Microneedle patch and method of manufacturing

Abstract

The present invention relates to a microneedle patch (3) useful in the administration or application of a medicament or a cosmetic, as well as a method of forming the same. The microneedles (4) contain the medicament or cosmetic. The patch consists of an insoluble base comprising one or more insoluble protrusions extending from a surface of the base; and one or more bio-soluble microneedles (4) comprising a tip and a base, wherein each of the one or more bio-soluble microneedles extends from a surface of each of the one or more protrusions.

Description

MICRONEEDLE PATCH AND METHOD OF MANUFACTURING

[0001] This invention relates to a microneedle patch and a method of forming a microneedle patch.BACKGROUND

[0002] Vaccination can provide safe and effective immune preparation against a variety of different viruses. However, the typical mechanism of vaccine delivery is an injection which many people do not like as it causes pain and tissue damage. In addition, in order to receive the vaccine, people usually must visit a hospital or doctor's surgery where a trained professional will inject the vaccine. Therefore, the process of being vaccinated can be painful, takes time, and is often stressful to users who are needle-phobic.

[0003] The stratum corneum constitutes the main barrier of the epidermis to exogenous substances, including small and high weight molecular bio-polymers compositions used as cosmetic fillers. Techniques aimed at removing the stratum corneum barrier, such as tape stripping and suction, laser, or thermal ablation are impractical, while needle-free injections have so far failed to replace known needle-based delivery. Such a method of delivery can be uncomfortable, and even painful, due to the shape of the needles and the viscosity of the composition and are thus non-attractive for the users.

[0004] Microneedles are easier to apply and overcome the various problems associated with the conventional vaccines.

[0005] GB 2618560 A discloses a microneedle patch comprising a base having a plurality of cylinders arranged in an array and extending perpendicularly away from a first surface of the base, the cylinders being coated with a matrix solution comprising a vaccine so as to define a series of microneedles. GB 2618560 A also discloses a method of forming a microneedle patch comprising the steps of: a) forming a first base having a plurality of cylinders arranged in an array and extending perpendicularly away from a first surface of the first base; b) applying a droplet comprising a vaccine to each of the plurality of cylinders of the first base; c) forming a second base having a second plurality of cylinders arranged in an array and extending perpendicularly away from a first surface of the second base; d) superimposing the first and second bases so as to adhere the droplets between opposing cylinders; and e) increasing the distance between the first and second bases so as to elongate and separate the droplets into microneedles forming two microneedle patches.

[0006] US 2008 / 108959 A1 discloses microneedles fabricated according to a methodcomprising: coating a surface of a substance with a biodegradable viscous material to form microneedles; drawing the coated biodegradable viscous material using a frame having pillar patterns formed thereon while the biodegradable viscous material is being solidified; and cutting the drawn biodegradable viscous material at a given position thereof. The microneedle may have an upper end diameter of 5-40 μm.

[0007] An aim of certain embodiments of the present invention is to provide a microneedle patch having microneedles that are less invasive than prior art patches, as well as a method of forming the same.

[0008] An aim of certain embodiments of the present invention is to provide a microneedle patch having microneedles that can effectively penetrate the corneum, but that are less brittle than the prior art patches and are therefore less subject to breaking upon application, as well as a method of forming the same.

[0009] An aim of certain embodiments of the present invention is to provide a microneedle patch having a sturdier base than the prior art patches, and that allows for easier application, as well as a method of forming the same.BRIEF SUMMARY OF THE DISCLOSURE

[0010] A first aspect of the invention provides a microneedle patch comprising:an insoluble base comprising one or more insoluble protrusions extending from a surface of the base; andone or more biosoluble microneedles comprising a tip and a base,wherein each of the one or more biosoluble microneedles extends from a surface of each of the one or more protrusions; andwherein the base diameter of the one or more microneedles is from about 0.2 mm to about 0.7 mm;wherein the tip diameter of the one or more microneedles is from about 0.1 mm to about 0.7 mm.

[0011] Having a base diameter of the one or more microneedles that is from about 0.2 mm to about 0.7 mm provides microneedles patches that are less invasive. Microneedles having a base diameter of greater than 0.7 mm will cause a larger opening in the epidermis, causing damage to the skin and more pain to the subject.

[0012] Microneedles having a tip diameter of from about 0.1 mm to about 0.7 mm canefficiently penetrate the corneum without causing significant patient discomfort but are wide enough to be resilient (and therefore less brittle / prone to breakage upon application).

[0013] In a preferred embodiment, the insoluble base comprises a plurality of protrusions and the microneedle patch comprises a plurality of microneedles.

[0014] A second aspect of the invention provides a method of forming a microneedle patch, the method comprising:a) providing an insoluble patch base comprising one or more insoluble protrusions extending from a surface of the insoluble patch base, wherein the one or more protrusions comprise a surface facing away from the surface of the insoluble patch base;b) wetting the surface of at least one of the one or more protrusions of the insoluble patch base;c) depositing biosoluble polymer powder onto the wetted surface of the at least one protrusion of the insoluble patch base;d) forming a droplet comprising the biosoluble polymer on the wetted surface of the at least one protrusion of the insoluble patch base;e) providing a template base comprising one or more protrusions extending from a surface of the template base, wherein the one or more protrusions comprise a surface facing away from the surface of the template base;f) superimposing the insoluble patch base and the template base so that the surface of one of the one or more protrusions of the template base contacts the polymer droplet on the at least one wetted protrusion of the insoluble patch base;g) increasing the distance between the one or more protrusions of the insoluble patch base and the one or more protrusions of the template base so as to elongate the polymer droplet; andh) forming a bio-soluble microneedle from the elongated polymer droplet on the surface of the at least one wetted protrusion of the insoluble patch base to form the microneedle patch,wherein the diameter of the surface of the one or more protrusions of the template base is smaller than the diameter of the surface of the one or more protrusions of the insoluble patch base.

[0015] Due to the use of polymer powder in step c), microneedle patches comprising one or more microneedles having a base diameter that is from about 0.2 mm to about 0.7 mm can be fabricated. The method also allows microneedle patches comprising one or more microneedles having a tip diameter of from about 0.1 mm to about 0.7 mm to be fabricated.

[0016] The method of the second aspect of the invention may be a method of forming a microneedle patch according to the first aspect of the invention.

[0017] In a preferred embodiment, the insoluble patch base comprises a plurality of protrusions extending from the surface of the insoluble patch base; and the template base comprises a plurality of protrusions extending from the surface of the template base. Therefore, the method of the second aspect of the invention may be a method of forming a microneedle patch, the method comprising:a) providing an insoluble patch base comprising a plurality of insoluble protrusions extending from a surface of the insoluble patch base, wherein each of the plurality of protrusions comprises a surface facing away from the surface of the insoluble patch base;b) wetting the surfaces of the protrusions of the insoluble patch base;c) depositing biosoluble polymer powder onto the wetted surfaces of the protrusion of the insoluble patch base;d) forming droplets comprising the biosoluble polymer on the wetted surfaces of the protrusions of the insoluble patch base;e) providing a template base comprising a plurality of protrusions extending from a surface of the template base, wherein each of the plurality of protrusions comprise a surface facing away from the surface of the template base;f) superimposing the insoluble patch base and the template base so that the surfaces of the protrusions of the template base contact the polymer droplets on the wetted surfaces of the protrusions of the insoluble patch base;g) increasing the distance between the protrusions of the insoluble patch base and the protrusions of the template base so as to elongate the polymer droplets; andh) forming a plurality of bio-soluble microneedles from the elongated polymer droplets on the wetted surfaces of the protrusion of the insoluble patch base to form the microneedle patch,wherein the diameter of the surfaces of the plurality of protrusions of the template base is smaller than the diameter of the surfaces of the plurality of protrusions of the insoluble patch base.

[0018] A third aspect of the invention provides a microneedle patch obtained by the method of the second aspect of the invention.

[0019] A fourth aspect of the invention provides a method of medical treatment, the method comprising applying the microneedle patch according to the first aspect of the invention, wherein the one or more microneedles comprise a medicament, or a microneedle patch obtained by the method of the second aspect of the invention, wherein step c) further comprises depositing a medicament onto the wetted surface of the at least one protrusion of the insoluble patch base, to a subject.

[0020] A fifth aspect of the invention provides a method of vaccination, the method comprising applying the microneedle patch according to the first aspect of the invention, wherein the one or more microneedles comprise a vaccine, or a microneedle patch obtained by the method of the second aspect of the invention, wherein step c) further comprises depositing a vaccine onto wetted surface of the at least one protrusion of the insoluble patch base, to a subject.

