Method of making microneedles

The present invention relates to a method of making microneedles, such as those that may be used to penetrate into or through biological barriers, such as the stratum corneum.

Many methods are known for the manufacture of microneedles. Conventional methods comprise the use of lithography and the like to generate microneedles. Such methods are expensive and time-consuming. The use of moulds to produce microneedles is not widely known, but the method of WO2004/062899 uses a PDMS mould to manufacture polymeric microneedles. The method involves the use of lithography to manufacture the mould, which is complex and expensive. The method further uses lithography to form the microneedles themselves and this too is complex, time-consuming and expensive. The method of the present invention addresses at least one of the problems presented by the prior art.

In accordance with a first aspect of the present invention there is provided a method of forming an array of solid microneedles, the method comprising (i) providing a mould having an array of cavities for the formation of microneedles

(ii) providing a substrate on which the array of solid microneedles is to be formed

(iii) providing the array of cavities with a substance from which an array of solid microneedles may be formed and (iv) forming the array of solid microneedles on the substrate from the substance.

Steps (i) to (iv) are not necessarily sequential steps.

The microneedles may be about 10 microns to 3mm long, preferably greater than 100 microns long and more preferably less than lmm long. The most preferred length is from about 200 to 800 microns.

The substance may be in non-solid form. Such a substance may flow or be flowable. Alternatively, the substance may not flow under certain circumstances, for example, if merely deposited on a surface with no stimulus to flow other than gravity. It may be in the form of a liquid, gel, emulsion, cream, paste or thixotropic material. It should be noted that the substance may comprise solids, such as particles. These particles may be suspended or dispersed in a carrier so that the bulk substance is non-solid. The substance may be a solid until heat or other form of energy is applied.

Step (iii) may comprise depositing said substance onto the substrate and bringing the mould into proximity with the substance so that said substance enters the array of cavities. This provides one method of providing the cavities with the said substance.

Alternatively, step (iii) may be performed in the absence of the substrate.

Said substance may be deposited onto the surface of the mould provided with the cavities. If the cavities extend through the thickness of the mould (i.e. from a first surface of the mould to a second surface) , then said substance may be deposited onto one or both of said first

surface or said second surface; references hereafter to "the surface provided with cavities" or "the surface of the mould provided with cavities" should also be taken to refer to one or both of the said first and second surfaces referred to above when the cavities extend through the thickness of the mould. The substance may be deposited directly into the cavities, for example by an array of micro-syringes or the like. Alternatively, the substance may be deposited onto the surface provided with the cavities and the substance urged into the cavities, for example, by relative movement of said surface and an applicator.

A stencil may be provided to assist in step (iii) .The stencil may assist in the deposition of the substance onto the surface of the mould provided with the cavities. The stencil may be provided with a plurality of holes therethrough. The stencil may be placed in proximity to the mould (and preferably against the mould) so that the holes are in registration with at least some of the cavities in the mould. The cavities may be provided with substance through the holes in the stencil. This may be done, for example, by depositing the substance onto the stencil and moving the substance across the stencil (for example, by using an applicator, such as a squeegee or blade) , urging the substance through the holes and into the cavities of the mould.

It is preferred that the stencil is provided with an array of holes, the array of holes corresponding to the array of cavities provided in the mould.

The stencil may be used to deposit an array of portions of substance onto the substrate. The mould may then be brought into proximity with the substrate so that the array of cavities is provided with substance.

If step (iii) is performed in the absence of the substrate, then step (iv) may comprise contacting the substrate with said substance and then causing the formation of at least partially-solidified structures from the substance. It is preferred that step (iv) comprises contacting the substrate with said substance and then forming the array of solid microneedles on the substrate.

The term "causing the formation of at least partially- solidified structures" is not restricted to the meaning of causing the substance to take a more solid form, without change to the chemical structure. It also encompasses causing the formation of a more solid material, for example by exposing the substance to heat or electromagnetic radiation, that exposure causing one or more reactions to occur. Thus, the at least partially-solidified structures (and, indeed, the solid microneedles) may not have (and probably will not have) the same chemical structure as said substance.

Step (iv) may alternatively comprise causing the formation of at least partially-solidified structures from said substance and then contacting the substrate with the at least partially-solidified structures. The substance may be formed into an array of solid microneedles prior to contacting the substrate with the substance.

The substrate may be (or may have been) treated so as to increase the adhesion of the substrate to the microneedles, the substance from which an array of microneedles may be formed or the at least partially-solidified structures formed from the substance. Such a treatment may be exposing a relevant surface of the substrate to a plasma. Such a treatment may be providing a relevant surface of the substrate with an adhesion promoter or, for example, an adhesive film. The increased adhesion is especially of benefit when the solid microneedles are formed prior to contacting the substrate with the solid microneedles; the solid microneedles are less adhesive than said substance from which microneedles may be formed. The microneedles, of course, may be provided with the adhesion-increasing treatment instead of, or as well as, the substrate.

The method may further comprise step (v) of removing the mould from the array of solid microneedles, the substance or the at least partially-solidified structures.

It is therefore apparent that steps (iv) and (v) may or may not be sequential. For example, step (v) may be performed before solid microneedles have been formed. For example, the mould may be removed when partially-solidified structures have been formed from the substance (for example, by exposure of the substance to ultraviolet radiation to form the partially-solidified structures) , and then the solid microneedles formed from the partially-solidified structures (for example, by further exposure to ultraviolet radiation) .

The method may comprise contacting the substrate with said substance, then removing the mould from the substance and

then causing the formation of at least partially-solidified structures from said substance.

The mould may be removed by movement of the mould and substrate away from one another. This would potentially allow the mould to be re-used.

Alternatively, the mould may be removed by its at least partial destruction. This may be performed, for example, by exposing the mould material to a suitable solvent. The mould may be exposed to a reagent that causes the mould to form a soluble material.

