ES2357079T3 - PROCEDURE OF PRODUCTION OF A MICRO-NEEDLE OR A MICROIMPLANT. - Google Patents

Abstract

A method of manufacturing a microneedle or microimplant, the method comprising (i) the deposition of a substance on a first surface (1, 11, 31, 41) and (ii) the formation of a solid needle form (52a, 52b ) from the substance characterized in that step (i) comprises depositing a first discrete part (32, 51a, 51b) or droplet of substance on the first surface.

Description

The present invention relates to a method of producing microneedles or microimplants, for use in particular, but not exclusively, in the pharmaceutical industry.

The transdermal administration of drugs is an important route for pharmaceutical active substances, 5 but the outer layer of skin, the 10 to 20 micrometer thick layer called the stratum corneum, is an effective barrier for many chemical entities. Therefore, the number of pharmaceutically active materials that can penetrate the body through the skin is very limited, and is defined by factors such as polarity, logP and molecular size. At the same time, many drugs that are not suitable for oral administration are being synthesized (for example, due to instability in the gastrointestinal tract, or the first step of liver metabolism). Therefore, the skin is an attractive route, although problematic, for the administration of these drugs, as well as drugs that act on the skin, but may have systemic side effects.

Several procedures have been developed to compromise the skin's barrier function to allow drug penetration, and to extract analytes (for monitoring purposes), from the body. They include sonophoresis, iontophoresis and microneedles. US-3,964,482 describes the use of microneedles to aid in the administration of drugs through the skin. The microneedles pierce the stratum corneum, allowing the passage of a drug to the subject but preferably without inducing a painful response because the microneedles do not penetrate the dermal layer of the skin that is provided with nerve cells.

Several procedures for the manufacture of microneedles have been proposed. US-6,558,361 and WO-2004 / 035,105 disclose the use of photolithography to produce microneedles. Document US-20 2002 / 0.020.688 discloses a process for manufacturing microneedles according to the preamble of claim 1 comprising the deposit of a polymer layer which is allowed to be combed on a network of columns. WO-2004 / 062,899 discloses the formation of microneedles using a mold. Other manufacturing procedures for needles and dies include etching techniques, thermal oxidation of silicon, League, stereolithography, laser machining and laser ablation. 25

Normally, such procedures are time consuming and require expensive facilities to manufacture microneedles. For example, molding presents other problems, such as the fact that the quality of the microneedles is limited by the quality of the die and the lifetime of the mold. In addition, the molds present problems in the case where the needles have a high height-width ratio; such molds may be difficult to fill and the microneedles formed by the mold may not be easily released. The present invention seeks to mitigate at least one or more of the problems of the prior art.

According to a first aspect of the present invention there is provided a method of manufacturing microneedles or microimplants, the process comprising

(i) the deposit of a substance on a first surface and

(ii) the formation of a solid needle form from the substance,

characterized because

step (i) comprises depositing a discrete first part or droplet of substance on the first surface.

This provides an effective and generally cheap procedure to produce microneedles.

This facilitates, for example, the sequential deposition of parts or droplets to produce microneedles, or 40 needle-like structures that will be extracted from a part or droplet.

The first surface is preferably a solid surface, although it may be a non-solid surface.

Step (i) may comprise the deposition of the substance in a non-solid form. Said non-solid substance may flow or be susceptible to flow.

The substance in its non-solid form may be, for example, in the form of a liquid, gel, emulsion, cream, paste or thixotropic material. It should be noted that the substance in non-solid form may comprise solids, for example, in the form of particles. These particles can be suspended or dispersed in a vehicle so that the substance by volume is not solid.

Step (i) may comprise the deposition of the substance in solid form. These substances may not flow. An example of such a step may include the deposition of a solid substance by laser printing. fifty

In the event that the substance is deposited on the first surface in a non-solid form, the formation stage

Solid from the substance may include, for example, exposure of the substance to ultraviolet radiation to form a solid polymer, loss of solvent to form a solid and hardening over time (for example, when the non-solid substance comprises an epoxy resin in two parts that, over time, hardens to form a solid). The solid needle type structure may not have (and more likely, will not have) the same chemical composition as the non-solid substance. 5

Step (ii) may comprise depositing a second part or droplet of substance on the first part or droplet of substance. Thus, a needle-like structure is allowed to be formed by the deposit of one part of substance over another. This also allows the rapid production of needle-type structures using automatic liquid deposition technology.