[0021] A sixth aspect of the invention provides a method of cosmetic treatment, the method comprising applying the microneedle patch according to the first aspect of the invention, wherein the one or more microneedles comprise a cosmetic, or a microneedle patch obtained by the method of the second aspect of the invention, wherein step c) further comprises depositing a cosmetic onto the wetted surface of the at least one protrusion of the insoluble patch base, to a subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which:Figure 1 depicts steps 4) to 6) of the method of forming a microneedle according to Example 1, showing droplets (1); template patch (2); customer patch (3); and formed microneedles (4).Figures 2a-d show 3D microscope images of a microneedle patch made according to Example 1 and certain microneedle parameter measurements.In Figure 2a measurement [1] is 0.43 mm, [2] is 0.20 mm, [3] is 0.18 mm, [4] is 0.47 mm, [5] is 0.23 mm, [6] is 0.23 mm, [7] is 0.43 mm, [8] is 0.45 m, [9] is 0.19 mm,

[0010] is 0.24mm,

[0011] is 0.48 mm,

[0012] is 0.48 mm,

[0013] is 0.26 mm,

[0014] is 0.53 mm,

[0015] is 0.28 mm,

[0016] is 0.48 mm,

[0017] is 0.23 mm,

[0018] is 0.27 mm,

[0019] is 0.53 mm, and

[0020] is 0.53 mm.In Figure 2b measurement

[0021] is 0.48 mm,

[0022] is 0.27 mm,

[0023] is 0.26 mm,

[0024] is 0.45 mm,

[0025] is 0.48 mm,

[0026] is 0.29 mm,

[0027] is 0.16 mm,

[0028] is 0.53 m,

[0029] is 0.39 mm,

[0030] is 0.26 mm,

[0031] is 0.21 mm,

[0032] is 0.50 mm,

[0033] is 0.44 mm,

[0034] is 0.31 mm,

[0035] is 0.21 mm,

[0036] is 0.52mm,

[0037] is 0.20 mm,

[0038] is 0.48 mm,

[0039] is 0.28 mm, and

[0040] is 0.56 m.In Figure 2c measurement [1] is 0.19 mm, [2] is 0.47 mm, [3] is 0.18 mm, [4] is 0.46 mm, [5] is 0.19 mm, [6] is 0.47 mm, [7] is 0.16 mm, [8] is 0.48 mm, [9] is 0.20 mm, and

[0010] is 0.45 mm.In Figure 2d, measurement

[0011] is 0.19 mm,

[0012] is 0.50 mm,

[0013] is 0.20 mm,

[0014] is 0.50 mm,

[0015] is 0.20 mm,

[0016] is 0.49 mm,

[0017] is 0.20 mm, and

[0018] is 0.45 mm.Figure 3 shows the CT scans of microneedle patches loaded with ipodominal (white specs in pictures 10 and 11 and blackspecs in negatives 1 and 2) and ipodominaldistribution in skin (marks on pictures 2 and 3, and negatives) taken during the penetration study of Example 3.Figure 4 shows pictures of microneedle patches loaded with blue dye (left) and the subsequent dissolution in artificial skin (top right) and porcine skin (bottom right) 5 minutes after application in the dissolution study of Example 4.Figure 5 is a picture of the application site on human skin immediately after application (left) and the 15 minutes after application (right) in the human patch test of Example 5.Figure 6 provides a graph showing the thermal stability of the influenza vaccine in the microneedle patch and the liquid control of Example 6.Figure 7 shows the force / displacement (distance) plot from the strength test of Example 7.Figure 8 is a force / displacement (distance) plot disclosed in B. H. Alrimawi, et al., RSC Pharm., 2024, 1, 227-233 (with the numbers on the X- and Y-axes removed). This figure shows the expected plot of microneedle breakage during a compression test.Figure 9 shows the results of the in vivo test of Example 8.DETAILED DESCRIPTIONMicroneedle PatchThe first aspect of the invention provides a microneedle patch.Microneedle Base Diameter

[0023] It may be that the base diameter of the one or more biosoluble microneedles is greater than, or equal to, about 0.25 mm. It may be that the base diameter of the one or more biosoluble microneedles is greater than, or equal to, about 0.3 mm. It may be that the base diameter of the one or more biosoluble microneedles is greater than, or equal to, about 0.35 mm.

[0024] It may be that the base diameter of the one or more biosoluble microneedles is less than, or equal to, about 0.6 mm. It may be that the base diameter of the one or more biosoluble microneedles is less than, or equal to, about 0.55 mm. It may be that the base diameter of the one or more biosoluble microneedles is less than, or equal to, about 0.5 mm.

[0025] Preferably, the base diameter of the one or more biosoluble microneedles is in the range of about 0.35 mm to about 0.6 mm. Typically, the one or more biosoluble microneedles will have the same, or substantially the same, diameter.Microneedle Tip diameter

[0026] It may be that the tip diameter of the one or more microneedles is from about 0.1 mm to about 0.65 mm. It may be that the tip diameter of the one or more microneedles is from about 0.1 mm to about 0.6 mm. It may be that the tip diameter of the one or more microneedles is from about 0.1 mm to about 0.55 mm. It may be that the tip diameter of the one or more microneedles is from about 0.1 mm to about 0.5 mm. It may be that the tip diameter of the one or more microneedles is from about 0.1 mm to about 0.45 mm. It may be that the tip diameter of the one or more microneedles is from about 0.1 mm to about 0.4 mm. It may be that the tip diameter of the one or more microneedles is from about 0.1 mm to about 0.35 mm. It may be that the tip diameter of the one or more microneedles is from about 0.1 mm to about 0.3 mm. It may be that the tip diameter of the one or more microneedles is from about 0.1 mm to about 0.25 mm.

[0027] It may be that the tip diameter of the one or more microneedles is from about 0.15 mm to about 0.7 mm. It may be that the tip diameter of the one or more microneedles is from about 0.15 mm to about 0.65 mm. It may be that the tip diameter of the one or more microneedles is from about 0.15 mm to about 0.6 mm. It may be that the tip diameter of the one or more microneedles is from about 0.15 mm to about 0.55 mm. It may be that the tip diameter of theone or more microneedles is from about 0.15 mm to about 0.50 mm. It may be that the tip diameter of the one or more microneedles is from about 0.15 mm to about 0.45 mm. It may be that the tip diameter of the one or more microneedles is from about 0.15 mm to about 0.4 mm. It may be that the tip diameter of the one or more microneedles is from about 0.15 mm to about 0.35 mm. It may be that the tip diameter of the one or more microneedles is from about 0.15 mm to about 0.3 mm. It may be that the tip diameter of the one or more microneedles is from about 0.15 mm to about 0.25 mm.

[0028] As mentioned above, microneedles having a tip diameter within these ranges can efficiently penetrate the corneum without causing significant patient discomfort but are wide enough to be resilient (and therefore less brittle / prone to breakage upon application).Microneedle Height

[0029] The height of the one or more biosoluble microneedles may be less than or equal to about 1 mm. The height of the one or more biosoluble microneedles may be from about 0.1 mm to about 0.9 mm. The height of the one or more biosoluble microneedles may be from about 0.2 mm to about 0.7 mm. The height of the one or more biosoluble microneedles may be from about 0.3 mm to about 0.6 mm. The height of the one or more biosoluble microneedles may be from about 0.36 mm to about 0.56 mm. Microneedles of this height can effectively deliver the medicament or cosmetic to the target site but reduce the risk of reaching pain receptors.Microneedle Volume

[0030] The volume of the one or more microneedles calculated according to equation I:volume = ⅓π(MN base diameter / 2)² × microneedle height (I),may be from about 0.001 mm3to about 0.1 mm3. The volume of the one or more microneedles calculated according to equation I may be from about 0.001 mm3to about 0.05 mm3, e.g. from about 0.001 mm3to about 0.01 mm3. The volume of the one or more microneedles calculated according to equation I may be from about 0.001 mm3to about 0.006 mm3. The volume of the one or more microneedles calculated according to equation I may be from about 0.002 mm3to about 0.004 mm3.Microneedle Surface Area

[0031] The surface area of the one or more microneedles calculated according to equation II:J f MN base diameters 7,,.,, •> \ \ I - 1 + height^ I (II),may be from about 0.2 mm2to about 0.9 mm2, e.g. from about 0.3 mm2to about 0.8 mm2. The surface area of the one or more microneedles calculated according to equation II may be from about 0.4 mm2to about 0.7 mm2, e.g. from about 0.46 mm2to about 0.66 mm2.Microneedle Shape

[0032] The one or more biosoluble microneedles may be of any shape that is suitable to penetrate the corneum. For example, the one or more biosoluble microneedles may be substantially pyramidal or substantially conical in shape.

[0033] The one or more biosoluble microneedles may be substantially pyramidal in shape. For example, the one or more biosoluble microneedles may be substantially in the shape of a triangular, rectangular, square, pentagonal, or hexagonal based pyramid. The one or more biosoluble microneedles may be substantially in the shape of a right pyramid (whose apex is exactly over the middle of its base). The one or more biosoluble microneedles may be substantially in the shape of an oblique pyramid (whose apex is not exactly over the middle of its base). The one or more biosoluble microneedles may be substantially in the shape of a regular pyramid (whose base is a regular polygon, and lateral faces are the same). The one or more biosoluble microneedles may be substantially in the shape of an irregular pyramid (whose base is an irregular polygon, and lateral faces are different).

[0034] The one or more biosoluble microneedles may be substantially conical in shape. The one or more biosoluble microneedles may be substantially in the shape of a right cone (whose apex is exactly over the middle of its base). The one or more biosoluble microneedles may be substantially in the shape of an oblique cone (whose apex is not exactly over the middle of its base).

[0035] The one or more biosoluble microneedles may be substantially in the shape of an elliptic paraboloid.

[0036] Each of the one or more bio-soluble microneedles extends from a surface of each of the one or more protrusions. Typically, each of the one or more bio-soluble microneedles extends directly from the surface of the protrusion, such that there is no intermediate layer (e.g. biosoluble intermediate layer) between the bio-soluble microneedle and the surface of the protrusion from which it extends. The direct extension of a bio-soluble microneedle from the surface of the protrusion may improve the structural integrity of the microneedle patch.