The cavities may be closed i.e. they do not extend through the whole thickness of the mould. Alternatively, the cavities may extend through the whole thickness of the mould. In this case, this provides a flow path for said substance from a first surface of the mould to a second surface, the cavity extending between the first and second surfaces. This may allow the substance to be provided into the cavity from either the first or second surface.

The array of cavities may comprise one or more cavities that are closed and one or more cavities that extend through the thickness of the mould.

The step of forming the array of microneedles may comprise exposing the substance to electromagnetic radiation and/or elevated temperature. Electromagnetic radiation is preferably ultra violet radiation if the said substance is a UV-curable substance, such as a mixture of polymer precursors that form a polymer on exposure to UV radiation.

A mask may be provided to selectively irradiate desired areas of said substance. The mask may be arranged to allow irradiation of the substance in the cavities.

The mould may be at least partially transparent to said electromagnetic radiation. Said electromagnetic radiation may be transmitted via the mould to the substance.

A portion or all of the mould may be porous, for example, to gases. If the cavities are closed the portion of the mould in the region of the closed end of the cavity may preferably be porous. This allows the application of a vacuum in this region, thus drawing substance into the cavities during the filling process.

If the cavities extend through the thickness of the mould (i.e. from a first surface to a second surface as indicated above) , a blocking member may be placed against one of the first and second surfaces of the mould. This effectively closes-off one of the two open ends of the cavities. This is preferably done after step (iii) and prior to step (iv) . The blocking member may be provided with an array of indentations or the like that may be brought into registration with the array of cavities in the mould. The indentations may therefore assist in shaping the microneedles.

The substrate may be at least partially transparent to said electromagnetic radiation. Said electromagnetic radiation may be transmitted via the substrate to the substance. This provides a particularly effective method. Examples of

substrates that are at least partially transparent to ultraviolet radiation include polyurethane or polypropylene.

Alternatively, the substance may be at least partially solidified by means of temperature change or chemical reaction. The substrate may be provided with a catalyst or other chemical entity to promote a chemical reaction.

The method may further comprise the step of producing the mould. This may comprise providing a mould blank of deformable material and urging one or more projections (and preferably an array of projections) into the deformable material. One or more projections may form the array of cavities in the deformable material, for example, by repeatedly urging the one or more projections into different parts of the mould blank. It is preferred that the array of projections corresponds to the array of cavities in the mould; in this case, only one urging process is required to produce the array of cavities in the mould. The array of projections may be formed by any convenient process, for example, by the micromachining of steel.

It is preferred that the substrate is flexible. Such flexible substrates may typically deform to the contours of the surface onto which they are deployed.

It is preferred that the mould is flexible. This allows the mould to be formed into various shapes which may be assistance for the manufacture of microneedles.

It is preferred that the surface of the mould provided with the cavities has a low energy surface. This allows the

microneedles, the at least partially solidified structures or the substance to be readily parted from the mould while decreasing the chances of damage being caused during the separation process. The low energy surface may be formed by making cavities in a material having a low surface energy, such as polytetrafluoroethylene.

Alternatively, the low energy surface may be formed by making cavities in a surface of the mould and providing the said surface with a coating to provide a low energy surface. Thus, the relatively high energy surfaces may be coated to provide a low energy surface. Examples of such coatings include the silanization of surfaces (the application of a silane) .

Step (iii) may be performed by moving an applicator relative to the surface of the mould. The substance would typically be deposited on the surface of the mould associated with the cavities (optionally in batches located at different positions on the mould) and the applicator moved, this movement urging the substance into the cavities. The applicator may be in the form of a squeegee, pump or a blade. The applicator may be arranged so that its movement relative to the surface urges the substance into the cavities, but removes excess substance from those portions of the surface that do not have cavities.

It is preferred that the substance from which the array of microneedles may be formed is degassed prior to step (iii) . This reduces the chance of forming incomplete microneedles and of voids being formed in microneedles. The substance may conveniently be degassed in a vacuum chamber or vacuum oven.

A vacuum oven permits the substance to be heated; this often assists the degassing process. Alternatively, air could be removed by replacement with an alternative gas such as helium, or using ultrasound with or without vacuum. A worker skilled in the art will also realize that many other degassing methodologies could be used.

It is further preferred that step (iii) is performed under vacuum or that gas is removed from the cavities whilst the cavities are filled with said substance. This reduces the chances of incomplete microneedles being formed (for example, where the tip region is not properly formed because said substance cannot enter the tip region of the mould) . Alternatively, a pump may be used to dispense substance onto the surface of the mould provided with the cavities.

Pressure in the region of the mould may be decreased to facilitate out-flow of gas. The array of cavities in the mould may then be filled with said substance.

Liquids and gases may also be used with pumping and negative pressure to displace the air from the holes.

The method may further comprise removing excess substance from the surface of the mould provided with the cavities after filling the array of cavities with said substance. As mentioned above, this may be performed using an applicator. Alternatively, removing excess substance may comprise providing a wiper, contacting the wiper with the substance and moving the wiper and the surface provided with the cavities relative to one another so as to remove at least some substance from said surface.

The method may comprise providing a first mould having an array of cavities for the formation of an array of base portions of microneedles and providing a second mould having an array of cavities for the formation of an array of tip portions of microneedles. The use of two different moulds to form the base and tip regions of microneedles facilitates the manufacture of tips with a high aspect ratio (or "sharp" needle tips) . A tip-forming substance may be introduced into the cavities of the second mould. A base-forming substance may be introduced into the cavities of the first mould. One or both of the tip-forming substance and the base-forming substance may initially be fluid (e.g. a liquid) and hence may flow.