If the first part or droplet is deposited in a non-solid form, then it is preferred that the first part or droplet be at least partially solidified before the deposit of the second part or droplet of substance. Partial solidification of the first part or droplet of substance may include exposure of the first part or droplet to electromagnetic radiation, for example, or simply waiting a predetermined time before the deposit of the second part or droplet.

One or both parts of the first and second substance can be deposited in solid form. This would facilitate the production of microneedles using certain printing techniques, such as laser printing.

It is preferred that the volume of the second droplet or part be smaller than the volume of the first droplet or part. This facilitates the production of needle-type structures.

Needle-like structures can be constituted by sequential deposition of droplets or parts of substance each on top of the previous one. twenty

Step (ii) may comprise the sequential deposition of a plurality of parts or droplets of substance on the first part or droplet. If one or more of the parts or droplets are deposited in a non-solid form, it is preferred that said one or more parts or droplets be solidified at least partially before depositing an additional part or droplet of substance thereon. If one or more of the parts or droplets are deposited in non-solid form, it is preferred that each of the parts or droplets be deposited in non-solid form. This facilitates the production of 25 needle shapes. In this case, it is preferred that the volume of the additional part or droplet be smaller than the volume of the immediately underlying part or droplet in the deposit of the immediately underlying part or droplet.

Additionally, or as an alternative, to the deposition in sequence of droplets or parts as described above, step (ii) may comprise the supply of a second surface that is in contact with the substance (preferably not solid) and the movement of the first surface and the second surface with respect to each other 30 to form a needle shape. This needle extraction is especially advantageous when the substance is in non-solid form. Needle extraction is relatively easy to achieve and also lends itself to a fast and automated procedure. For example, the process of the present invention may comprise the deposit of one or more parts of substance using the sequence-deposited procedure as described above and then extracting a needle shape from said substance. 35

Step (i) may comprise the supply of a part or droplet of non-solid substance on the second surface, and the movement of the second surface in proximity to the first surface so that the droplet or part of non-solid substance comes into contact With the first surface. The supply of a part or droplet of non-solid substance on the second surface can be achieved, for example, by providing the non-solid substance in a reservoir and contacting the second surface with the non-solid substance in the reservoir. Thus, the second surface is allowed to take the substance from a reservoir and deposit it on the first surface before needle removal. Alternatively, the second surface may be associated with an opening or gauge through which the non-solid substance is passed so that the substance is deposited (possibly as a discrete part or droplet) on the second surface.

Alternatively, step (i) may comprise the deposition of the non-solid substance on the first surface in the absence of the second surface. The non-solid substance can be deposited in the form of a droplet or part.

As a further alternative, step (i) may comprise placing the second surface in proximity to the first surface and subsequently supplying the non-solid substance on the first surface so that it forms a contact between the non-solid substance and the second surface. This could be achieved by introducing the substance through an opening provided at or in proximity to the first surface or an opening provided at or in proximity to the second surface.

The second surface can be provided by a solid or a liquid.

When the process of the present invention comprises the movement of the second surface in relation to the first surface, step (ii) may comprise the steps in sequence of (a) movement of the first surface and the second surface one with respect to the other to form a needle shape and (b) formation of

a solid needle shape. The contact between the substance and the second surface can be maintained during the formation of the solid needle shape. Alternatively, the second surface can be removed from the substance after stage (a) and before stage (b).

Step (ii) may comprise the formation of a solid needle shape while the first surface and the second surface move relative to each other. 5

The deposit of the substance can be achieved using a printing procedure, such as a deposit based on a stencil template, contact printing (for example, needle transfer) and other printing procedures such as recording, transfer printing, electronic printing including the Xerographic and laser printing, bubble printing or inkjet, flexography, magnetography and direct loading deposit. Such procedures may conveniently be used to deposit a first part or droplet 10 of substance (in solid or non-solid form). They can be conveniently used for the sequential deposition of a plurality of parts or droplets on one another so that the needle shape is formed.