[0037] It may be that the one or more biosoluble microneedles is in contact with the full crosssection of the surface of each of the one or more protrusions from which it extends.

[0038] It may be that the one or more bio-soluble microneedles do not protrude or extend into the protrusion from which they extend.Microneedle Polymer Matrix

[0039] Typically, the one or more biosoluble microneedles comprise a biosoluble polymer matrix. Due to the intended use of the microneedle patches of the present invention, the biosoluble polymer matrix should be biocompatible.

[0040] The biosoluble polymer may be selected from: polyacrylamide, polyacrylic acid, polyallylamine, polyethylene glycol, polyethylene oxide, polylysine, polymaleic acid, polymethacrylic acid, polystyrenesulfonic acid, polyvinyl acetate, polyvinyl alcohol, polyvinylamine, polyvinylphosphonic acid, polyvinylpyrrolidone (PVP), poly(2-ethyl-2-oxazoline), poly(2-vinylpyridine), poly(4-vinylpyridine), and poly(n-isopropylacrylamide), and mixtures, copolymers, pharmaceutically acceptable salts, and pharmaceutically acceptable N-oxides thereof.

[0041] The biosoluble polymers may also be a biopolymer, such as a protein (e.g., collagen, elastin, gelatin, and keratin), or polysaccharide (e.g., cellulose, carboxymethylcellulose, hydroxypropyl cellulose, carboxymethyl starch, dextran, pectin, alginic acid, carrageenan, heparin, gellan gum, agarose, hyaluronic acid, chitosan, or a pharmaceutically acceptable salt thereof).

[0042] It may be that the polymer matrix is a polyvinylpyrrolidone (PVP) matrix. The PVP may have a molecular weight of <500,000, e.g. <100,000. The PVP may have a molecular weight of <50,000. The PVP may have a molecular weight of 2000 to 20,000.

[0043] The one or more biosoluble microneedles may comprise greater than 75 wt% of the biosoluble polymer matrix. The one or more biosoluble microneedles may comprise from 90 to 99.9 wt% of the biosoluble polymer matrix.Medicaments and Cosmetics

[0044] Typically, the one or more microneedles will comprise a medicament or a cosmetic.

[0045] The one or more microneedles may comprise a cosmetic. The cosmetic may be a cosmetic selected from botulinum toxin (e.g. botulinum toxin Type A), dermal fillers / biostimulators (e.g., hyaluronic acid, calcium hydroxylapatite, polymethylmethacrylate, poly-L-lactic acid, polynucleotides, collagen, and mixtures thereof), deoxycholic acid, vitamins, and tattoo ink. The one or more microneedles may comprise tattoo ink.

[0046] The one or more microneedles may comprise a medicament. The total amount ofmedicament in the one or more microneedles should be therapeutically acceptable.

[0047] The medicament may be a dermatological agent (e.g., an acne agent, an antiinflammatory agent, an antipruritic agent, a calcineurin inhibitor, a caustic agent, an emollient, a genital wart agent, a mitotic inhibitor, a non-melanoma skin cancer agent, a photochemotherapy agent, a psoriasis agent, or a wound care agent).

[0048] The medicament may be nicotine. The microneedle patch may therefore be a nicotine patch for use in a nicotine replacement therapy.

[0049] The medicament may be a nicotine replacement compound. The nicotine replacement compound may be selected from varenicline, bupropion, and cytisine.

[0050] The medicament may be an antibiotic.

[0051] The medicament may be an anaesthetic. The medicament may be a local anaesthetic.

[0052] The medicament may be insulin.

[0053] The medicant may be selected from vitamins, micronutrients, nutraceuticals, dietary supplements, and cannabinoids (e.g. cannabidiol).

[0054] In preferred embodiments, the medicament is a vaccine. The medicament may be a vaccine antigen. For example, the medicament may be selected from tetanus toxoid and tetanus-diphtheria (Td) combinations, influenza virus antigens (inactivated or subunit), hepatitis A antigens, typhoid antigens (including Vi polysaccharide), and protein subunit vaccine antigens (general class).

[0055] The one or more microneedles may comprise from 2.5μg to 100μg vaccine per microneedle patch.

[0056] The medicament may be a biologic. The medicament may be an advanced therapy medicinal product. For example, the medicament may be selected from GLP-1 receptor agonists and related incretin-based therapies, mRNA-based vaccines and therapeutics (including m RNA— lipid nanoparticle formulations), DNA-based vaccines, peptide- and protein-based biologies, and monoclonal antibody fragments and antibody-derived constructs.

[0057] The medicament may be a small-molecule pharmaceutical. For example, the medicament may be selected from analgesics and anti-inflammatory agents, hormones and endocrine therapies, anti-infectives (including antibiotics and antivirals), and cardiovascular and metabolic therapeutics.

[0058] There may be a concentration gradient of the medicament or cosmetic along the lengthof the base to the tip of the one or more microneedles. The concentration gradient may increase towards the tip of the one or more microneedles.

[0059] Typically, the one or more microneedles comprise medicament or cosmetic at the tip of the microneedle. It may be that the one or more microneedles do not comprise any medicament or cosmetic at the interface between the base of the one or more microneedles and the surface of the one or more insoluble protrusions from which they extend.

[0060] A medicament or cosmetic concentration gradient that increases towards the tip of the one or more microneedles from the base thereof may be advantageous in ensuring adequate administration of the medicament or cosmetic to the area of skin onto which the microneedle patch is applied in the event that complete penetration of the microneedle into the skin is not achieved.

[0061] Alternatively, it may be that there is not a concentration gradient of the medicament or cosmetic along the length of the base to the tip of the one or more microneedles, i.e. the concentration of the medicament or cosmetic substantially uniform along the length of the base to the tip of the one or more microneedles.

[0062] The one or more microneedles may also comprise a biocompatible dye. For example, biocompatible dyes in powder form can be incorporated into the microneedle. For example, the microneedles may comprise E133 dye.

[0063] It may be that the one or more microneedles comprise tattoo ink. It may be that the one or more microneedles comprise tattoo ink and the insoluble base comprises a plurality of insoluble protrusions extending from a surface of the base arranged in a pattern or in the form of an image. It may be that the one or more microneedles comprise a pigment.Protrusion Shape

[0064] Typically, the surface of the one or more protrusions from which the one or more biosoluble microneedles extend faces away from the surface of the insoluble base from which the one or more protrusions extend. It may be that the surface of the one or more protrusions from which the one or more biosoluble microneedles extend is substantially parallel to the surface of the insoluble base from which the protrusions extend.

[0065] Typically, the surface of the one or more protrusions from which the one or more biosoluble microneedles extend is substantially flat.

[0066] It may be that the one or more protrusions are substantially cylindrical in shape. The one or more protrusions may be substantially in the shape of a right cylinder (having its axisperpendicular to the plane of its bases). The one or more protrusions may be substantially in the shape of an oblique cylinder (with its axis not perpendicular to the plane of its bases). The one or more protrusions may be substantially in the shape of an elliptic cylinder (with bases in the form of an ellipse). The one or more protrusions may be cylinders.

[0067] The one or more protrusions may be substantially in the shape of a prism, e.g. a triangular, rectangular, square, pentagonal, hexagonal, heptagonal, octagonal, or trapezoidal prism.

[0068] The one or more protrusions may be substantially in the shape of a hyperboloid.

[0069] It may be that the shape of the base of the one or more biosoluble microneedles will be substantially the same as the shape of the surface of the protrusion from which the one or more biosoluble microneedles extend. For example, if the one of more protrusions are substantially cylindrical in shape, then the one or more biosoluble microneedles will be substantially conical in shape.Protrusion Height

[0070] It may be that the height of the one or more insoluble protrusions is in the range from about 0.1 mm to about 1.5 mm, e.g. from about 0.2 mm to about 1.0 mm. It may be that the height of the one or more insoluble protrusions is in the range from about 0.3 mm to about 0.9 mm, e.g. from about 0.4 mm to about 0.8 mm. It may be that the height of the one or more insoluble protrusions is in the range from about 0.4 mm to about 0.6 mm. It may be that the height of the one or more insoluble protrusions is in the range from about 0.5 mm to about 0.7 mm.

[0071] A shorter protrusion will provide less invasive microneedle insertion, although the risk of not inserting the microneedle properly and / or incomplete dissolution will be higher.

[0072] A taller protrusion will provide more invasive microneedle insertion, although the risk of not inserting the microneedle properly and / or incomplete dissolution will be lower.Protrusion Surface Diameter

[0073] It may be that the diameter of the surface of the one or more protrusions (from which each of the one or more biosoluble microneedles extends) is from about 0.2 mm to about 0.9 mm, e.g. from about 0.3 mm to about 0.8 mm. It may be that the diameter of the surface of each of the one or more protrusions is from about 0.4 mm to about 0.7 mm, e.g. from about 0.45 mm to about 0.65 mm. It may be that the diameter of the surface of each of the one or more protrusions is from about 0.5 mm to about 0.7 mm. It may be that the diameter of the surface ofeach of the one or more protrusions is from about 0.5 mm to about 0.6 mm.