The method may further comprise forming an array of solid base portions of microneedles and forming an array of solid tip portions of microneedles. The method may comprise forming solid base and tip portions and securing said solid tip and base portions together to form an array of microneedles. The solid base portions may be made from a base-forming substance by exposing the base-forming substance to electromagnetic radiation, such as ultraviolet radiation. The base-forming substance may be irradiated via the substrate or the first mould.

The solid tip and base portions may be secured together, for example, by use of an adhesive or the like. A surface of one or both of the tip portions and the base portions may be plasma-treated to facilitate adhesion of the base portions to the tip portions. The solid tip and base portions may be secured together with the solid tip portions remaining in the mould. It may be simpler to apply the tip portions to

the base portions with the tip portions in the mould. The mould would then be removed from the tip portions.

Alternatively, the method may comprise forming an array of solid base portions of the microneedles, and subsequently- forming the solid tip portions from the tip-forming substance in situ on top of the base portions.

Formation of the tip portions from a tip-forming substance may be realized by cooling the tip-forming substance. The solid tip portions may comprise a thermoplastic.

The solid base portions may be non-biodegradable and/or non- bioresorbable, preferably both non-biodegradable and non- bioresorbable. The solid tip portions may be biodegradable and/or bioresorbable, preferably both biodegradable and bioresorbable .

The microneedle may comprise a break region between the base portion and the tip portion, the break region facilitating removal of the tip portion from the microneedle. The tip may ^¬ be retained in a biological barrier in which the microneedle is inserted.

The break region may be provided by a notch or the like between the base and tip portions. This provides a convenient mechanism for providing a break region.

The break region may be provided by an adhesive layer which connects the base portion and the tip portion, wherein the strength of the adhesive layer decreases on exposure to one or more pre-determined stimuli. This may allow the user to

selectively increase the ease with which the microneedle may be broken.

The strength of the adhesive layer may decrease on exposure to one or more of heat, cold, a gas or electromagnetic radiation. For example, the strength of the adhesive layer may decrease on exposure to air; such exposure may occur over a period of time. The strength of the adhesive layer may decrease on exposure to certain (possible raised) temperatures . The electromagnetic radiation which may cause a decrease in the strength of the adhesive may be infrared or ultraviolet radiation, for example.

The microneedle may comprise a barb. The tip portion may provide the barb. In this case, a microneedle may be inserted into a biological barrier (such as the skin of a patient) and the barb provided by the tip portion may inhibit removal of the tip portion. The tip portion may be removed from the rest of the microneedle by withdrawal of the microneedle away from the biological barrier. The barb may be provided in addition to a break region between the base portion and the tip portion which facilitates removal of the tip portion from the microneedle.

The tip portion may be provided with a therapeutic substance for administration to a patient. The therapeutic substance may be provided as a coating on the outer surface of a microneedle. Alternatively or additionally, the tip portion may be porous, said pores being provided with the therapeutic substance.

The tip portion may be provided with a substance for bonding to a biological barrier. Such a substance for forming a bond to a biological barrier may be sensitive to stimuli (such as heat) . The strength of the bond between the tip portion and the biological barrier may be increased in response to stimuli associated with the tip portion being in proximity to the biological barrier.

The microneedle may be provided with one or more delivery channels extending from the base portion to the tip portion, the one or more delivery channels being for administration of a therapeutic substance to a patient. The one or more delivery channels may be in fluid communication with a reservoir for the storage of a therapeutic substance.

In accordance with a second aspect of the present invention there is provided a method of making microneedles, the method comprising:

(i) providing a first mould having an array of cavities for the formation of base portions of microneedles and a second mould having an array of cavities for the formation of tip portions of microneedles

(ii) providing a substrate on which the array of solid microneedles is to be formed (iii) providing the array of cavities for the formation of base portions of microneedles with a base-forming substance from which an array of solid base portions of microneedles may be formed;

(iv) providing the array of cavities for the formation of tip portions of microneedles with a tip-forming substance from which an array of solid tip portions of microneedles may be formed; and

(v) forming the array of solid microneedles from the base- forming and tip-forming substances.

Steps (i) to (v) are not necessarily sequential steps.

The microneedles may be about 10 microns to 3mm long, preferably greater than 100 microns long and more preferably less than lmm long. The most preferred length is from about 200 to 800 microns.

One or both of the base-forming substance and the tip- forming substance may be in non-solid form. Such a substance may flow or be flowable. Alternatively, the base-forming substance or the tip-forming substance may not flow under certain circumstances, for example, if merely deposited on a surface with no stimulus to flow other than gravity. It may be in the form of a liquid, gel, emulsion, cream, paste or thixotropic material. It should be noted that the tip- forming substance or the base-forming substance may comprise solids, such as particles. These particles may be suspended or dispersed in a carrier so that the bulk substance is non- solid. The base-forming substance or the tip-forming substance may be a solid until heat or other form of energy is applied.

Step (iii) may comprise depositing the base-forming substance onto the substrate and bringing the mould into proximity with the substance so that said substance enters the array of cavities. This provides one method of providing the cavities with the said substance.

Alternatively, step (iii) may be performed in the absence of the substrate.

References to "mould" in relation to the second aspect of the present invention refer to one or both of the first mould and the second mould, as will be generally clear from the context of the use of the term "mould".

The base-forming substance or the tip-forming substance may be deposited onto the surface of the respective mould provided with the cavities. If the cavities extend through the thickness of the mould (i.e. from a first surface of the mould to a second surface) , then the base-forming or the tip-forming substance may be deposited onto one or both of said first surface or said second surface; references hereafter to "the surface provided with cavities" or "the surface of the mould provided with cavities" should also be taken to refer to one or both of the said first and second surfaces referred to above when the cavities extend through the thickness of the mould. The base-forming or tip-forming substance may be deposited directly into the cavities, for example by an array of micro-syringes or the like. Alternatively, the base-forming or tip-forming substance may be deposited onto the surface provided with the cavities and the substance urged into the cavities, for example, by relative movement of said surface and an applicator.