If the droplets or parts are deposited in a non-solid form, then it is preferred that a part or droplet be solidified at least partially before the deposit of an additional part or droplet of substance thereon.

Step (i) may comprise the supply of a stencil template comprising at least one opening, and the deposition of the substance (preferably in non-solid form) through the at least one opening on the first surface. The deposition of the substance (preferably in a non-solid form) through the at least one opening can be achieved by pushing the substance into the at least one opening (as opposed to allowing the substance to pass spontaneously through the at least one opening) . This can be achieved, for example, by depositing the substance in the stencil template and sweeping the substance through the stencil template and through the at least one opening.

Step (ii) may comprise the movement of the stencil template with respect to the first surface, thus forming a needle shape. In this way, the stencil template is acting as the second surface referred to above. The needle shape can be solidified as described elsewhere in the present specification. 25

Alternatively, step (ii) may comprise the movement of the stencil template with respect to the first surface, the first surface approaching a second surface so that the second surface comes into contact with the substance, and the movement of the second surface with respect to the first surface so that a needle shape is formed.

Step (ii) may comprise the supply of a stencil template comprising at least one opening, and the deposition of a plurality of parts or droplets of substance (preferably in non-solid form) through the at least one opening of the stencil template. If a part or droplet is deposited in a non-solid form, it is then preferred that said part or droplet be solidified at least partially before the deposit of an additional part or droplet of substance therein. This can be achieved, for example, by the deposition of substance in a non-solid form on the stencil template, the sweep of the substance over the at least one opening, the movement 35 of the stencil template and the first surface moving away from each other, the solidification of the substance, the approximation of the stencil template to the first surface, and then the sweep of the substance in a non-solid form over the at least one opening.

The deposition of a part or droplet of substance can be done by one or more between inkjet printing, screen printing or micropipette. Such procedures can be conveniently used to quickly produce microneedles and micro-needle networks.

The deposition of the substance (and preferably a part or droplet of non-solid substance) can be carried out by means of an automated handling system. The automated handling system may employ one or more between piezo valves, solenoid valves, syringe pumps, microelectromechanical devices or means of displacement of air or other gas. These constitute convenient means to control the deposition of substance, especially if the substance must be deposited in parts or droplets.

The substance can be deposited by means of a microgrid forming device or another automated contact printing device. These constitute convenient means to control the deposition of the substance, especially if the substance must be deposited in parts or droplets.

The first surface may be part, or a precursor, of a transdermal patch. fifty

The solid needle shape may comprise one or both of organic or silicone polymers, including epoxy resins, acrylic polymers and silicone resins.

Alternatively or additionally, the solid needle shape may comprise a metal, such as titanium. The solid needle shape may comprise a mixture of a metal and nonmetals (such as silica). The needle may comprise silicon (for example, porous silicon), a ceramic or a mineral. 55

The solid needle shape may comprise silica.

Additional preferred materials include UV radiation curable plastics such as acrylates, urethane acrylates and bioabsorbable or biodegradable materials such as polylactides. Combinations of any material can be used to form the needle. For example, the base of a needle could be made of acrylate polymers, with one or more different strata of other materials, such as polylactides, or materials with special characteristics such as ease of breakage to allow the tip of a needle to remain in the organism.

The process may comprise inserting an elongate shaper into the substance before solidification so that a groove or needle-shaped gauge is formed. Said groove may be useful for supplying fluids through the needle into the subject or article into which the needle can be inserted.

The solid needle shape can be porous. A porous needle can be formed, for example, between one or more 10 of causing a gas to pass through the needle shape during its formation; providing a substance that spontaneously forms a solid needle shape having a porous structure; provide the substance with a component that can be extracted (by dissolution, combustion or others) from the solid needle shape, and provide a substance that, during the formation of a solid needle shape, forms a porous fiber mesh. Said porosity can be useful for supplying fluids through the needle into the subject or article in which the needle can be inserted. fifteen

The process may further comprise the introduction of a doping agent into the substance so that the doping agent is released from the resulting solid at a later time.