[0074] Typically, the surfaces of each of the one or more protrusions will have substantially the same diameter. It may be that the base diameter of the one or more biosoluble microneedles will be substantially the same as the diameter of the surface of each of the one or more protrusions from which each of the one or more biosoluble microneedles extends. It may be that the base diameter of the one or more biosoluble microneedles will be slightly smaller (e.g. <0.1 mm smaller) than the diameter of the surface of each of the one or more protrusions from which each of the one or more biosoluble microneedles extends.Protrusion Array

[0075] Typically, the insoluble base will comprise a plurality of insoluble protrusions extending from a surface of the base. It may be that the insoluble base comprises at least 30, e.g. at least 40, insoluble protrusions. It may be that the insoluble base comprises at least 50, e.g. at least 60, insoluble protrusions. It may be that the insoluble base comprises at least 70, e.g. at least 80, insoluble protrusions. It may be that the insoluble base comprises at least 45, e.g. at least 50, insoluble protrusions. It may be that the insoluble base comprises at least 90, e.g. at least 100, insoluble protrusions.

[0076] It may be that the insoluble patch base comprises no more than 350 insoluble protrusions, e.g. no more than 340 insoluble protrusions. It may be that the insoluble patch base comprises no more than 330 insoluble protrusions, e.g. no more than 320 insoluble protrusions. It may be that the insoluble patch bases comprise no more than 310 insoluble protrusions, e.g. no more than 300 insoluble protrusions.

[0077] The patch base may comprise from 100 to 300 insoluble protrusions, e.g. from 125 to 275 insoluble protrusions. The patch base may comprise from 150 to 250 insoluble protrusions, e.g. from 175 to 225 insoluble protrusions. The patch base may comprise 196 protrusions.

[0078] Typically, the plurality of protrusions are arranged in an array on the surface of the base.

[0079] The plurality of protrusions may be arranged in an array such that the number of protrusions arranged along the x-axis of the array is from 4 to 24, e.g. from 6 to 22. The plurality of protrusions may be arranged in an array such that the number of protrusions arranged along the x-axis of the array is from 8 to 20, e.g. from 10 to 18. The plurality of protrusions may be arranged in an array such that the number of protrusions arranged along the x-axis of the array is from 12 to 16.

[0080] The plurality of protrusions may be arranged in an array such that the number ofprotrusions arranged along the y-axis of the array is from 4 to 24, e.g. from 6 to 22. The plurality of protrusions may be arranged in an array such that the number of protrusions arranged along the y-axis of the array is from 8 to 20, e.g. from 10 to 18. The plurality of protrusions may be arranged in an array such that the number of protrusions arranged along the y-axis of the array is from 12 to 16.

[0081] It may be that the patch base comprises 196 protrusions and the plurality of protrusions are arranged in an 14x14 array.

[0082] It may be that alternate rows of the plurality of cylinders in the array are offset from each other.

[0083] It may be that the array has a density of up to about 1600 protrusions per cm2. It may be that the array has a density of up to about 1225 protrusions per cm2. It may be that the array has a density of up to about 900 protrusions per cm2. It may be that the array has a density of up to about 625 protrusions per cm2. It may be that the array has a density of up to about 400 protrusions per cm2. It may be that the array has a density of up to about 225 protrusions per cm2.

[0084] It may be that the array has a density of about 9 to about 225 protrusions per cm2, e.g. about 16 to about 196 protrusions per cm2. It may be that the array has a density of about 25 to about 169 protrusions per cm2, e.g. about 36 to about 144 protrusions per cm2. It may be that the array has a density of about 49 to about 121 protrusions per cm2, e.g. about 64 to about 100 protrusions per cm2. It may be that the array has a density of about 64 to about 100 protrusions per cm2. It may be that the array has a density of about 81 protrusions per cm2

[0085] The skilled person will appreciate that protrusions having a smaller diameter will allow for a larger array density.

[0086] It may be that the distance between the centre point of adjacent protrusions is from 1.5 to 2.5 times the diameter of the surface of the one or more protrusions. It may be that the distance between the centre point of adjacent protrusions is about 2 times the diameter of the surface of the one or more protrusions.Insoluble Patch Base Dimensions

[0087] The insoluble patch base may be from about 1 to about 100 mm in length. The insoluble patch base may be from about 1 to about 50 mm in length, e.g. from about 5 mm to about 50 mm in length. The insoluble patch base may be from about 10 to about 40 mm in length, e.g. from about 15 mm to about 35 mm in length. The insoluble patch base may be from about 20 toabout 30 mm in length.

[0088] The insoluble patch base may be from about 1 to about 100 mm in width. The insoluble patch base may be from about 1 to about 50 mm in width, e.g. from about 5 mm to about 50 mm in width. The insoluble patch base may be from about 10 to about 40 mm in width, e.g. from about 15 mm to about 35 mm in width. The insoluble patch base may be from about 20 to about 30 mm in width.

[0089] The length and width of the insoluble patch base may be independently from about 1 to about 100 mm. The length and width of the insoluble patch base may be independently from about 1 to about 50 mm, e.g. from about 5 mm to about 50 mm. The length and width of the insoluble patch base may be independently from about 10 to about 40 mm, e.g. from about 15 mm to about 35 mm. The length and width of the insoluble patch base may be independently from about 20 to about 30 mm.

[0090] The thickness of the insoluble patch base may be less than or equal to about 15 mm, e.g. less than or equal to about 12.5 mm. The thickness of the insoluble patch base may be less than or equal to about 10 mm, e.g. less than or equal to about 7.5 mm. The thickness of the insoluble patch base may be greater than or equal to about 1 mm, e.g. less than or equal to about 2.5 mm. The aforementioned thicknesses (heights) of the patch base do not include the height of the one or more insoluble protrusions.

[0091] The surface of the patch base from which the one or more insoluble protrusions extend will typically be substantially square, or substantially rectangular in shape rectangular. Other shapes, e.g. circles, or 3, other 4, 5, 6, etc, sided shapes are also possible, so long as the patch can be applied.Insoluble Patch Base Material

[0092] The insoluble base may be a silicon, metallic, ceramic, glass, or polymeric base.Preferably, the insoluble base is an insoluble polymeric base. The insoluble base may comprise (e.g. consist of) an insoluble polymer.

[0093] The insoluble polymer may be selected from acrylonitrile butadienestyrene (ABS) (chemical formula (C8H8·C4H6·C3H3N)n); polycarbonate / acrylonitrile butadiene styrene alloys (PCABS); polybutylene terephthalate (PBT); polyethylene terephthalate glycol (PETG); polyphenylene oxide; polyphthalamide (PPA); polyphenylene sulfide (PPS); polyphenylene ether; modified polyphenylene ether containing polystyrene; liquid crystal polymers; polystyrene; styrene-acrylonitrile copolymer; rubber-reinforced polystyrene; poly ether ketone (PEEK);polyetherketoneketone (PEKK); polyetherimide; acrylic resins such as polymers and copolymers of alkyl esters of acrylic and methacrylic acid styrene-methyl methacrylate copolymer, styrenemethyl methacrylate-butadiene copolymer, polymethyl methacrylate and methyl methacrylatestyrene copolymer; polyvinyl acetate; polysulfone; polyether sulfone; polyether imide; polyarylate; polyamideimide; polyvinyl chloride; vinyl chloride-ethylene copolymer; vinyl chloride-vinyl acetate copolymer; polyimides, polyamides; polyolefins such as polyethylene; ultra-high molecular weight polyethylene; high density polyethylene; linear low density polyethylene; polyethylene napthalate; polyethylene terephthalate; polypropylene; chlorinated polyethylene; ethylene acrylic acid copolymers; polyanilines; polypyrroles; polyurethanes; polyepoxides; epoxy resins; phenylene oxide resins; phenylene sulfide resins; polyoxymethylenes; polyesters; polyvinyl chloride; vinylidene chloride / vinyl chloride resins; vinyl aromatic resins such as polystyrene; poly(vinylnaphthalene); poly(vinyltoluene); and mixtures, copolymers, salts, and derivatives (including side-chain functionalised derivatives) thereof.

[0094] The insoluble base may comprise (e.g. consist of) an insoluble polymer that is suitable for 3D printing. The insoluble base may comprise (e.g. consist of) an insoluble polymer that is suitable for laser engraving. The insoluble base may comprise (e.g. consist of) an insoluble polymer that is suitable for moulding. The insoluble base may comprise (e.g. consist of) an acrylic resin, e.g. polymethyl methacrylate.

[0095] The insoluble base may comprise (e.g. consist of) a material that is suitable for moulding. Such materials include plastics, metals, ceramics, rubbers, elastomers, composites, resins, natural materials, foams, glass, cementitious materials, paper-based materials, waxes, gels, and sand / refractory materials.

[0096] Typically, the insoluble base and the one or more insoluble protrusions are a single unit and are therefore formed from the same material.

[0097] Typically, the insoluble base is formed entirely from an insoluble material. Typically, the insoluble base does not contain any bio-soluble material. It may be that the insoluble base does not comprise any internal region having a solubility different from that of the bulk of the insoluble base. It may be that the insoluble base does not encapsulate or include any bio-soluble material. It may be that the insoluble base does not comprise any internal hollow structure, such as a cavity, through-hole, or aperture. It may be that the insoluble base does not comprise any internal hollow structure, such as a cavity, through-hole, or aperture, in which a bio-soluble material is provided.