A stencil may be provided to assist in one or both of steps (iii) and (iv) .The stencil may assist in the deposition of the base-forming or tip-forming substance onto the surface of the respective mould provided with the cavities . The stencil may be provided with a plurality of holes

therethrough. The stencil may be placed in proximity to the mould (and preferably against the mould) so that the holes are in registration with at least some of the cavities in the mould. The cavities may be provided with the substance through the holes in the stencil. This may be done, for example, by depositing the tip-forming or base-forming substance onto the stencil and moving the substance across the stencil (for example, by using an applicator, such as a squeegee or blade) , urging the substance through the holes and into the cavities of the mould.

It is preferred that the stencil is provided with an array of holes, the array of holes corresponding to the array of cavities provided in the mould.

The stencil may be used to deposit an array of portions of substance onto the substrate. The mould may then be brought into proximity with the substrate so that the array of cavities is provided with substance.

The mould may be brought into proximity to the substrate, with the stencil in proximity to the mould. In this manner, substance may be deposited through the holes in the substrate into the cavities of the mould, thereby depositing the substance onto the substrate.

If step (iii) is performed in the absence of the substrate, then step (v) may comprise contacting the substrate with said base-forming substance and then causing the formation of at least partially-solidified base portions from the substance .

It is preferred that step (v) comprises contacting the substrate with the base-forming substance and then forming the array of solid base portions of microneedles on the substrate .

Solid base portions are preferably formed from the base- forming substance by exposing the base-forming substance to electromagnetic radiation, preferably ultraviolet radiation. It is preferred that the substrate is sufficiently transparent to the electromagnetic radiation so that electromagnetic radiation may be transmitted through the substrate with sufficient intensity to cause the base- forming substance to form solid base portions.

Step (v) may comprise forming solid tip portions from the tip-forming substance. It is preferred that solid tip portions are formed by cooling the tip-forming substance. The solid tip portions may comprise a thermopolymer . The formation of at least partially solidified tip portions may be performed prior to adhering of the at least partially solidified tip portions to the at least partially solidified base portions . An adhesive may be used to faclilitate the attachment of the base portions to the tip portions. Alternatively, a surface of one or both of the base portion and the tip portion may be plasma-treated to facilitate attachment of the base portions to the tip portions.

The formation of at least partially solidified tip portions may be performed in situ on top of the at least partially solidified base portions. This may comprise bringing the second mould provided with the tip-forming substance into proximity to the at least partially solidified base portions

and then forming solid tip portions from the tip-forming substance.

The term "causing the formation of at least partially- solidified structures" is not restricted to the meaning of causing the substance to take a more solid form, without change to the chemical structure. It also encompasses causing the formation of a more solid material, for example by exposing the substance to heat or electromagnetic radiation, that exposure causing one or more reactions to occur. Thus, the at least partially-solidified structures (and, indeed, the solid microneedles) may not have (and probably will not have) the same chemical structure as said substance.

Step (v) may alternatively comprise causing the formation of at least partially-solidified base portions from the base- forming substance and then contacting the substrate with the at least partially-solidified base portion. The base-forming substance may be formed into an array of solid base portions of microneedles prior to contacting the substrate with the substance.

The substrate may be (or may have been) treated so as to increase the adhesion of the substrate to the base portion of the microneedles, the base-forming substance from which an array of base portions may be formed or the at least partially-solidified base portions formed from the substance. Such a treatment may be exposing a relevant surface of the substrate to a plasma. Such a treatment may be providing a relevant surface of the substrate with an adhesion promoter or, for example, an adhesive film. The

increased adhesion is especially of benefit when the solid base portions of microneedles are formed prior to contacting the substrate with the solid microneedles; the solid base portions of the microneedles may be less adhesive than the base-forming substance from which the base portions of the microneedles may be formed. The base portions of the microneedles, of course, may be provided with the adhesion- increasing treatment instead of, or as well as, the substrate.

The method may further comprise step (vi) of removing the first or second mould from the array of solid base portions or tip portions, the base-forming or tip-forming substance, or the at least partially-solidified base portions or tip portions.

It is therefore apparent that steps (v) and (vi) may or may not be sequential. For example, the first mould may be removed before solid base portions have been formed. For example, the first mould may be removed when partially- solidified structures have been formed from the base-forming substance (for example, by exposure of the substance to ultraviolet radiation to form the partially-solidified structures) . Likewise, the second mould may be removed when partially-solidified structures have been formed from the tip-forming substance. The solid microneedles may then be formed from the partially-solidified base and tip structures (for example, by further exposure to ultraviolet radiation) . Alternatively, a solid base portion may be formed prior to depositing a partially solidified tip portion on the solid base portion. The second mould may then be removed, and then

the solid tip portion formed from the partially solidified tip portion.

The method may comprise contacting the substrate with said base-forming substance, then removing the first mould from the base-forming substance and then causing the formation of at least partially-solidified base portion structures from said substance.

The first mould may be removed by movement of the first mould and substrate away from one another. This would potentially allow the mould to be re-used.

Alternatively, the first or second mould may be removed by its at least partial destruction. This may be performed, for example, by exposing the mould material to a suitable solvent. The respective mould may be exposed to a reagent that causes the mould to form a soluble material.

The cavities in the first or second mould may be closed i.e. they do not extend through the whole thickness of the respective mould. Alternatively, the cavities may extend through the whole thickness of the mould. In this case, this provides a flow path for the respective substance from a first surface of the respective mould to a second surface, the cavity extending between the first and second surfaces. This may allow the respective substance to be provided into the cavity from either the first or second surface.

It is preferred that the cavities in the first mould extend through the whole thickness of the mould. It is preferred

that the cavities in the second mould are closed i.e. they do not extend through the whole thickness of the mould.

The array of cavities may comprise one or more cavities that are closed and one or more cavities that extend through the thickness of the mould.