Step (i) or (ii) may comprise the deposition of a catalyst or other reaction promoter. For example, a catalyst could be deposited to harden the substance first on the first surface, and deposit the substance in a non-solid form on the top of the catalyst. The catalyst would begin to harden the substance with contact.

The needle shape can be totally or partially biodegradable.

The needle shape must be easily separated from the first surface. This can facilitate the transfer of the needle from the first surface to an additional surface. It may be desirable that the needle shape can be easily detached in use. 25

The solid needle shape can be easily broken to produce a first part associated with the first surface and a second dissociated part.

The step of forming a solid needle form from a non-solid substance may comprise one or more of cooling the substance, heating the substance, waiting for a given period or exposing the non-solid substance to electromagnetic radiation (normally, radiation ultraviolet). If the substance cools, it can cause the substance to spontaneously form a solid. If heated, the solvent can be expelled from the substance, thus forming the solid needle shape. If the substance is exposed to electromagnetic radiation, the formation of a solid can be caused, for example, if the non-solid substance is in the form of a UV-curable resin or adhesive. If a given period is expected, the formation of a solid can be caused if, for example, the substance in its non-solid form is an epoxy resin in two parts. 35

The needles may be approximately 10 micrometers to 3 mm in length, preferably more than 100 micrometers in length and more preferably less than 1 mm in length. The most preferred length is about 200 to 400 micrometers. Said projection length minimizes the possibility that a projection reaches the dermis that is provided with nerves that generate a painful response. The preferred length may vary depending on the biological layer that is intended to be perforated by the projections. For example, mucosal layers 40 may require projections of different length than the stratum corneum. In addition, if the microneedle is intended to pierce the stratum corneum of a human subject, then the preferred length of the microneedle may depend on the anatomical site at which the microneedle is intended to be used since the thickness of the stratum corneum may vary between sites. different anatomical

Most preferably, the microneedle is capable of piercing a biological barrier, most preferably the stratum corneum of a human being or an animal. In addition, the process is preferably a process for forming a device for drilling a biological barrier.

The first surface is preferably provided with a substrate that is part of a transdermal patch. Alternatively, the first surface may be provided with paper, glass, plastic, an adhesive dressing film, metal and the adhesive side of a pressure sensitive adhesive tape. fifty

The solid needle type structure may include a pharmaceutically active material. This can be achieved by introducing the pharmaceutically active material into the liquid before solidification or after solidification.

The first surface on which the needle-shaped structure of the present invention can be formed can be provided with columns, projections or the like. Therefore, the process of the present invention can

used to make microneedles with pre-existing protruding or needle-like structures.

The solid needle shape can be conical. The solid needle shape can be pyramidal (for example, with three or four sides that converge at one point). The solid needle shape can be curved. This can be achieved, for example, by using the needle removal procedure mentioned above and by moving the first and second surfaces together so that a curved shape is produced. The solid needle shape may be provided with a hook, for example, using the needle removal procedure mentioned above and by moving the first and second surfaces together so that a hook shape is produced.

According to an embodiment of the present invention a method of producing a microneedle network is provided, as defined in claim 14.

The process according to the second aspect of the present invention preferably does not involve the use of a mold.

Step (i) comprises depositing a network of first parts or droplets of substance on a first surface.

Step (i) may comprise the deposition of a substance in a non-solid or solid form.

The production of a network of droplets or parts can be achieved by serial deposition of droplets or 15 parts on the first surface. Alternatively, a network of droplets or parts corresponding to the microneedle network can be deposited simultaneously on the first surface.

Step (ii) may comprise depositing a network of second droplets or parts of substance on the network of first droplets or parts of substance. A network of third parties or droplets can be deposited on the network of second parties or droplets. As described above in relation to the production of only a microneedle, a network of needle-like structures can be developed by the deposition in sequence of droplets or parts of substance. The method used in relation to the network may incorporate the features described above in relation to the process of the first aspect of the present invention.