[0098] Typically, the one or more insoluble protrusions are formed entirely from an insoluble material. Typically, the one or more insoluble protrusions do not contain any bio-soluble material. It may be that the one or more insoluble protrusions do not comprise any internal region having a solubility different from that of the bulk of the insoluble base. It may be that the one or more insoluble protrusions do not encapsulate or include any bio-soluble material. It may be that the one or more insoluble protrusions do not comprise any internal hollow structure, such as a cavity, through-hole, or aperture. It may be that the one or more insoluble protrusions do not comprise any internal hollow structure, such as a cavity, through-hole, or aperture, in which a bio-soluble material is provided.Method of Forming a Microneedle Patch

[0099] The second aspect of the invention provides a method of forming a microneedle patch.Step a)

[0100] The insoluble patch base and the one or more insoluble protrusions may be as defined above in connection with the first aspect of the invention. It may be that the surface of the one or more protrusions of the insoluble patch base is substantially flat. The diameter of the surface of the one or more protrusions may be less than, or equal to, about 0.7 mm.Step b)

[0101] In step b) the surface of at least one of the one or more protrusions of the insoluble patch base is wetted with a solvent. Typically, the solvent will comprise water and / or a buffer solution. Preferably, the solvent is water. The solvent may however comprise an organic solvent. The organic solvent may be a polar organic solvent. The polar organic solvent may be a C1-C6alcohol, e.g. methanol, ethanol, or isopropyl alcohol.

[0102] It may be that step b) comprises spraying the surface of the at least one of the one or more protrusions with the solvent. This may be achieved via the use of an atomiser. Alternatively, step b) may comprise contacting the surface of the at least one of the one or more protrusions with (bulk liquid) solvent, e.g. dipping the at least one of the one or more protrusions in the solvent.Step c)

[0103] Typically, step c) will be achieved by contacting the wetted surface of the at least one protrusion of the insoluble patch base with the polymer powder. It may be that the insoluble patch base is inserted into a box comprising the polymer powder so that the wetted surface of the at least one protrusion contacts the powder, wherein the shape of the box iscomplementary to the shape of the insoluble patch base.

[0104] It may be that the wetted surface of the at least one protrusion is contacted with polymer powder at least twice, e.g. at least three times.

[0105] The biosoluble polymer may be selected from: polyacrylamide, polyacrylic acid, polyallylamine, polyethylene glycol, polyethylene oxide, polylysine, polymaleic acid, polymethacrylic acid, polystyrenesulfonic acid, polyvinyl acetate, polyvinyl alcohol, polyvinylamine, polyvinylphosphonic acid, polyvinylpyrrolidone (PVP), poly(2-ethyl-2-oxazoline), poly(2-vinylpyridine), poly(4-vinylpyridine), and poly(n-isopropylacrylamide), and mixtures, copolymers, pharmaceutically acceptable salts, and pharmaceutically acceptable N-oxides thereof.

[0106] The biosoluble polymers may also be a biopolymer, such as a protein (e.g., collagen, elastin, gelatin, and keratin), or polysaccharide (e.g., cellulose, carboxymethylcellulose, hydroxypropyl cellulose, carboxymethyl starch, dextran, pectin, alginic acid, carrageenan, heparin, gellan gum, agarose, hyaluronic acid, chitosan, or a pharmaceutically acceptable salt thereof).

[0107] It may be that the biosoluble polymer is PVP. The PVP may have a molecular weight of <500,000, e.g. <100,000. The PVP may have a molecular weight of <50,000. The PVP may have a molecular weight of 2000 to 20,000.

[0108] Preferably, step c) further comprises depositing a medicament or a cosmetic onto the wetted surface of the at least one protrusion of the insoluble patch base. The medicament or cosmetic will typically be powdered. The medicament may be a lyophilized vaccine.

[0109] It may be that step c) comprises contacting the wetted surface of the at least one protrusion of the insoluble patch base with a mixture comprising the polymer powder and the (optionally powdered) medicament or cosmetic. The mixture comprising the polymer powder and the (optionally powdered) medicament or cosmetic may comprise up to 50 wt% of the (optionally powdered) medicament or cosmetic. For example, the mixture comprising the polymer powder and the (optionally powdered) medicament or cosmetic may comprise up from 10 to 40 wt% of the (optionally powdered) medicament or cosmetic.

[0110] Step c) may comprise:contacting the wetted surface of the at least one protrusion of the insoluble patch base with the polymer powder, e.g. at least twice, or at least three times; andcontacting the wetted surface of the at least one protrusion of the insoluble patch base with a mixture comprising the polymer powder and the (optionally powdered) medicament or cosmetic, e.g. at least twice, or at least three times.

[0111] This process may result in the build-up of polymer powder layers followed by layers of a mixture of polymer powder and medicament or cosmetic. This process may result in a concentration gradient of the medicament or cosmetic that increases towards the tip of the one or more microneedles from the base thereof.

[0112] Prior to contact with wetted surface of the at least one protrusion, the polymer powder and / or the mixture comprising the polymer powder and the (optionally powdered) medicament or cosmetic may be distributed evenly on a surface. The powder / mixture may be distributed using a powder dispenser and a roller. The powder / mixture may be distributed using a 3D printed leveller. The surface on which the powered / mixture is distributed may be smooth. Alternatively, the surface may be engraved.Step d)

[0113] Typically, step d) will comprise dissolving and / or suspending the biosoluble polymer powder on the wetted surface to form a droplet of polymer solution and / or suspension on the surface of the at least one protrusion.

[0114] Step d) may comprise drying the insoluble patch base, e.g. at room temperature. It may be that the patch base is dried for no longer than 30 seconds, e.g. no longer than 20 second. It may be that the patch base is dried for no longer than 15 seconds, e.g. no longer than 10 seconds. It may be that the insoluble patch base is dried, e.g. at room temperature, in a humidification chamber. It may be that the insoluble patch base is dried at a relative humidity of <40%.

[0115] The skilled person will appreciate that certain conditions of step d) may need to be altered depending on the solubility of the biosoluble polymer powder in the solvent on the wetted surface of the at least one protrusion. Such conditions include the length for which, and / or the temperature and / or the relative humidity at which, the insoluble patch base is dried.Step eVTemplate base

[0116] The protrusion shape, protrusion height, protrusion surface diameter, protrusion array, patch base length, patch base width, patch base thickness, patch base, shape, distance between protrusions, and / or patch base composition of the template base may be as defined above regarding the insoluble patch base of the first aspect of the invention.

[0117] Preferably, the one or more protrusions of the insoluble patch base are a plurality of protrusions and the one or more protrusions of the template base are a plurality of protrusions. In these embodiments, the plurality of protrusions of the insoluble patch base and the plurality of protrusions of the template base are arranged in superimposable arrays on the surfaces of the respective bases. This ensures that each protrusion on the template base can properly line up with the corresponding protrusion on the insoluble patch base, such that droplets are properly adhered between each opposing protrusion.

[0118] It may be that the insoluble patch base and the template base have the same protrusion shape, number of protrusions, protrusion array, base length, base width, base thickness, base shape, and / or base composition.

[0119] The template base may aid in the formation of a more defined biosoluble microneedle, or microneedles, on the insoluble patch base. For example, the template base may aid in the formation of biosoluble microneedles on the first insoluble patch base that have smaller tip diameters. The template base will typically not form the patch base of a microneedle patch. It may be that the diameter of the surface of the one or more protrusions of the template base is from about 0.1 mm to about 0.5 mm. It may be that the diameter of the surface of the one or more protrusions of the template base is from about 0.15 mm to about 0.45 mm. It may be that the diameter of the surface of the one or more protrusions of the template base is from about 0.15 mm to about 0.35 mm. It may be that the diameter of the surface of the one or more protrusions of the template base is from about 0.15 mm to about 0.25 mm. It may be that the diameter of the surface of the one or more protrusions of the template base is from about 0.2 mm to about 0.4 mm. It may be that the diameter of the surface of the one or more protrusions of the template base is from about 0.25 mm to about 0.35 mm.

[0120] It may be that the height of the one or more protrusions of the template base is at least 0.2 mm. It may be that the height of the one or more protrusions of the template base is in the range from about 0.3 mm to about 0.7 mm. It may be that the height of the one or more protrusions of the template base is in the range from about 0.4 mm to about 0.6 mm. It may be that the height of the one or more protrusions of the template base is smaller than the height of the one or more insoluble protrusions of the insoluble patch base.Step f)

[0121] The bases may be in any orientation whilst they are superimposed. For example, the bases may be arranged substantially parallel to the ground. More preferably, however, is that the bases are arranged substantially perpendicular to the ground.

[0122] Preferably, the template base faces upwards (i.e. the at least one protrusion of the template base faces away from the centre of gravity) and the insoluble patch base is superimposed over the template base. Alternatively, however, it may be that the insoluble patch base faces upwards (i.e. the at least one protrusion of the insoluble patch base faces away from the centre of gravity) and the template base is superimposed over the insoluble patch base.

[0123] Step f) may be carried out using automated machinery. It may be that one base is superimposed other the other via a robot arm. It may be that the template base is stationary, and the insoluble patch base is superimposed over the template base by the robot arm.Alternatively, it may be that the insoluble patch base is stationary, and the template base is superimposed over the insoluble patch base by the robot arm.Stepg)

[0124] It may be that the distance between the one or more protrusions of the insoluble patch base and the one or more protrusions of the template base is increased to no greater than about 1.2 mm in step g). It may be that the distance is increased to a length in the range from 0.1 to 1 mm, e.g. from about 0.1 to about 0.9 mm. It may be that the distance is increased to a length in the range from 0.2 to 0.8 mm, e.g. from about 0.3 to about 0.7 mm. It may be that the distance is increased to a length in the range from about 0.4 to about 0.6 mm.