The step of forming the array of microneedles may comprise exposing the base-forming or tip-forming substance to electromagnetic radiation and/or elevated temperature. Electromagnetic radiation is preferably ultra violet radiation if the said substance is a UV-curable substance, such as a mixture of polymer precursors that form a polymer on exposure to UV radiation.

A mask may be provided to selectively irradiate desired areas of the base-forming or tip-forming substance. The mask may be arranged to allow irradiation of the respective substance in the cavities.

The mould may be at least partially transparent to said electromagnetic radiation. Said electromagnetic radiation may be transmitted via the mould to the base-forming or tip- forming substance.

A portion or all of the mould may be porous, for example, to gases. If the cavities are closed the portion of the mould in the region of the closed end of the cavity may preferably be porous. This allows the application of a vacuum in this region, thus drawing substance into the cavities during the filling process.

If the cavities extend through the thickness of the mould (i.e. from a first surface to a second surface as indicated above) , a blocking member may be placed against one of the first and second surfaces of the mould. This effectively closes-off one of the two open ends of the cavities. This may be done prior to step (iii) or (iv) . The blocking member may be provided with an array of indentations or the like that may be brought into registration with the array of cavities in the mould. The indentations may therefore assist in shaping the microneedles .

The substrate may be at least partially transparent to said electromagnetic radiation. Said electromagnetic radiation may be transmitted via the substrate to one or both of the base-forming and tip-forming substance. This provides a particularly effective method. Examples of substrates that are at least partially transparent to ultraviolet radiation include polyurethane or polypropylene.

Alternatively, the base-forming or tip-forming substance may be at least partially solidified by means of temperature change or chemical reaction. The substrate may be provided with a catalyst or other chemical entity to promote a chemical reaction.

The method may further comprise the step of producing the mould. This may comprise providing a mould blank of deformable material and urging one or more projections (and preferably an array of projections) into the deformable material. One or more projections may form the array of cavities in the deformable material, for example, by repeatedly urging the one or more projections into different

parts of the mould blank. It is preferred that the array of projections corresponds to the array of cavities in the mould; in this case, only one urging process is required to produce the array of cavities in the mould. The array of projections may be formed by any convenient process, for example, by the micromachining of steel.

It is preferred that the substrate is flexible. Such flexible substrates may typically deform to the contours of the surface onto which they are deployed.

It is preferred that the mould is flexible. This allows the mould to be formed into various shapes which may be of assistance for the manufacture of microneedles.

It is preferred that the surface of the mould provided with the cavities has a low energy surface. This allows the microneedles, the at least partially solidified structures or the substance to be readily parted from the mould while decreasing the chances of damage being caused during the separation process. The low energy surface may be formed by making cavities in a material having a low surface energy, such as polytetrafluoroethylene .

Alternatively, the low energy surface may be formed by making cavities in a surface of the mould and providing the said surface with a coating to provide a low energy surface. Thus, the relatively high energy surfaces may be coated to provide a low energy surface. Examples of such coatings include the silanization of surfaces (the application of a silane) .

One or both of steps (iii) and (iv) may be performed by moving an applicator relative to the surface of the mould. The base-forming or tip-forming substance would typically be deposited on the surface of the mould associated with the cavities (optionally in batches located at different positions on the mould) and the applicator moved, this movement urging the respective substance into the cavities. The applicator may be in the form of a squeegee, pump or a blade. The applicator may be arranged so that its movement relative to the surface urges the respective substance into the cavities, but removes excess substance from those portions of the surface that do not have cavities.

It is preferred that one or both of the tip-forming and base-forming substances is degassed prior to step (iii) or (iv) . This reduces the chance of forming incomplete microneedles and of voids being formed in microneedles. The respective substance may conveniently be degassed in a vacuum chamber or vacuum oven. A vacuum oven permits the respective substance to be heated; this often assists the degassing process. Alternatively, air could be removed by replacement with an alternative gas such as helium, or using ultrasound with or without vacuum. A worker skilled in the art will also realize that many other degassing methodologies could be used.

It is further preferred that step (iii) or (iv) is performed under vacuum or that gas is removed from the cavities whilst the cavities are filled with the respective tip-forming or base-forming substance. This reduces the chances of incomplete microneedles being formed (for example, where the tip region is not properly formed because said substance

cannot enter the tip region of the mould) . Alternatively, a pump may be used to dispense base-forming or tip-forming substance onto the surface of the mould provided with the cavities. Pressure in the region of the mould may be decreased to facilitate out-flow of gas. The array of cavities in the mould may then be filled with the respective substance.

Liquids and gases may also be used with pumping and negative pressure to displace the air from the holes.

The method may further comprise removing excess tip-forming or base-forming substance from the surface of the mould provided with the cavities after filling the array of cavities with the respective substance. As mentioned above, this may be performed using an applicator. Alternatively, removing excess tip-forming or base-forming substance may comprise providing a wiper, contacting the wiper with the respective substance and moving the wiper and the surface provided with the cavities relative to one another so as to remove at least some substance from the respective surface. The solid base portion may be non-biodegradable and/or non- bioresorbable (preferably non-biodegradable and non- bioresorbable) . The solid tip portion may be biodegradable and/or bioresorbable (preferably biodegradable and bioresorbable) . A biodegradable tip portion may be formed from poly ( β-hydroxybutyrate) , for example, or a biodegradable polyethylene or polyester amide.

The microneedle may comprise a break region between the base portion and the tip portion, the break region facilitating removal of the tip portion from the microneedle. The tip may

be retained in a biological barrier in which the microneedle inserted.

The break region may be provided by a notch or the like between the base and tip portions. This provides a convenient mechanism for providing a break region.

The break region may be provided by an adhesive layer which connects the base portion and the tip portion, wherein the strength of the adhesive layer decreases on exposure to one or more pre-determined stimuli. This may allow the user to selectively increase the ease with which the microneedle may be broken.