The substance may be deposited in a non-solid form and step (ii) may comprise the supply of a second surface in contact with the substance and the movement of the first surface and the second surface together to form a needle shape. Therefore, a network of needle-like structures can be extracted from the substance as described above with reference to the first aspect of the present invention. This substance can be deposited as discrete parts or droplets. Step (ii) may comprise the introduction of a network of second surfaces in contact with the non-solid substance and the extraction of the substance in a network of needle shapes. Alternatively, the microneedle structures can be extracted from the network of droplets or parts by introducing a second surface in contact with the network of parts or droplets and extracting the network of droplets or parts into a network of needle shapes. This can be achieved using a second single substantially flat surface.

Alternatively, one or more second surfaces can be used to sequentially extract needle shapes from the substance (optionally deposited as droplets or parts), the one or more second surfaces being able to move so that the needle network can be produced. 35

The method of the second aspect of the present invention may comprise the features described above with reference to the procedure of the first aspect of the present invention. For example, a stencil template can be used to provide a network, as described with reference to the first aspect of the present invention.

According to a third aspect of the present invention, there is provided a method of manufacturing 40 microneedles or microimplants, alone or in networks, using the deposition of a liquid on a solid surface with subsequent or concurrent hardening or other solidification in a needle shape. Solid, without the use of a mold.

The process of the third aspect of the present invention may comprise the features described above with reference to the procedure of the first aspect of the present invention.

A product obtained from the invention can be a device for application to a biological barrier, the device comprising a substrate provided with one or more microneedles made according to the process of the first, second or third aspects of the present invention. The device may comprise a first surface on which one or more microneedles has been deposited using a method according to the first, second or third aspects of the present invention. The first surface can be flexible. The device can be, for example, a transdermal patch. The device may comprise a sensor, a pump or a 50 drug delivery device. The device may be provided with a means to push the one or more microneedles into a biological barrier. The device may comprise an endovascular prosthesis for drug elution.

The invention will now be described by way of an example with reference only to the following schematic figures in which:

Figure 1 shows a first embodiment of the present invention that involves the extraction of a microneedle from a non-solid material;

Figure 2 shows a second embodiment of the present invention that involves the extraction of a microneedle from a non-solid material;

Figure 3 shows a third embodiment of the present invention involving the sequential deposition of 5 droplets of non-solid material to form a microneedle; Y

Figure 4 shows a fourth embodiment of the present invention that involves the use of a stencil template to sequentially deposit droplets of non-solid material on top of others to form a microneedle.

Next, a first embodiment of the process of the present invention is described with reference to Figure 1. In reference to Figure 1a, a droplet 2 of liquid is dispensed on a first surface 1 on which it is intended to form microneedles. The droplet 2 is preferably dispensed by an automated liquid handling means. A second surface 3 is carried to produce a needle shape to the droplet 2, whereby the second surface 3 is touching the surface of the droplet 2. In this case, the second surface is a solid surface, although a surface could be used liquid, for example a liquid surface formed by a liquid disposed at the end of a solid rod or needle. The second surface 3 is then moved away from the first surface 1, removing the liquid droplet 2 in a needle shape 4. The liquid is made to cure or solidify by other means in a microneedle 5 and then the second surface is removed 3.

The second surface 3 can be removed before hardening or solidification has taken place, or even during the hardening or solidification process. Removal of the second surface during hardening or solidification can produce especially sharp needles.

As an alternative for introducing the second surface 3 into the droplet 2 deposited on the first surface 1, the second surface 3 can be provided with the liquid and the liquid contacted with the first surface 1. Alternatively, the second surface 3 can be placed in proximity of the first surface 1 and the liquid dispensed so as to make contact with the first surface and the second surface. This can be influenced by providing a gauge associated with the second surface and dispensing the liquid through the gauge.

The relative movement of the first surface 1 and the second surface 3 is important and, therefore, the position of the second surface 3 can be fixed, with the first surface 1 moving to bring the second surface 3 into contact with the droplet 2.