[0125] It may be that one of the insoluble patch base and the template base is stationary, and the non-stationary base is moved away from the stationary base. It may be that the template base is stationary, and the insoluble patch base is moved away from the template base. It may be that the template base is stationary and faces upwards, and the insoluble patch base is moved away from the template base.

[0126] The bases may be separated from each other by a robot arm that holds one of the bases and separates from the other. The bases may be separated from each other by a linear actuator. The linear actuator may comprise a screw and a stepper motor. This ensures that a distance between the bases can be easily and smoothly controlled.

[0127] The distance between the one or more protrusions of the insoluble patch base and the one or more protrusions of the template base may be increased continuously (i.e. without stopping). Alternatively, the distance between the one or more protrusions of the insoluble patch base and the one or more protrusions of the template base may be increased intermittently (i.e. in intervals), the distance between the one or more protrusions of the insoluble patch base and the one or more protrusions of the template base being maintained ata specific length for a fixed period of time before being increased further. The distance between the one or more protrusions of the insoluble patch base and the one or more protrusions of the template base may be maintained at 1, 2, or 3 separate distances. The distance, or distances, may be maintained for up to one minute each time.

[0128] Preferably, step g) is carried out in a dynamic airflow environment. This may be achieved via the use of a fan, or fans, to direct airflow over the elongated polymer droplet. The airflow over the elongated polymer droplet may be from 10 to 20 CFM.

[0129] It may be that step g) further comprises cooling the one or more protrusions of the insoluble patch base (e.g. to a temperature from 0 to 10 °C) before increasing the distance between the one or more protrusions of the insoluble patch base and the one or more protrusions of the template base so as to elongate the polymer droplet.Step h)

[0130] Step h) may comprise maintaining the (final) distance between the one or more protrusions of the insoluble patch base and the one or more protrusions of the template base. The distance may be maintained for at least one minute, e.g. at least two, three or four minutes.

[0131] Preferably, step h) is also carried out in a dynamic airflow environment. This may be achieved via the use of a fan, or fans, to direct airflow over the elongated polymer droplet. The airflow over the elongated polymer droplet may be from 10 to 20 CFM.

[0132] Step h) may comprise separating the template base from the biosoluble microneedle formed on the at least one wetted protrusion of the insoluble patch base, e.g by moving the template base away from the biosoluble microneedle.Methods of Treatment

[0133] The fourth, fifth and sixth aspects of the invention provide a method of medical treatment, vaccination, and cosmetic treatment, respectively.

[0134] Typically, the microneedle patches of the present invention will be applied to an area of skin of a subject. Typically, the subject will be a human. The microneedle patch may be applied with the use of an applicator. The applicator may comprise a housing for the microneedle patch. The housing may have a button for displacing the microneedle patch from the housing and a protective adhesive tape layer for applying the applicator to the skin of the subject. The housing ensures that the microneedles are maintained at an appropriate humidity level so as to increase the shelf life of the medicament or cosmetic. The applicator may be placed onto the skin of the subject and the button may be pressed so that the microneedlepatch is displaced from the housing. The microneedles pierce the protective adhesive layer, and the medicament or cosmetic is delivered to the skin of the subject.

[0135] The fourth and fifth aspects of the invention will typically be carried out by a healthcare professional, e.g. a nurse or physician. The method may comprise applying the microneedle patch to an arm of the subject. Once applied, the microneedle patch may be left in the subject for 3 to 10 minutes, e.g. for 3 to 7 minutes. The microneedle patch may be left in the subject for around 5 minutes.

[0136] The sixth aspect of the invention may be carried out by a healthcare professional, e.g. a nurse or physician. Alternatively, the sixth aspect of the invention may be carried out by the user of the patch, e.g. at home. Where the cosmetic is botulinum toxin, a dermal filler / biostimulator, or deoxycholic acid, the microneedle patch may be applied to the face of the subject. Where the cosmetic is tattoo ink, the method may be carried out by a trained tattoo artist.Definitions

[0137] The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure.

[0138] For the absence of doubt, the base diameter of a microneedle is larger than the tip diameter.

[0139] The term “array” means an ordered series or arrangement.

[0140] The term “biocompatible” means that ability to be in contact with a living system without producing an adverse effect.

[0141] The term “biosoluble” means soluble in a biological system, e.g. a cell system and / or a biological fluid, of an animal. The biological fluid may be the extracellular fluid (e.g., interstitial fluid) of a mammal. The biological system maybe the mammalian dermis.Biosoluble materials are typically “soluble" (i.e., water soluble).

[0142] Biosoluble / soluble polymers may have a water absorbing capacity of more than 5%, e.g. 10%, by weight in water at room temperature. Biosoluble / soluble polymers may have a solubility in water of more than 25 mg / mL.

[0143] Biosoluble polymers will typically be pharmaceutical grade.

[0144] Insoluble polymers may have a water absorbing capacity of less than 5% byweight in water at room temperature. Insoluble polymers may have a solubility in water of less than 25 mg / mL, e.g. less than 20 mg / mL. Insoluble polymers may have a solubility in water of less than 15 mg / mL, e.g. less than 10 mg / mL.

[0145] Common polymer salts include, but are not limited to, ammonium (including primary, secondary, and tertiary ammonium), hydrobromide, hydrochloride, and sodium salts.

[0146] Polymer “copolymers” include random, block, graft, and alternating copolymers.

[0147] The water absorbing capacity (l / l / w) of a material (e.g., a polymer) maybe calculated via equation III:Ww=m-mx 100 (III),wherein Wwis water absorbing capacity (%); m2is the mass of material saturated with water (g);and m1 is the mass of material in absolute dry state (g).

[0148] A “medicament” (or medicinal product) is any substance or combination of substances that is intended to treat, prevent or diagnose a disease, or to restore, correct or modify physiological functions by exerting a pharmacological, immunological or metabolic action. Medicaments include pharmaceuticals and biologies. Pharmaceuticals include smallmolecule pharmaceuticals. Illustrative medicaments include analgesics (e.g., non-opioid analgesics and opioid analgesics, anesthetics (e.g., local anesthetics); antibacterials (e.g., aminoglycosides, cephalosporins, penicillins, and other beta-lactams, macrolides, quinolones, sulfonamides, tetracyclines, antifolates, glycopeptides, lincomycins, nitrofurans, and oxazolidinones); anticonvulsants (e.g., calcium channel modifying agents, gamma-aminobutyric acid (gaba) augmenting agents, glutamate reducing agents, and sodium channel inhibitors); antidementia agents (e.g., cholinesterase inhibitors, glutamate pathway modifiers, antidementia agents); antidepressants (e.g., monoamine oxidase inhibitors, serotonin / norepinephrine reuptake inhibitors, and tricyclics); antidotes, deterrents, and toxicologic agents; antiemetics; antifungals; antigout agents; anti-inflammatory agents (e.g., glucocorticoids and nonsteroidal anti-inflammatory drugs); antimigraine agents (e.g., abortive and prophylactic antimigraine agents); antimyasthenic agents (e.g., parasympathomimetics); antimycobacterials (e.g., antituberculars); antineoplastics (e.g., alkylating agents, antiangiogenic agents, antiestrogens / modifiers, antimetabolites, aromatase inhibitors, 3rd generation, molecular target inhibitors, monoclonal antibodies, and retinoids); antiparasitics (e.g., anthelmintics, antiprotozoals, and pediculicides / scabicides); antiparkinson agents;antipsychotics (e.g., atypical and conventional antipsychotics); antispasticity agents; antivirals (e.g., anti-cytomegalovirus agents, antihepatitis agents, antiherpetic agents, anti-human immunodeficiency virus agents, fusion inhibitors, anti-hiv agents, and anti-influenza agents); anxiolytics (e.g., antidepressants); bipolar agents; blood glucose regulators (e.g., antidiabetic agents, glycemic agents, and insulins); blood products / modifiers / volume expanders (e.g., anticoagulants, blood formation products, coagulants, and platelet aggregation inhibitors); cardiovascular agents (e.g., alpha-adrenergic agonists, alpha-adrenergic blocking agents, antiarrhythmics, beta-adrenergic blocking agents, calcium channel blocking agents, diuretics, dyslipidemics, renin-angiotensin-aldosterone system inhibitors, and vasodilators); central nervous system agents (e.g., amphetamines, and non-amphetamines); dental and oral agents; dermatologicalagents; enzyme replacements / modifiers; gastrointestinal agents (e.g., antispasmodics, histamine2blocking agents, irritable bowel syndrome agents, protectants, and proton pump inhibitors); genitourinary agents (e.g., antispasmodics, benign prostatic hypertrophy agents, phosphate binders); hormonal agents; immunological agents (e.g. immune stimulants, such as vaccines, immune suppressants, immunizing agents, passive, and immunomodulators); inflammatory bowel disease agents (e.g., glucocorticoids, salicylates, and sulfonamides); metabolic bone disease agents; ophthalmic agents (e.g., ophthalmic anti-allergy agents, ophthalmic antiglaucoma agents, ophthalmic anti-inflammatories, ophthalmic prostaglandin, and prostamide analogs); otic agents; respiratory tract agents (e.g., antihistamines, anti-inflammatories, inhaled corticosteroids, antileukotrienes, bronchodilators, mast cell stabilizers, and pulmonary antihypertensives); sedatives, skeletal muscle relaxants; and therapeutic nutrients, minerals, and electrolytes. The medicament may be in the form of a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0149] Biologies (also known as biological drugs) are a class of drugs that are produced using a living system, such as a microorganism, plant cell, or animal cell. Biologies include antigens, allergens, hormones, enzymes, cytokines, growth factors, nucleic acids (e.g. DNA, RNA, mRNA, saRNA, siRNA, antisense oligonucleotides, and aptamers).