The strength of the adhesive layer may decrease on exposure to one or more of heat, cold, a gas or electromagnetic radiation. For example, the strength of the adhesive layer may decrease on exposure to air; such exposure may occur over a period of time. The strength of the adhesive layer may decrease on exposure to certain (possible raised) temperatures. The electromagnetic radiation which may cause a decrease in the strength of the adhesive may be infrared or ultraviolet radiation, for example.

The microneedle may comprise a barb. The tip portion may provide the barb. In this case, a microneedle may be inserted into a biological barrier (such as the skin of a patient) and the barb provided by the tip portion may inhibit removal of the biocompatible tip portion. The tip portion may be removed from the rest of the microneedle by withdrawal of the microneedle away from the biological barrier. The barb may be provided in addition to a break

region between the base portion and the tip portion which facilitates removal of the tip portion from the microneedle.

The tip portion may be provided with a therapeutic substance for administration to a patient. The therapeutic substance may be provided as a coating on the outer surface of a microneedle. Alternatively or additionally, the tip portion may be porous, said pores being provided with the therapeutic substance.

The tip portion may be provided with a substance for bonding to a biological barrier. Such a substance for forming a bond to a biological barrier may be sensitive to stimuli (such as heat) . The strength of the bond between the tip portion and the biological barrier may be increased in response to stimuli associated with the tip portion being in proximity to the biological barrier.

The microneedle may be provided with one or more delivery channels extending from the base portion to the tip portion, the one or more delivery channels being for administration of a therapeutic substance to a patient. The one or more delivery channels may be in fluid communication with a reservoir for the storage of a therapeutic substance.

Intermediate portions of a microneedle may be formed between the base portion and the tip portion. For example, a third, central portion may be formed using a mould substantially as described above in relation to the base portion and the tip portion. The central portion may be formed atop the solid base portion. The tip portion may then be formed atop the central portion. In this manner, microneedles with complex

geometries may be constructed which may not be readily be manufactured using a single mould.

In accordance with a third aspect of the present invention there is provided a microneedle comprising a nonbiodegradable and/or non-bioresorbable base portion and a biodegradable and/or bioresorbable tip portion. It is preferred that the base portion is non-biodegradable and non-bioresorbable. It is preferred that the tip portion is biodegradable and bioresorbable.

Such a microneedle facilitates the removal of the tip from the base, the tip remaining in the biological barrier in which the microneedle is inserted.

The tip portion may comprise a thermopolymer, such as poly ( β-hydroxybutyrate) . Other biodegradable polymers, such as biodegradable polyethylene or polyester amide may be used.

The microneedle may comprise a break region between the base portion and the tip portion, the break region facilitating removal of the tip portion from the microneedle. The tip may be retained in a biological barrier in which the microneedle inserted. The break region may be provided by a notch or the like between ¹ the base and tip portions. This provides a convenient mechanism for providing a break region.

The break region may be provided by an adhesive layer which connects the base portion and the tip portion, wherein the strength of the adhesive layer decreases on exposure to one or more pre-determined stimuli. This may allow the user to

selectively increase the ease with which the microneedle may be broken.

The strength of the adhesive layer may decrease on exposure to one or more of heat, cold, a gas or electromagnetic radiation. For example, the strength of the adhesive layer may decrease on exposure to air; such exposure may occur over a period of time. The strength of the adhesive layer may decrease on exposure to certain (possible raised) temperatures. The electromagnetic radiation which may cause a decrease in the strength of the adhesive may be infrared or ultraviolet radiation, for example.

The microneedle may comprise a barb. The tip portion may provide the barb. In this case, a microneedle may be inserted into a biological barrier (such as the skin of a patient) and the barb provided by the tip portion may inhibit removal of the biocompatible tip portion. The tip portion may be removed from the rest of the microneedle by withdrawal of the microneedle away from the biological barrier. The barb may be provided in addition to a break region between the base portion and the tip portion which facilitates removal of the tip portion from the microneedle.

The tip portion may be provided with a therapeutic substance for administration to a patient. The therapeutic substance may be provided as a coating on the outer surface of a microneedle. Alternatively or additionally, the tip portion may be porous, said pores being provided with the therapeutic substance.

The tip portion may be provided with a substance for bonding to a biological barrier. Such a substance for forming a bond to a biological barrier may be sensitive to stimuli (such as heat) . The strength of the bond between the tip portion and the biological barrier may be increased in response to stimuli associated with the tip portion being in proximity to the biological barrier.

The microneedle may be provided with one or more delivery channels extending from the base portion to the tip portion, the one or more delivery channels being for administration of a therapeutic substance to a patient. The one or more delivery channels may be in fluid communication with a reservoir for the storage of a therapeutic substance.

The invention will now be described by way of example only with reference to the following Figures of which: Figure 1 is a schematic representation of two embodiments of the present invention, one embodiment comprising a substrate being brought into contact with mould prior to the formation of the microneedles and another comprising a substrate being brought into contact with the mould subsequent to the formation of microneedles; Figure 2 is a schematic representation of a further embodiment of the present invention, wherein the substance from which the microneedles are to be made is deposited onto the substrate and the mould then brought into contact with the substance; Figure 3 is a schematic representation of a further embodiment of the present invention, wherein the mould is filled with substance from which the microneedles are to be made, then placed against the substrate, and the mould

removed to leave portions of substance from which microneedles may be formed; and

Figure 4 is a schematic representation of a further embodiment of the present invention, wherein an array of solid base portions of microneedles are formed on a substrate and an array of solid tip portions are then adhered to the base portions.