The needle shape can be solidified by cooling or hardening. This can be done, for example, using a hardenable liquid, such as a UV curable acrylate adhesive, and exposing the liquid to UV light to harden the adhesive. The liquid can be an epoxy resin. In this case, the first surface can move relative to the second surface to produce an elongated structure. This elongated structure is allowed to solidify over time. The elongated structure is then cut to allow the second surface to be removed from the first surface. This cutting action causes the formation of a needle structure on the first surface. 35

A second example of the invention is described below with reference to Figure 2. An element can be used as a networking device to place the liquid on a surface so that it acts as a reservoir. A pin P of diameter 0.4 mm was fixed pointing downwards to a stationary support. A deposit of non-solid substance was moved from which the microneedle would be made (in this case, a point of commercially available UV hardened acrylate adhesive) in a translation phase so that the head of the pin P was submerged in the substance for three seconds to produce a droplet of liquid 12 in contact with the end of pin pin P. The solid surface 11 on which the microneedle would form moved toward the second surface 13 (provided by pin P) until the Liquid 12 present at the end of the pin touched the solid surface 11. The solid surface 11 was allowed to touch the pin covered with liquid so that the liquid 12 was allowed to form a point (see (b)). A UV source (a UV photo-emitting diode, not shown) supplies UV radiation to harden the liquid 12. During hardening, the solid surface 11 moves away from the second surface 13 in a controlled manner using the translation phase to produce a shape of needle 14 (see (c)). After hardening, the finished needle 15 is left on surface 1 (see (d)). This procedure produced a sharp needle structure approximately 400 microns high.

The needles were produced using a variety of solid surfaces, including paper, glass, plastic, a transdermal drug delivery patch, a semipermeable adhesive dressing film and the adhesive side of pressure sensitive adhesive tape. The use of pins of a larger diameter allowed the production of sharp needles of a height greater than 1 mm. The pins of a smaller diameter allowed the production of 250 250m high structures.

A third example of the process of the present invention is described below. 55 points of a viscous epoxy resin were dispensed on a first glass surface using contact printing. The first glass surface was then placed in a mobile phase in the z direction. The first approached

glass surface to a second fixed glass surface, so that the epoxy resin drops touched the second glass surface. The first and second glass surfaces slowly moved away during resin hardening, so that needle structures were removed from each surface. After 3 hours, the resin had solidified, and the residual connection strands between the two surfaces were cut with scissors. The result was two glass surfaces with very hard and sharp microneedle structures protruding perpendicular to the surface. During hardening, the tips of the needles were easy to bend, and could deviate in a curved structure or even a hook. Loops could also be formed by pressing the flexible tips against the glass surface. These forms persisted after the hardening was completed.

In the previous examples, the second surface may have a low surface area for contact with the liquid. This allows fine needle-like structures to be produced. The second surface can be provided 10 by the tip of a pointed object such as a pin, which normally has a diameter of 0.4 mm.

The second surface may remain in needle extraction contact with the liquid by virtue of the surface properties of the liquid and the second surface. This can be achieved, for example, using an adhesive as a liquid. Alternatively, the second surface can be kept in contact with the liquid by using a vacuum with the second surface. Alternatively, the second surface can be provided by a structure provided with a gauge in which the liquid can flow by virtue of capillary action.

The method may further comprise the movement of the first surface with respect to the second surface before solidification or hardening so that a needle structure is formed that is one or more between curved or inclined with respect to the first surface or support Hook.

The previous three examples used a two-surface separation movement procedure to extract a needle shape. Printing procedures can be used as a stencil template or contact printing deposit to deposit drops of various sizes, or the same material sizes on top of the former, in order to produce a needle shape. An example of such a procedure is described below with reference to Figure 3. Referring to Figure 3, a first part 32 of non-solid substance is deposited in the form of a UV curable adhesive on a first surface 31 using a system 25 automated liquid handling (not shown) (see (a)). The substance is then hardened or at least partially hardened using a UV light source (not shown). A second part 33 is then deposited on the first part 32 of the substance, and subsequently hardened as previously described (see (b)). This procedure is repeated until several parts 32, 33, 34, 35, 36, 37 and 38 are deposited on top of each other (see (c)). The volume of each part is smaller than that of the immediately underlying part. In this way, a solid needle-shaped or conical structure can be constructed.

