the microneedles are fabricated from silicon and form an integral precursor array. The silicon may be single crystal silicon. The silicon may be of a purity comparable to that of silicon used in integrated circuits. It may have impurities, on a molar basis, of less than about 10^"'%, or less than about 10^"2, 10^'3 or 10^"Vo, or between about 10^"1 and 10^"Vo, 10^"2 and \Q^Λ%, 10^"3 and ΪO^A% or 10^"1 and 10^"3%. Thus it may have a purity of about 99.9%, 99.95%, 99.99%, 99.995%, 99.999%, 99.9995% or 99.9999% or greater than 99.9999%.

The process then comprises providing a protecting substance to the first side of the base, such that a tip portion of each microneedle precursor distal to the base is exposed (i.e. not coated by, protected by or in contact with the protecting substance) and the remainder of each microneedle precursor and the first side of the base are coated by (i.e. protected by or in contact with) the protecting substance. Following this, the exposed tip portion of each of the microneedle precursors is converted into a biodegradable microneedle tip. Each microneedle tip may or may not have a microneedle tip channel therethrough, such that the microneedle tip channel communicates with a microneedle body channel to form a microneedle channel through the array for the administration of the fluid to the patient. The biodegradable tips may have the same shape as the tip portions or they may have a different shape. The conversion of the exposed tip portion of the microneedle precursors may convert the tip portions from a form in which they are not biodegradable, or in which they are only slowly biodegradable, into a form in which they more rapidly biodegradable. Thus, for example, the tip portions before conversion, if inserted into the skin of a patient, may not be converted to a soluble form(s) (i.e. biodegraded) to a substantial degree within about 4 weeks, or within about 5, 6, 7, 8, 9 or 10 weeks. By contrast, after conversion, the biodegradable tips may be converted to a soluble form(s) within about 3-4 weeks or less, as described elsewhere herein. For example, if the tip portions comprise single crystal silicon they may be only slowly biodegraded in vivo, whereas, following conversion to biodegradable microporous silicon tips, they may be more rapidly biodegraded. The conversion may comprise etching the tip portions. Following the conversion, a biodegradable tip may comprise less material than was present in the tip portion from which it was formed. This may lead to more rapid biodegradation when inserted into the skin of a patient. Following the conversion, a biodegradable tip may be porous, e.g. microporous, and may therefore have a higher surface area than the tip portion from which it was formed (i.e. the conversion may comprise increasing the surface area of the tip portion). This may lead to more rapid biodegradation when inserted into the skin of a patient. The protecting substance is applied to the precursor array such that the tip portions are exposed, in order that the tip portions may be subsequently converted into biodegradable microneedle tips. This may be achieved by applying the protecting substance to the first side of the base and the microneedle precursors so that the first side and the microneedle precursors are completely covered by the protecting substance, and then removing the protecting substance from the tip portion of each microneedle precursor distal to the base, i.e. exposing said tip portions. The layer of protecting substance may be between about IOnm and 1 micron thick. It may be between about 10 and 500 nm thick, or 10 and 200, 10 and 100, 10 and 50, 50 and 500, 100 and 500, 200 and 500 or 100 and 200nm thick, or between about lOOnm and 10 micron or 500nm and 1 micron thick, and may be about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800 or 900nm thick or may be 1 micron or more thick. In order to selectively remove the protecting substance from the tip portions, a coating substance may be applied to the protecting substance so that the protecting substance covering the first side and the microneedle precursors are completely coated by the coating substance, and then a portion of the coating substance may be selectively removed so as to expose the protecting substance in contact with the tip portions. The selective removal process may depend on the nature of the protecting substance and of the coating substance. The coating substance may be applied to a thickness that is comparable to or less than the length of the microneedle precursor. It may be applied to a thickness of between about 50 and about 140 microns, or between about 50 and 120, 50 and 100, 50 and 80, 80 and 140, 100 and 140, 120 and 140, 80 and 120, 80 and 100 or 100 and 120, and may be applied to a thickness of about 50, 60, 70, 80, 90, 100, 110, 120, 130 or 140 microns, or may be applied to a thickness of less than about 50 microns or of greater than about 140 microns. The thickness of the coating substance may depend on the length of the microneedle precursors. The exposed protecting substance is then subjected to conditions sufficient to remove the protecting substance from the tip portions, but not sufficient to remove the coating substance. This may expose the tip portions of the microneedles. These conditions will depend on the nature of the protecting substance and of the coating substance. After the step of subjecting the exposed protecting substance, i.e. after exposing the tip portions, the coating substance may be removed, for example by dissolving the coating substance in a suitable solvent. The solvent may be a solvent for the coating substance and a non-solvent for the protecting substance. It may be an organic solvent, and may be, for example, acetone, ethyl acetate, toluene, xylene, benzene, chloroform, methylene chloride, diethyl ether, methyl ethyl ketone or some other suitable solvent.