Method 1 A first embodiment of the present invention, method 1, is shown schematically in Figures IA, IB, 1C, ID and IG. A mould 1 is provided, the mould 1 having an array of cavities, only three of which (2a, 2b, 2c) are shown for the purpose of clarity (Figure IA) . The cavities 2a, 2b, 2c are provided with portions 4a, 4b, 4c of a substance from which an array of microneedles may be formed (Figure IB) . This is achieved by depositing the substance on the surface 3 of the mould, the surface 3 being provided with the array of cavities. An applicator (not shown) (for example, in the form of a blade or a squeegee) is moved across the surface 3, urging the substance into the cavities. Excess substance on the surface 3 may then be removed by bringing a blade (not shown) into contact with the surface 3 and moving the blade across the surface 3. Once excess substance has been removed, the portions 4a, 4b, 4c of substance in the cavities 2a, 2b, 2c are exposed to ultraviolet radiation (shown as wavy lines labeled 6) (Figure 1C) ; this causes the substance to form hardened polymeric microneedles (shown by reference numerals 7a, 7b, 7c in Figure ID) . After the microneedles are formed, substrate 5 is brought into contact with the microneedles (Figure ID) . The surface of the substrate 5 that contacts the microneedles 7a, 7b, 7c is

provided with an adhesion promoter that causes the microneedles to stick to the substrate 5. Substrate 5 and mould 1 are then moved away from one another to provide a substrate provided with an array of microneedles and a mould which may be readily reused (Figure IG) .

Method 2

A second embodiment of the present invention, method 2, is shown schematically in Figures IA, IB, IE, IF and IG. A mould 1 is provided, the mould 1 having an array of cavities, only three of which (2a, 2b, 2c) are shown for the purpose of clarity (Figure IA) . The cavities 2a, 2b, 2c are provided with portions 4a, 4b, 4c of a substance from which an array of microneedles may be formed (Figure IB) . The portions 4a, 4b, 4c are formed as described above with reference to method 1 and excess substance removed as described above. Substrate 5 in then brought into contact with the portions 4a, 4b, 4c (Figure IE) . The substrate 5 is transparent to ultraviolet radiation, and the portions 4a, 4b, 4c of substance are exposed to ultraviolet radiation

(shown as wavy lines labeled 6) through substrate 5 (Figure IF) . This provides an effective method of forming microneedles (shown by reference numerals 7a, 7b, 7c in Figure IG) on the substrate 5. Substrate 5 and mould 1 are then moved away from one another (Figure IG) to provide a substrate 5 provided with an array of microneedles 7a, 7b, 7c and a mould 1 which may be readily reused. This method is advantageous in that no adhesion promoter is required between the microneedles and the substrate.

Method 2 may be readily adapted, for example, by forming partially-solidified structures in step IF (as opposed to

solid, finished microneedles) prior to removal of the substrate 5 from the proximity of the mould 1. The partially-solidified structures may then be further treated to form solid microneedles.

Method 3

A third embodiment of the present invention, method 3, is shown schematically in Figures 2A-2D. A mould 1 is provided, the mould 1 having an array of cavities, only three of which (2a, 2b, 2c) are shown for the purpose of clarity (Figure 2A) . A substrate 5 is provided, the substrate 5 being provided with a substance 14 from which an array of microneedles may be formed (Figure 2A) . The mould 1 is brought into proximity with the substrate 5 so that the cavities 2a, 2b, 2c are filled with the substance 14. This produces portions 4a, 4b, 4c of substance 14 that fill the cavities 2a, 2b, 2c (Figure 2B) . The substrate 5 is transparent to ultraviolet radiation, and the substance 14, including the portions 4a, 4b, 4c of substance in the cavities 2a, 2b, 2c are exposed to ultraviolet radiation

(shown as wavy lines labeled 6) through substrate 5 (Figure 2C) . This provides an effective method of forming microneedles (shown by reference numerals 7a, 7b, 7c in Figure 2D) on the substrate 5. Substrate 5 and mould 1 are then moved away from one another (Figure 2D) to provide a substrate 5 provided with an array of microneedles 7a, 7b, 7c and a mould 1 which may be readily reused. This method is advantageous in that no adhesion promoter is required between the microneedles and the substrate.

Method 4

A fourth embodiment of the present invention, method 4, is shown schematically in Figures 3A-3F. A mould 1 is provided, the mould 1 having an array of cavities, only three of which (2a, 2b, 2c) are shown for the purpose of clarity (Figure 3A) . The cavities 2a, 2b, 2c are provided with portions 4a, 4b, 4c of a substance from which an array of microneedles may be formed (Figure 3B) . The portions 4a, 4b, 4c are formed as described above with reference to method 1 and excess substance removed as described above. Substrate 5 is then brought into contact with the portions 4a, 4b, 4c (Figure 3C) . Substrate 5 and mould 1 are then moved away from one another (Figure 3D) to yield a substrate 5 provided with portions 4a, 4b, 4c of substance from which an array of microneedles may be formed. The portions 4a, 4b, 4c of said substance are then exposed to ultraviolet radiation (shown as wavy lines 6) (Figure 3E) , thus forming an array of microneedles 7a, 7b, 7c on substrate 5 (Figure 3F) .