[0150] Advanced therapy medicinal products (ATMPs) are medicines for human use that are based on genes, tissues or cells. ATMPs can be classified into three main types: gene therapy medicines, somatic-cell therapy medicines and tissue-engineered medicines.

[0151] Gene therapy medicines contain genes that lead to a therapeutic, prophylactic or diagnostic effect. They work by inserting 'recombinant' genes into the body, usually to treat a variety of diseases, including genetic disorders, cancer or long-term diseases. A recombinant gene is a stretch of DNA that is created in the laboratory, bringing together DNA from differentsources.

[0152] Somatic-cell therapy medicines contain cells or tissues that have been manipulated to change their biological characteristics or cells or tissues not intended to be used for the same essential functions in the body. They can be used to cure, diagnose or prevent diseases.

[0153] Tissue-engineered medicines contain cells or tissues that have been modified so they can be used to repair, regenerate or replace human tissue.

[0154] A “vaccine” is a suspension of live (usually attenuated) or inactivated microorganisms (e.g., bacteria or viruses), fractions of the agent, or genetic material thereof administered to induce immunity and prevent infectious diseases and their sequelae. The infectious disease that is prevented may be selected from: anthrax, chikungunya, cholera, COVID-19, dengue, diphtheria, enterotoxigenic Escherichia coli, group a streptococcus (gas), group b streptococcus (gbs), haemophilus influenzae type b (hib), haemophilus type b, hepatitis a, hepatitis b, herpes simplex virus, hiv-1, human papillomavirus (hpv), improved influenza vaccines, influenza, Japanese encephalitis, malaria, measles, meningococcal meningitis, mumps, Neisseria gonorrhoeae, nontyphoidal salmonella disease, norovirus, papillomavirus disease, paratyphoid fever, pertussis, pneumococcal disease, poliomyelitis, poliovirus, rabies, respiratory syncytial virus (rsv), rotavirus, rubella, schistosomiasis disease, shigella, tetanus, tick-borne encephalitis, tuberculosis, typhoid, varicella, yellow fever, and zoster.

[0155] The vaccine may be an inactivated vaccine, a live-attenuated vaccines, a messenger RNA (mRNA) vaccine, a subunit, recombinant, polysaccharide, and conjugate vaccine, a toxoid vaccine, or a viral vector vaccine.

[0156] A “cosmetic” (or cosmetic product) refers to any substance or mixture intended to restore, improve, or alter a person's appearance. Cosmetics appropriate for use in the present invention are typically injectable cosmetics, e.g. injectable fillers or tattoo ink.

[0157] Dermal fillers, also known as injectable implants, soft tissue fillers, lip and facial fillers, or wrinkle fillers, help to create a smoother and / or fuller appearance in the face, including nasolabial folds (the lines extending from the sides of the nose to the edges of the mouth), cheeks, chin, lips, and back of the hands.

[0158] The term “biostimulator” is typically used to describe a substance that stimulates the immune system to produce collagen. Biostimulators differ from dermal fillers which correct volume loss.

[0159] A concentration gradient exists when there is a region of high medicament or cosmetic concentration leading to a region of low medicament or cosmetic concentration. The concentration gradient, or the medicament or cosmetic concentration in any given region (e.g. tip, intermediate portion, and base) of a microneedle can be determined using conventional analytical techniques known to the skilled person. For example, the microneedle may be sectioned along its length and the medicament or cosmetic content in that region analysed using chromatographic, spectroscopic, or mass spectrometric methods. Alternatively, imaging techniques such as confocal microscopy, Raman mapping, etc, may be used to assess the distribution of the medicament or cosmetic within the microneedle.

[0160] Illustrative organic solvents include, but are not limited to acetonitrile, alcohols (e.g. methanol, ethanol and isopropanol); ethers (e.g. tetrahydrofuran, 1,4-dioxane, diethyl ether, methyl-tert-butyl ether); ketones (e.g. acetone and methyl isobutyl ketone); halogenated solvents (e.g. dichloromethane, chloroform and 1,2-dichloroethane); an ester (e.g. EtOAc); an amide (e.g. DMF, NMP), or mixtures thereof.

[0161] A ‘small molecule’ may be considered to be a chemical (e.g. organic) molecule (or salt thereof) having a molecular mass below 5000 gmol’1. It may be that the ‘small molecule’ has a molecular mass below 1000 gmol-1. A ‘small molecule’ may be a chemical (e.g. organic) molecule (or salt thereof) comprising less than 100 atoms. A ‘small molecule’ may be a chemical (e.g. organic) molecule (or salt thereof) comprising less than 50 heavy atoms (heavy atoms being atoms other than hydrogen).

[0162] In the context of the present invention, the term “diameter” (e.g., of the base of the one or more microneedles, the tip of the one or more microneedles, or the surface of the one or more protrusions), refers to the longest line segment that passes through the centre of the referred to base, tip, surface, etc. For example, the diameter of a surface / base having a substantially square or rectangular shape will be the diagonal. The diameter of a surface / base having a substantially elliptical shape will be the longest diameter (i.e. the major axis).

[0163] The base diameter of the one or more microneedles, tip diameter of the one or more microneedles, height of the one or more biosoluble microneedles, height of the one or more insoluble protrusions, and diameter of the surface of each of the one or more protrusions may be determined via the use of a 3D microscope. Measurements can be made from the images by the 3D microscope.

[0164] Protrusions may be formed on the bases used in the microneedle patches and methods of the present invention by methods known in the art, such as moulding (e.g. injectionmoulding), laser ablation or 3D printing. In laser ablation, solid material can be removed by irradiating a solid base (e.g. a polymeric sheet) with a laser (e.g. a CO2laser). Etching the solid material in this manner allows for the formation of protrusions (from non-etched material). Acrylic bases are particularly suitable for laser ablation. Protrusions having a specific shape, height, and / or surface diameter can be attained using methods known in the art, such as moulding, laser ablation or 3D printing.

[0165] Suitable 3D printing methods include fused deposition modelling (FDM), stereolithography (SLA), digital light processing (DLP), and selective laser sintering (SLS), and can be used to print polymeric bases comprising protrusions. Polymers suitable for 3D printing include acrylonitrile butadiene styrene (ABS), polycarbonate, high performance polymers (e.g., PEEK, PEKK, and ULTEM), polypropylene (PP), polyamides, thermoplastic polyurethane, and polyethylene terephthalate glycol.

[0166] Throughout the specification these abbreviations have the following meanings:CFM Cubic Feet per MinuteDMF DimethylformamideMN microneedleNMP N-methylpyrrolidonePEEK Polyether ether ketonePEKK PolyetherketoneketoneULTEM Polyetherimide

[0167] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0168] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is notrestricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0169] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

[0170] For the avoidance of doubt, it is hereby stated that the information disclosed earlier in this specification under the heading “Background” is relevant to the invention and is to be read as part of the disclosure of the invention.

[0171] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.EXAMPLESExample 1: Fabrication of microneedle patch using a template base

[0172] Certain terms used in this example have the following definitions:• Customer patch: the patch that will be applied to a subject having 196 cylinders. Patch dimensions: W: 25mm, L: 25mm, H: 4.4mm; cylinder dimensions: Diameter: 0.5mm, H:0.6mm; Patch produced from acrylic sheets using a laser engraver.• Template patch: the patch used to form microneedles on consumer patches also having 196 cylinders; Patch dimensions: W: 25mm, L: 25mm, H: 4.4mm; cylinder dimensions: Diameter: 0.2mm, H: 0.6mm; Patch produced from acrylic sheets using a laser engraver.• Reusable powder box: a box containing an acrylic plate with slightly engraved surfaces onto which matrix powder is distributed using a 3D printed leveller. The acrylic plate may be changed after each patch production.• Fixed powder box: a box containing an acrylic plate with slightly engraved surfaces onto which matrix powder mixed with medicament or cosmetic is distributed using a 3D printed leveller. The acrylic plate is not typically changed after each patch production.• Acrylic plate: a part made from acrylic sheets with an engraved surface made using a laser cutter.

[0173] A HPC Laser, LS3040 laser cutter with a 50W laser tube was used to etch the patches and powder plate.

[0174] This method is depicted in Figure 1.

[0175] Method of production:1 ) The customer patch model is sprayed with water using 2x20mm atomization discs located 1 cm away from each other. This is automated.2) The customer patch is inserted into the reusable powder box 3 times, then 3 times in the Fixed Powder Box and dried for 5 seconds at room temperature. This is automated. 3) The customer patch with powder on the cylinders is then transported using a microneedle positioning system with a suction cup into a humidification chamber and dried at room temperature. This is automated.4) Cylinders of the customer patch with droplets are connected to empty cylinders of the template patch using a robot arm. This is automated.5) After this, two 10.8W fans (14.7 CFM) are turned on from opposite sides of the patches sequentially. This is automated. At the same time, using the microneedle positioning system, the distance between cylinders is evenly increased until the cylinders of both patches are 0.5mm away from each other. Microneedles are then allowed to form. 6) After that, patches are separated. The microneedle patch with microneedles may be inserted into an applicator.