The protecting substance may be for example silicon nitride. It may be applied using chemical vapour deposition (CVD), for example low pressure CVD (LPCVD). The coating substance may be a photoresist, and may be a positive photoresist, for example AZ9620. The coating substance may be applied by spin coating or spray coating. The step of removing the coating substance may comprise reflowing the coating substance and/or exposing the coating substance to a plasma, for example an oxygen plasma, and may comprise plasma etching. The conditions sufficient to remove the protecting substance may comprise using a dry reactive ion etching process, for example in trifluoromethane/oxygen.

The step of converting the tip portions of the microneedle precursors into biodegradable microneedle tips may comprise an anodisation process. In an example of this process, the base of the precursor array is connected to one electrode (the anode). The other electrode (the cathode) may be for example a platinum mesh with about the same size as the base. The electrolyte, located between the electrodes, may comprise for example diluted hydrofluoric acid. The electrolyte may be a mixture of aqueous hydrofluoric acid and an organic solvent. The organic solvent may be a water miscible organic solvent, such as dimethylsulfoxide (DMSO), dimethylformide (DMF) or acetonitrile (MeCN). The concentration of hydrogen fluoride in the electrolyte may be between about 1 and 20 wt%, or between about 1 and 10, 1 and 5, 5 and 10, 5 and 20, 3 and 20, 1 and 17, 3 and 17, 5 and 17, 10 and 17 or 3 and 19wt%, e.g. about 1, 2, 3, 4, 5, 6,

7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20%. A voltage may then be applied between the two electrodes such that the precursor tip portions of the precursor array act as anodes and the platinum mesh acts as a cathode. On applying the voltage between the precursor tip portions as anodes and the platinum mesh cathode, a current passes between the precursor tip portions and the cathode via the electrolyte, thereby converting the precursor tip portions into biodegradable microneedle tips, which may be microporous. The current may be between about 1 and 100mA, or between about 1 and 50, 1 and 20, 1 and 10, 1 and 5, 5 and 100, 10 and 100, 20 and 100, 50 and 100, 2 and 50, 5 and 50, 10 and 50, 20 and 50 or 10 and 2OmA, for example about 1, 2, 3, 4, 5, 6, 7, 8 ,9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90- or 100mA, or more than 100mA. The time required for conversion of the tip portions into biodegradable microneedle tips may be between about 0.1 and 20 minutes, or between about 0.5 and 20, 1 and 20, 5 and 20, 10 and 20, 0.5 and 10, 0.5 and 1, 1 and 10 or 2 and 5 minutes, e.g. about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1,5 16, 17, 18, 19 or 20 minutes, or may be more than 20 minutes.

By varying the current density, different pore sizes may be achieved in the microneedle tips. The process may additionally comprise removing the protecting substance after converting the tip portions into biodegradable microneedle tips. For example a silicon nitride protecting substance may be removed using H₃PO₄ (orthophosphoric acid) or other suitable method. This may be accomplished at elevated temperature, for example in a heated tank at a temperature between about 150 and about 200⁰C, or between about 150 and 180, 150 and 160, 160 and 200, 180 and 200 or 160 and 18O⁰C (e.g. at about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 200⁰C).