A further embodiment of a method of producing needle shapes by sequential deposition of parts of substance with reference to Figure 4 is described below. A stencil template 49 is placed in proximity to a first surface 41 (see Figure 4a ). On the first surface 41 the upper surface of a flexible substrate is provided. In the stencil template 49 approximately 1,000 openings are provided, each 100 µm in diameter, in an area of 1 cm 2. Only two of the openings, 48a and 48b, are shown here for clarity. A non-solid substance, in this case a UV-hardened acrylate 42, was deposited on the upper surface 49a of the stencil template 49 using a brush 50 that was swept over the upper surface 49a. This scanning action propelled the acrylate 42 into the openings 48a and 48b and pushes the stencil 49 in contact with the first surface 41. The acrylate 42 adheres to the first surface 41 so that when the stencil template 49 is separated from the first surface 41 (see Figure 4b), acrylate parts 51a, 51b remain on the first surface 41. The acrylate parts 51a, 51b are then hardened by exposure to UV radiation (schematically shown as 57) emitted by a "point" UV source 56 (Figure 4c) to form solid structures 53a, 53b. Stencil template 49 was replaced so that additional parts of non-solid substance 42 could be deposited on existing structures 53a, 53b. Steps 45 were further repeated as described with reference to Figures 4a, 4b and 4c to form a network of needle shapes 52a, 52b of approximately 0.7 mm in height and having a tip diameter of approximately 20  m. Needle networks produced by this procedure proved capable of penetrating the human stratum corneum in vitro.

Using this technique, the height of the needles can be increased in any size, and the diameter of the tip can be varied by changing variables such as the rheology of the material, the size of the opening and the speed of the brush or the movement in the z-axis.

The sequence deposition technique described above with reference to Figures 3 and 4 can be combined with a needle extraction methodology as described above. Such techniques can also be used to produce needles of different composition, for example with a type of material forming a rod or other structure within a needle of different composition. The internal structure can be formed from a porous material, or it can be dissolved to allow passage through the microneedle.

Claims (15)

1. A method of manufacturing a microneedle or microimplant, the process comprising (i) the deposit of a substance on a first surface (1, 11, 31, 41) and (ii) the formation of a solid needle form (52a, 52b) from the substance characterized in that 5 step (i) comprises depositing a first discrete part (32, 51a, 51b) or droplet of substance on the first surface. 2. A process according to claim 1 wherein step (i) comprises depositing the substance in a non-solid form. 3. A method according to claim 1 or 2 wherein step (ii) comprises depositing a second part (33) or droplet of substance in the first part or droplet of substance. 4. A method according to claim 3 wherein the volume of the second droplet or part is smaller than the volume of the first droplet or part. 5. A method according to claim 3 or 4 wherein the first part or droplet of substance is deposited in a non-solid form and step (ii) comprises at least partially solidification of the first part or droplet before the deposit of the second part or droplet of substance. 6. A method according to any one of claims 3 to 5 wherein step (ii) comprises the sequential deposition of a plurality of parts or droplets of substance. 7. A method according to claim 6 wherein the volume of a part or droplet is smaller than the volume of the immediately underlying part or droplet. twenty 8. A method according to claim 6 or 7 wherein step (ii) comprises the sequential deposition of a plurality of parts or droplets of substance in non-solid form, each part or droplet being at least partially solidified before the deposition of a part or droplet of additional substance in non-solid form over the previous one. 9. A method according to any of the preceding claims wherein the substance is deposited in a non-solid form and step (ii) comprises the supply of a second surface that is in contact with the substance and the movement of the first surface and the second surface together to form a needle shape. 10. A method according to any of the preceding claims wherein the deposition of the substance is carried out by printing. 11. A method according to any of the preceding claims wherein step (i) comprises providing a stencil template (49) having at least one opening (48a, 48b), and depositing the substance through of the at least one opening on the first surface. 12. A method according to claim 11 wherein step (ii) comprises sequentially depositing a plurality of parts or droplets of substance through the at least one opening of the stencil template. 13. A method according to any of the preceding claims wherein the first surface is part of, or a precursor of, a transdermal patch. 14. A method according to claim 1 for producing a microneedle network, wherein step (i) comprises depositing a network of discrete first parts or droplets of substance on a first surface and 40 step (ii) comprises the formation of a network of solid needle shapes from the substance. 15. A method according to claim 14 wherein step (ii) comprises depositing a network of second droplets or parts of substance on the network of the first droplets or parts of substance.