Method 5

A further embodiment of the present invention, method 5, is shown schematically in Figures 4A, 4B, 4C, 4D, 4E, 4K, 4G, 4H, 41 and 4J. A mould 101 is provided, the mould 101 having an array of cavities for the formation of an array of base portions of microneedles. Only three of the cavities (102a, 102b, 102c) are shown for the purpose of clarity (Figure 4A) . The cavities 102a, 102b, 102c are provided with portions 104a, 104b, 104c of a substance from which an array of base portions of microneedles may be formed (Figure 4B) . This is achieved by depositing the substance on the surface 103 of the mould, the surface 103 being provided with the array of cavities. An applicator (not shown) (for example,

in the form of a blade or a squeegee) is moved across the surface 103, urging the substance into the cavities. Excess substance on the surface 103 may then be removed by bringing a blade (not shown) into contact with the surface 103 and moving the blade across the surface 103. Once excess substance has been removed, the portions 104a, 104b, 104c of substance in the cavities 102a, 102b, 102c are exposed to ultraviolet radiation (shown as wavy lines labeled 106) (Figure 4C) ; this causes the substance to form hardened polymeric base portions of microneedles (shown by reference numerals 107a, 107b, 107c in Figure 4D) . After the base portions of the microneedles are formed, substrate 105 is brought into contact with the base portions of the microneedles (Figure 4D) . The surface of the substrate 105 that contacts the base portions 107a, 107b, 107c is provided with an adhesion promoter that causes the base portions to stick to the substrate 105. Substrate 105 and mould 101 are then moved away from one another to provide a substrate provided with an array of base portions of microneedles (Figure 4E) .

The substrate 105 is substantially transparent to ultraviolet radiation and therefore the portions 104a, 104b, 104c of base-forming substance may be irradiated via the substrate 105. The substrate 105 may be corona treated polypropylene sheet.

A second mould 201 is provided, the second mould 201 having an array of cavities for the formation of an array of tip portions of microneedles. Only three of the cavities (202a, 202b, 202c) are shown for the purpose of clarity (Figure 4F) . The cavities 202a, 202b, 202c are provided with

portions 204a, 204b, 204c of a substance from which an array of tip portions of microneedles may be formed (Figure 4G) . This is achieved by depositing the substance on the surface 203 of the mould, the surface 203 being provided with the array of cavities. An applicator (not shown) (for example, in the form of a blade or a squeegee) is moved across the surface 203, urging the substance into the cavities. Excess substance on the surface 203 may then be removed by bringing a blade (not shown) into contact with the surface 203 and moving the blade across the surface 203. Once excess substance has been removed, the portions 204a, 204b, 204c of substance in the cavities 202a, 202b, 202c are cooled; this causes the substance to form hardened polymeric tip portions of microneedles (shown by reference numerals 207a, 207b, 207c in Figure 4H) . After the tip portions of the microneedles are formed, the tip portions are brought into contact with the base portions (107a, 107b, 107c) (Figure 41) . The surfaces of the base portions (107a, 107b, 107c) that contact the tip portions (207a, 207b, ^' 207c) are provided with an adhesion promoter that causes the base portions and tip portions to adhere together. Substrate 105 and mould 201 are then moved away from one another to provide a substrate provided with an array of microneedles (307a, 307b, 307c) (Figure 4J) . The base portions of the microneedles are non-biodegradable. The tip portions of the microneedles are biodegradable. Those skilled in the art will realize that the base portions and the tip portions may be made simultaneously, and then adhered together. The tip portions may be made from a biodegradable thermopolymer, such as poly (β-hydroxybutyrate) . The base portions may be made from a UV-cured polymer, such as a UV-cured acrylic polymer.

Method 6

A further embodiment of the present invention is now described. A stencil is brought into contact with the surface of a first mould for the formation of base portions of a microneedle. The stencil is provided with apertures which are aligned with the cavities in the first mould. Base-forming substance is introduced through the apertures in the stencil into the cavities of the first mould using a pressurized injector (in this case, a ProFlow® system from DEK (DEK UK, Weymouth, United Kingdom) ) . A substrate is then brought into contact with the first mould so that the base- forming substance contacts the substrate. Alternatively, the substrate may be brought into contact with the first mould prior to filling the cavities of the first mould with the base-forming substance.

The base-forming substance is then exposed to ultraviolet (UV) radiation through the UV-transparent substrate, thus producing solid base portions. The first mould is then removed, leaving a substrate with solid base portions deposited thereon.

The tip portions are then made. A stencil is provided against a second mould for the formation of tip portions. Apertures in the stencil align with the cavities in the second mould. The pressure injector is used to inject tip- forming substance through apertures in the stencil into the cavities in the second mould. The tip-forming substance is then cooled to form solid tip portions.

Surfaces of one or both of the solid base portions and solid tip portions are plasma-treated to increase adhesion between

the tip portions and base portions. The tip portions are then brought into contact with the base portions to form microneedles. The second mould is then moved away from the substrate .

Example 1

An array of microneedles was made using a method as generally outlined in Method 2 above. The mould was produced by urging a male master against a mould blank multiple times in different places so as to produce an array of cavities in the mould. The male master was a column which had a base section of right-circular cylindrical shape, having a diameter of 200 microns and a height of 400 microns. A tip section was formed atop the base section, the tip section being of generally right-circular cylindrical shape, having a diameter of 70 microns and height of 100 microns, but with a chisel point. The stepped columns were formed by micro- milling. The mould blank was provided by 2mm thick skived polytetrafluoroethylene tape. This formed a mould that was flexible.

The substance to be formed into microneedles was a mixture of precursors of UV-curable acrylic polymer. These precursors were provided in the cavities in the mould by depositing the precursors on the surface of the mould provided with the cavities and moving a squeegee across the surface so as to urge the precursors into the cavities. Excess precursors were removed using the squeegee. A substrate, in the form of a sheet of a thin, flexible corona treated polypropylene sheet, was brought into contact with the mould and precursors of the polymer. UV radiation was shone through the substrate onto the polymer precursors,

causing the formation of solid polymeric microneedles from the precursor. The microneedles were bonded to the substrate.

The microneedles so formed were from 500 to 2000 microns tall.

Example 2

The method of Example 1 was repeated using a polyurethane film as the substrate, instead of polypropylene.

Microneedles having a height of from 500 to 2000 microns were formed on the substrate.

Example 3 The method of Example 1 was repeated using a different male master to manufacture the mould. The male master was a 150μm diameter steel needle with tungsten carbide tip, instead of an array of stepped columns. Microneedles having a height of from 500 to 2000 microns were formed on the substrate.