Thus an example of a process according to the present invention is illustrated in Fig.

8, in which the main steps are exemplified by the following: a) generation of microneedle profile, b) LPCVD S1₃N₄ deposition, c) photoresist spin-coating d) photoresist etching in O₂ plasma, e) etching of S13N₄ layer from unprotected regions of the tips f) etching of LPCVD Si₃N₄ from the back side of the wafer, g) removing of photoresist h) porous silicon generation. Thus Fig. 8a shows a precursor array 5 as described above. The array comprises base 10. Precursor array 5 also comprises a plurality of silicon microneedle precursors 25 extending from first side 15. Microneedle body 30, which is proximal to base 10 and distal tip portion 35 of silicon microneedle precursor 25 are indicated. In Fig. 8b, a silicon nitride layer 40 is applied to first side 15 and silicon microneedle precursors 25 of precursor array 5. In Fig. 8c photoresist 45 is applied to silicon nitride layer 40. In Fig. 8d photoresist 45 has been partially removed in order to expose silicon nitride layer 40 in contact with tip portions 35. Microneedle bodies 30 and first side 15 remain covered by photoresist 45. In Figs; 8e and f, exposed silicon nitride layer 40 is subjected tp a dry RIE process in order to remove it from tip portions 35 (e) and the second side of array 5 (f). In Fig. 8g, photoresist 45 is removed from the array. In Fig. 8h, each tip portion 35 is converted into a porous silicon tip 50 using an anodisation process, thereby forming a microneedle array comprising base 10 and a plurality of microneedles extending therefrom, each of said microneedles comprising a microneedle body 30 and a biodegradable tip 50.

The microneedle array of the present invention may be used to administer a fluid, e.g. a liquid, to a patient. The administering may be in order to treat or alleviate a condition in the patient, for example by administering a drug to the patient. In order to administer the fluid to the patient, the array (i.e. the microneedles of the array) may be inserted into the skin of the patient. Commonly the microneedles are not sufficiently long that this insertion causes substantial pain to the patient. If the array has array channels, the fluid may be administered through the array while it is inserted in the skin of the patient. Commonly the array channels are hydrophilic, so the fluid may be drawn into the array by capillary action and diffuse from the microneedles of the array into the skin of the patient Alternatively the array may be withdrawn and the fluid applied to the skin of the patient. In this case the array may or may not have array channels. The array may leave microfluidic channels in the skin of the patient, and when the fluid is applied to the microfluidic channels in the skin, it may penetrate the stratum corneum and enter the patient. Commonly in order to form the microfluidic channels in the skin of the patient, it is useful to leave the array in the skin of the patient for a period of time before it is withdrawn. The period may be at least about 5 seconds, or at least about 10, 20, 30, 40 or 50 seconds or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or 30 minutes and may be between about 5 seconds and about 30 minutes, or between about 10 seconds and 10 minutes or between about 5 seconds and 1 minute, 5 and 30 seconds, 5 and 20 seconds, 10 and 20 seconds, 1 and 30 minutes, 5 and 30 minutes, 15 and 30 minutes, 30 seconds and 5 minutes, 30 seconds and 2 minutes or 30 seconds and 1 minutes, e.g. about 5, 10, 15, 20, 25, 30, 40, 50 or 55 seconds, or about 1, 2, 3, 4, 5, 6, 7, 8, 9 10, 15, 20, 25 or 30 minutes. The microneedle array is then withdrawn from the skin of the patient. If, in the process of withdrawal (or insertion) one or more tips 50 breaks off and lodges in the skin of the patient, it will be degraded and/or dissolved in 2 to 3 weeks by the body fluid of the patient. Because the residence time of biodegradable tip 50 in the body is relatively short (2 to 3 weeks) the risk to the patient of an associated infection is low. EXAMPLE