[0176] This method is depicted in Figure 1.Example 2: Microneedle patch measurements

[0177] Certain measurements of a microneedle patch made according to the method of Example 1 and according to a method analogous to that described in GB 2618560 A are provided in Table 1, below. In the method analogous to that described in GB 2618560 A the plurality of cylinders of the first base had a diameter of 1 mm.

[0178] Due to the application of a droplet to each of the plurality of cylinders of the first base in step b) of the method described in GB 2618560 A, the plurality of cylinders of the first base must be of a certain diameter to accommodate the droplet, i.e. >0.7 mm (due to droplet overspill). The method of GB 2618560 A therefore imposes a limitation on the minimum base diameter of the microneedles. The given values are the mean values.Table 1Microneedle of Example 1 Microneedle of GB 2618560 A Volume 0.03 mm3(SD = 0.00 mm3) 0.39 mm3(SD = 0.13 mm3)Surface Area 0.56 mm2(SD = 0.04 mm2) 3.31 mm2(SD = 0.63 mm2)Tip Diameter 0.19 mm (SD = 0.02 mm) 0.40 mm (SD = 0.14 mm)Base Diameter 0.48 mm (SD = 0.02 mm) 1.08 mm (SD = 0.05 mm)Height 0.46 mm (SD = 0.05 mm) 1.29 mm (SD = 0.42 mm)

[0179] An image of a microneedle patch made according to Example 1 captured with a 3D microscope is shown in Figure 2. The image includes the measurements of a number of microneedle parameters.Example 3: Penetration in Artificial Skin

[0180] Microneedle patches made according to Example 1 were loaded with Ipodominal, as a visualising agent for CT scans. The patches loaded with white specs in pictures 10 and 11 of Figure 3 were then applied to artificial skin for 5 minutes. Ipodominal distribution in artificial skin was then visualised in a CT scan as seen through black specs in negatives and marks on pictures 2 and 3 of Figure 3 (0.5mm - 1 mm penetration depth).Microneedle patches made according to Example 1 can therefore adequately penetrate skin.Example 4: Dissolution Study in Porcine and Artificial Skin

[0181] A dissolution study was carried out to assess the extent to which the microneedles of microneedle patches made according to Example 1 dissolve into skin. Patches were loaded with blue dye and applied for 5 minutes on both porcine skin and artificial skin. As shown in Figure 4, microneedles of patches applied to both artificial skin (top) and porcine skin (bottom) sufficiently dissolved.Example 5: Patch Testing in Humans

[0182] Microneedle patches made according to Example 1 were applied to human skin for 5 minutes. Figure 5 shows the application site immediately after application (left), and the application site 15 minutes after application (right). As can be seen in these pictures, the microneedle patches were well tolerated by human skin and caused no adverse reactions. Example 6: Accelerated Stability

[0183] The stability of a microneedle patch made according to Example 1 containing influenza vaccine was assessed and compared to a liquid control of the influenza vaccine. Both the microneedle patch and the liquid control were incubated at 50 °C for over 14 weeks. Theamount of vaccine (pg) in both the patch and the control were assessed at certain time points during this period. The amount of vaccine was determined by an enzyme-linked immunosorbent assay (ELISA). The plot is shown in Figure 6. The microneedle patch of Example 1 was shown to demonstrate superior thermal stability when compared to a liquid control. Example 7: Strength Test

[0184] A compression test to determine the strength of a microneedle patch made according to Example 1 was carried out. The study utilised a force displacement machine. Results are shown in Figure 7. The tested microneedle patch contained 111 microneedles. It has been found in the literature that 0.058N of force per microneedle is required to break the skin barrier (see, e.g., S. P. Sullivan, etal., Nat. Med., 2010, 16, 915–920; J. D. Kim, etal., J. Control. Release, 2013, 170, 430-436; and C. Lee, et al., Adv. Healthcare Mater., 2018, 7, 1701381). It was therefore postulated that a microneedle patch containing 111 microneedles would require a force of at least 6.4N to break the skin barrier. As shown by the linearity of the graph in Figure 7, the microneedles were significantly stronger than the required 6.4N.

[0185] A force / displacement (distance) plot of a microneedle that broke during a compression test is shown in Figure 8. The dip shown in the graph represents the breaking of the microneedle tip. Given that there is no dip in the graph of Figure 7, the microneedles of the microneedle patch of Example 1 did not break over the applied force. The microneedles of the microneedle patch of Example 1 are therefore sufficiently strong enough to withstand forces greater than that required to break the skin barrier.Example 8: In Vivo Test

[0186] Mice were administered either a microneedle patch made according to Example 1 comprising influenza vaccine (HA patch), a microneedle patch made according to Example 1 not comprising a medicament (Empty patch), or an intramuscular (IM) influenza vaccine (l.m.) at day 0 and day 14. Blood was sampled and assayed at day 28 to detect anti-HA igG1 levels. Antibody levels at day 28 after application are shown in Figure 9. The data shows that the microneedle influenza patches achieved antibody levels akin to the IM influenza vaccine and therefore elicited an immune response.

Claims

CLAIMS1. A microneedle patch comprising:an insoluble base comprising one or more insoluble protrusions extending from a surface of the base; andone or more bio-soluble microneedles comprising a tip and a base,wherein each of the one or more bio-soluble microneedles extends from a surface of each of the one or more protrusions; andwherein the base diameter of the one or more microneedles is from about 0.2 mm to about 0.7 mm;wherein the tip diameter of the one or more microneedles is from about 0.1 mm to about 0.7 mm.

2. The microneedle patch of claim 1, wherein the height of the one or more bio-soluble microneedles is from about 0.2 mm to about 0.7 mm.

3. The microneedle patch of claim 1 or claim 2, wherein the base diameter of the one or more bio-soluble microneedles is greater than, or equal to, about 0.25 mm.

4. The microneedle patch of any preceding claim, wherein the one or more protrusions are substantially cylindrical or substantially pyramidal in shape.

5. The microneedle patch of any preceding claim, wherein the one or more microneedles are substantially conical in shape, or are substantially in the shape of a prism.

6. The microneedle patch of any preceding claim, wherein the volume of the one or more microneedles calculated according to equation I:volume = ⅓π(microneedle base width / 2)2× microneedle height (I),is from about 0.001 mm3to about 0.1 mm3.

7. The microneedle patch of any preceding claim, wherein the one or more bio-soluble microneedles comprise a polymer matrix.

8. The microneedle patch of claim 7, wherein the polymer matrix is a polyvinylpyrrolidone matrix.

9. The microneedle patch of any preceding claim, wherein the one or more microneedles comprise a medicament or a cosmetic.

10. The microneedle patch of claim 9, wherein the one or more microneedles comprise a medicament.

11. The microneedle patch of claim 10, wherein the medicament is a vaccine.

12. The microneedle patch of any preceding claim, wherein the one or more protrusions are a plurality of protrusions, optionally wherein the plurality of protrusions are arranged in an array on the surface of the base.

13. The microneedle patch of 12, wherein the array has a density of about 9 to about 225 protrusions per cm2.

14. A method of forminga microneedle patch, the method comprising:a) providing an insoluble patch base comprising one or more insoluble protrusions extending from a surface of the insoluble patch base, wherein the one or more protrusions comprise a surface facing away from the surface of the insoluble patch base;b) wetting the surface of at least one of the one or more protrusions of the insoluble patch base;c) depositing biosoluble polymer powder onto the wetted surface of the at least one protrusion of the insoluble patch base;d) forming a droplet comprising the biosoluble polymer on the wetted surface of the at least one protrusion of the insoluble patch base;e) providing a template base comprising one or more protrusions extending from a surface of the template base, wherein the one or more protrusions comprise a surface facing away from the surface of the template base;f) superimposing the insoluble patch base and the template base so that the surface of one of the one or more protrusions of the template base contacts the polymer droplet on the at least one wetted protrusion of the insoluble patch base;g) increasing the distance between the one or more protrusions of the insoluble patch base and the one or more protrusions of the template base so as to elongate the polymer droplet; andh) forming a bio-soluble microneedle from the elongated polymer droplet on the surface of the at least one wetted protrusion of the insoluble patch base to form the microneedle patch,wherein the diameter of the surface of the one or more protrusions of the template base is smaller than the diameter of the surface of the one or more protrusions of the insoluble patch base.

15. The method of claim 14, wherein the diameter of the surface of the one or more protrusions of the insoluble patch base is less than, or equal to, about 0.7 mm.

16. The method of claim 14 or claim 15, wherein the diameter of the surface of the one or more protrusions of the template base is from about 0.1 mm to about 0.5 mm.

17. The method of any one of claims 14 to 16, wherein the one or more protrusions of the insoluble patch base is a plurality of protrusions and the one or more protrusions of the template base is a plurality of protrusions, optionally wherein the plurality of protrusions of the insoluble patch base and the template base are arranged in superimposable arrays on the surfaces of the respective bases.

18. The method of any one of claims 14 to 17, wherein step c) further comprises depositing an optionally powdered medicament or an optionally powdered cosmetic onto the surface of the at least one wetted protrusion of the insoluble patch base.

19. The method of claim 18, wherein step c) further comprises depositing an optionally powdered medicament onto the surface of the at least one wetted of protrusion of the insoluble patch base.

20. The method of claim 19, wherein the medicament is a vaccine, optionally wherein the medicament is a lyophilised vaccine.

21. The method of any one of claims 14 to 20, wherein the microneedle patch is the microneedle patch of anyone of claims 1 to 13.

22. A microneedle patch obtained by the process of any one of claims 14 to 20.

Images