A fabrication process for microneedles with isotropic profile is described in Figure 8. The first step consists of generation of a wafer having a microneedle profile, using an RIE process (Figure 8a). For this step a SiO₂ PECVD layer was used as mask. After removing the mask in a classical BOE solution, a SIsN₄ -LPCVD layer was deposited on the wafer surface (Figure 8b). A thick layer of photoresist AZ9620 was spun on the surface with the microneedles (Figure 8c). In order to release the tips of the microneedles the photoresist was reflowed, and after this an O₂ plasma etching process was performed (Figure 8d). In this way the top part of the needles were free of photoresist enabling removal of the exposed SiaN₄ layer using a dry RBE process in CHF3/O2 (Figure 8e). After removing SIsN₄ from the back of the wafer (for contact) using the same process (Figure 8f) the photoresist was removed from the front (Figure 8g) and porous silicon was generated using a classical anodization process (Figure 8h).

Thus the main steps in the fabrication of microneedles with biodegradable tips are: a) Generation of microneedles profile, b) LPCVD SisN₄ deposition, c) Photoresist spin- coating d) Photoresist etching in O₂ plasma, e) Etching of SisN₄ layer from unprotected regions of the tips f) Etching of LPCVD SisN₄ from the back side of the wafer, g) Removing of photoresist h) Porous silicon RESULTS

Figure 9 shows the results of fabrication process: two SEM images of microneedles: top view (left image) and side view (right image). CONCLUSIONS

The present specification discloses a solution to problems relating to transdermal drug delivery using microneedles array with biodegradable tips fabricated by porous silicon. By using the microneedle array produced as described above, the permittivity of the skin was improved by about 3-4 orders of magnitude.

Claims

G2006/00006927Claims:

1. A microneedle comprising:

- a microneedle body; and

- a biodegradable microneedle tip.

2. The microneedle of claim 1 wherein the biodegradable tip comprises porous silicon.

3. The microneedle of claim 1 wherein the microneedle body comprises a nonbiodegradable material.

4. The microneedle of claim 1 wherein microneedle body comprises silicon.

5. The microneedle of claim 1 having a length of between about 50 and about

150 microns.

6. The microneedle of claim 1 having a length such that, when fully inserted into the skin of a patient, the biodegradable tip is in the epidermis of the patient.

7. The microneedle of claim 1 wherein the microneedle body comprises a microneedle body having a microneedle body channel therethrough, and the biodegradable microneedle tip defines an aperture proximate the end of said tip and has a tip channel therethrough which communicates with said aperture, wherein said tip channel communicates with the microneedle body channel to form a continuous microneedle channel through the microneedle for the administration of a fluid to a patient.

8. The microneedle of claim 7 wherein the tip channel comprises an open porous structure.

9. A microneedle array comprising a base having a first side and a second side, and a plurality of microneedles extending from the first side of the base, each of said microneedles comprising a microneedle body and a biodegradable microneedle tip.

10. A microneedle array according to claim 9 wherein:

- the base has a plurality of holes therein, each hole communicating from the first side of the base to the second side of the base, and

- each of the microneedles of the array comprises a microneedle body having a microneedle body channel therethrough, and a biodegradable microneedle tip defining an aperture proximate the end of said tip and having a tip channel therethrough which communicates with said aperture, wherein said tip channel communicates with the microneedle body channel to form a continuous microneedle channel through the microneedle, wherein each of the holes has one of the microneedles associated therewith, the microneedle channel of said microneedle being in communication with the hole such that the hole and the microneedle channel form a continuous array channel extending from the first side of the base to the biodegradable tip such that, in use, fluid entering the hole from the second side of the base passes through the microneedle channel and exits the aperture of the tip of the microneedle in order to administer the fluid to a patient.

11. The microneedle array of claim 9 wherein the base is planar.

12. The microneedle array of claim 9 wherein the base comprises the same material as the bodies of the microneedles.

13. The microneedle array of claim 9 wherein the microneedles are integral with the first side of the base.

14. A process for making a microneedle array for administration of a fluid to a patient, said process comprising:

• a plurality of microneedle precursors extending from the first side of the base;

- providing a protecting substance to the first side of the base, such that a tip portion of each microneedle precursor distal to the base is exposed and the remainder of each microneedle precursor and the first side of the base are coated by the protecting substance; and

- converting each exposed tip portion into a biodegradable tip.

15. The process of claim 14 wherein the microneedle precursors are integral with the first side of the base.

16. The process of claim 14 wherein the base and the microneedle precursors comprise silicon.

17. The process of claim 14 wherein the step of providing the protecting substance comprises:

- removing the protecting substance from the tip portion of each microneedle precursor distal to the base.

18. The process of claim 17 wherein the step of removing the protecting substance from the tip portions comprises:

- applying a coating substance to the protecting substance so that the protecting substance covering the first side and the microneedle precursors is completely ^■ coated by the coating substance,

- removing a portion of the coating substance so as to expose the protecting substance in contact with the tip portions, and

- subjecting the exposed protecting substance to conditions sufficient to remove the protecting substance from the tip portions, but not sufficient to remove the coating substance.

19. The process of claim 18 additionally comprising removing the coating substance after subjecting the exposed protecting substance to conditions sufficient to remove the protecting substance from the tip portions.

20. The process of claim 14 wherein the protecting substance is silicon nitride.

21. The process of claim 17 wherein the protecting substance is removed using a dry reactive ion etching process.

22. The process of claim 18 wherein the coating substance is a photoresist.

23. The process of claim 18 wherein the step of removing the coating substance comprises plasma etching.

24. The process of claim 14 wherein the step of converting the exposed tip portions into biodegradable tips comprises an anodisation process.

25. The process of claim 14 additionally comprising removing the protecting substance after converting the exposed tip portions into biodegradable tips.

26. A microneedle array when made by a process comprising: - providing a precursor array comprising:

• a base having a first side and a second side; and

- converting each exposed tip portion into a biodegradable tip.

27. A fluid administration apparatus for administration of a fluid to a patient, comprising:

- a microneedle array according to claim 10; and

- a fluid reservoir coupled to the second side of the base of the array and capable of holding the fluid; wherein the fluid is capable of passing from the reservoir through the array channels of the array and exiting the array through the biodegradable tips.

28. A method for administering a fluid to a patient, comprising:

- applying a fluid administration apparatus according to claim 27 to the skin of the patient; and

- passing the fluid from the reservoir through the fluid administration channels of the array into the skin of the patient.

29. A method for administering a fluid to a patient, said method comprising:

- applying a microneedle array according to claim 9 to a region of the skin of the patient, thereby creating microchannels in said region;

- withdrawing the microneedle array from the skin of the patient; and

- applying the fluid to at least a portion of the region of the skin; whereby the fluid penetrates at least some of the microchannels and enters the skin of the patient.

30. A method for administering a fluid to a patient, said method comprising:

- applying a microneedle array according to claim 10 to a region of the skin of the patient such that the microneedles of the array penetrate the skin of the patient; and

- applying the fluid to the second side of the base of the microneedle array; thereby allowing the fluid to pass through the array channels of the array and into the skin of the patient.

31. A method for treating a condition in a patient comprising administering a fluid to the patient using a microneedle array according to claim 9 or a fluid administration apparatus according to claim 27, said fluid being indicated for the treatment of the condition.

32. The microneedle of claim 1 wherein the biodegradable microneedle tip is coupled to or integral with the microneedle body.

33. The microneedle array of claim 9 wherein each of the microneedles comprises a microneedle body and a biodegradable microneedle tip wherein said biodegradable microneedle tip is coupled to or integral with said microneedle body.