Microneedle devices

Abstract

A microneedle device is disclosed comprising a base and an array of microneedles on one side of the base. Each microneedle extends to a tip from the base and at least one, preferably each, microneedle is a single polymeric matrix, containing a first compound and a second compound. The first compound has a molecular weight that differs from the second compound and the first and second compounds are differentially distributed between the tip and the base. A process for preparing said microneedle device and use of the microneedle device for administration of two or more compounds into a biological tissue of a subject are also described.

Description

B ACKGROUND Microneedles are an array of very small needles typically with lengths in the micrometer range (i.e. less than 1000 micrometers), which are commonly used for the transport of therapeutic, diagnostic, cosmetic, biological or other compounds across biological tissue, such as the skin. Microneedles work by creating tiny pores within the biological tissue of an individual through which compounds can be delivered directly into the epidermis or dermis of said individual. This direct delivery of a compound to the epidermis or dermis of an individual results in the compound coming into quick and direct contact with biological mediums (e.g. sweat, sebum, interstitial fluid) located in the epidermis or dermis. Upon dissolution in these biological mediums, the compounds are then diffused into the epidermis or dermis and in turn throughout the body of the individual. The mechanism by which microneedles work means they generally result in quicker delivery of compounds to an individual compared to conventional administration routes such as topical administration. Microneedles also allow for large molecules (e.g. molecules with a molecular weight of greater than 500 Daltons) to be more easily delivered through the skin into biological mediums than is achievable using conventional administration routes such as topical administration, where a diffusion limit of circa. 500 Daltons typically exists. There are several types of microneedles known in the art, including: solid microneedles, hollow microneedles, coated microneedles, dissolving microneedles, and hydrogel microneedles. Dissolving microneedles (DMNs), for example, are generally formed from materials (e.g. biologically friendly polymeric materials) which readily dissolves upon contact with moisture within the biological tissue. Dissolving microneedles tend not to leave sharp needle waste and harmful material in the biological tissue after administration of the desired compound(s). The present invention relates to new microneedle devices, a process for their preparation, and the use said microneedle devices for administration of two or more compounds into a biological tissue of a subject. SUMMARY At its most general, the invention relates to a microneedle device comprising a tip, a base, and a first and a second compound which are differentially distributed between the tip and the base of the microneedle device. The inventors have found that such devices allow better control and efficiency in the delivery of multiple compounds, particularly multiple compounds of differing molecular weights. Accordingly, in a first aspect of the invention, there is provided a microneedle device comprising: a base; and an array of microneedles on one side of the base, where a microneedle extends to a tip from the base, and wherein at least one, such as each, microneedle: is a single polymeric matrix, containing a first compound and a second compound, and the first compound has a molecular weight that differs from the second compound; and the first and second compounds are differentially distributed between the tip and the base. The inventors have found that the microneedle devices of the first aspect which allow for a first compound and a second compound (and optionally further compounds) to be differentially distributed within the microneedle allow the compounds to be differentially administered into a biological tissue of a subject. By “differentially distributed”, it is meant that the concentration of each of the first and second compounds varies differently between the tip and the base. For example, the first compound may have a higher concentration at the tip and a lower concentration at the base; whereas, the second compound may have a lower concentration at the tip and a higher concentration at the base. Accordingly, a region within the at least one microneedle may include both the first and second compounds, where the concentrations of both the first and second compounds are different at this region. For example, the concentration of high molecular weight compounds may be higher towards the tip relative to the concentration of low molecular weight compounds. In such embodiments, high molecular weight compounds which generally are not able to diffuse to large depths within the biological tissue of a subject due to their size are forced physically deeper into the biological tissue of the subject due to their relative position within the microneedle, thereby aiding the administration of these compounds to the subject. As low molecular weight compounds tend to display good diffusion properties within the biological tissue of a subject, there is no significant determent to having the compounds with low molecular weights more highly concentrated towards the base of the microneedle. Further still, low molecular weight compounds tend to have a greater mechanical strength than high molecular weight compounds due to their ability to pack more closely together. Thus, in embodiments where the concentration of low molecular weight compounds is higher towards the base relative to the concentration of high molecular weight compounds, the inventors have established that the mechanical strength of the base of the microneedle may also be increased, which in turn aids penetration performance of the microneedles. Further features of the microneedle device, such as the first and second compounds, are set out below. The inventors have also found that a microneedle device according to the first embodiment, may be prepared using a novel centrifugation method. Accordingly, in a second aspect of the invention, there is provided a process for preparing a microneedle device, wherein the microneedle device comprises a base and an array of microneedles on one side of the base, said process comprising the steps of: • adding a first composition into a mould for an array of microneedles, which composition comprises at least one polymer or polymerizable monomers capable of forming a polymer matrix, a first compound and a second compound which differ in their molecular weights; • centrifuging the moulds containing the first composition; • optionally curing the first composition directly after the step of centrifugation to form the array of microneedles; and • adding a base to the array of microneedles. The inventors have also found that the microneedle devices of the first aspect are useful in delivering two or more compounds into a biological tissue (e.g. skin). Accordingly, in a third aspect of the invention, there is provided a microneedle device for administration of two or more compounds into a biological tissue prepared according to process defined in the second aspect. In a fourth aspect of the invention, there is provided the use of a microneedle array according to the first aspect for administration of two or more compounds into a biological tissue of a subject. These and other aspects and embodiments of the invention are described in further detail below. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a schematic representation of the method used to prepare the microneedle devices of the invention. The schematic shows the process of adding a first composition (e.g. a homogenous polymeric gel comprising a first compound and a second compound) to a mould, centrifuging the mould containing the first composition, and adding a base (e.g. backing layer) to the array of microneedles (e.g. through lamination). Figure 2 shows a schematic representation of a microneedle according to the present invention, wherein a first compound has a higher molecular weight than a second compound, and the concentration of the first compound is higher towards the tip relative to the concentration of the second compound. Figures 3 shows a white-light microscopy image of a microneedle device (array) according to the present invention (prepared according to Example 1 described hereinbelow). The image depicts dyes molecules (mixture of Fluorescein isothiocyanatedextran and Rhodamine B isothiocyanate-Dextran) being differentially distributed within the Polyvinylpyrrolidone microneedle. Figures 4 and 5 show expanded views of the individual microneedles within the microneedle device (array) shown in Figure 3. DETAILED DESCRIPTION The invention relates to a microneedle device comprising a tip, a base, and a first and a second compound which are differentially distributed between the tip and the base of the microneedle device, and to the process of preparing such microneedle devices. Also provided is the use of the microneedle device for administration of two or more compounds into a biological tissue of a subject. The following features may apply to all aspects of the invention as described herein. The features may also be combined in any combination. First and Second Compounds The first compound has a molecular weight that differs from the second compound such that the first and the second compounds are differentially distributed between the tip and the base of the microneedle device. It will be appreciated that the first compound and the second compound may have a molecular weight that differs by any amount that suitably allows for the differential distribution of these compounds within the microneedle. In certain embodiments, the first and the second compounds differ in their molecular weights by at least 20 Daltons, or at least 50 Daltons, or at least 75 Daltons, or at least 100 Daltons, or at least 200 Daltons, or at least 500 Daltons, or at least 1000 Daltons, or at least 2000 Daltons, or at least 5000 Daltons, or at least 10000 Daltons. In certain embodiments, the first compound has a higher molecular weight than the second compound. For example, the first compound has a molecular weight that is 20 Daltons or more than the molecular weight of the second compound, or 50 Daltons or more than the molecular weight of the second compound, or 75 Daltons or more than the molecular weight of the second compound, or 100 Daltons or more than the molecular weight of the second compound, or 200 Daltons or more than the molecular weight of the second compound, or 500 Daltons or more than the molecular weight of the second compound, or 1000 Daltons or more than the molecular weight of the second compound, or 2000 Daltons or more than the molecular weight of the second compound, or 5000 Daltons or more than the molecular weight of the second compound, or 10000 Daltons or more than the molecular weight of the second compound. In some embodiments, the first compound has a molecular weight of between 1000 and 3,000,000 Daltons, and the second compound has a molecular weight of between 50 and 950 Daltons. Suitably, the first compound has a molecular weight of between 1000 and 1,000,000 Daltons, and the second compound has a molecular weight of between 50 and 950 Daltons. More suitably, the first compound has a molecular weight of between 1000 and 500,000 Daltons, and the second compound has a molecular weight of between 50 and 950 Daltons. Yet more suitably, the first compound has a molecular weight of between 1000 and 250,000 Daltons, and the second compound has a molecular weight of between 50 and 950 Daltons. Even more suitably, the first compound has a molecular weight of between 1000 and 100,000 Daltons, and the second compound has a molecular weight of between 50 and 950 Daltons. In certain embodiments, the first compound has a molecular weight of between 1000 and 70000 Daltons, and the second compound has a molecular weight of between 50 and 950 Daltons. Suitably, the first compound has a molecular weight of between 2000 and 60000 Daltons, and the second compound has a molecular weight of between 50 and 800 Daltons. More suitably, the first compound has a molecular weight of between 5000 and 60000 Daltons, and the second compound has a molecular weight of between 100 and 700 Daltons. Still more suitably, the first compound has a molecular weight of between 8000 and 60000 Daltons, and the second compound has a molecular weight of between 50 and 600 Daltons. Yet more suitably, the first compound has a molecular weight of between 10000 and 60000 Daltons, and the second compound has a molecular weight of between 100 and 500 Daltons. Most suitably, the first compound has a molecular weight of between 20000 and 60000 Daltons, and the second compound has a molecular weight of between 100 and 500 Daltons. It will be appreciated that the microneedle device, in addition to comprising a first and a second compound, may comprises one or more additional compounds. Here, it will be understood that each of the first compound, the second compound and any additional compounds (e.g. a third compound) will have a molecular weight that differs from any of the other compounds. Thus, in certain embodiments, the microneedle device further comprises a third compound, having a molecular weight between the molecular weights of the first compound and the second compound. For example, the first compound may have a higher molecular weight than the second and third compounds, and the third compound may have a higher molecular weight than the second compound. Furthermore, the concentration of the first compound may be higher towards the tip relative to the concentration of the second and third compounds, and the concentration of the second compound may be higher towards the base relative to the concentration of the first and third compounds. It will be appreciated that the terms “first compound”, “second compound”, “third compound” and the like refer to individual chemical compounds with one specific (average) molecular weight. For example, the “first compound” may refer to one or more compounds with a molecular weight of between 10000 and 60000 Daltons, the “second compound” may refer to one or more compounds with a molecular weight of between 100 and 500 Daltons, and the “third compound” may refer to one or more compounds with a molecular weight of between 1000 and 5000 Daltons. It will also be understood that in some embodiments, the “first compound”, “second compound”, “third compound” and the like may be selected from chemical compounds of the same type but with different (average) molecular weights. This, for example, may be the case where the first compound, second compound and / or third compound etc. are selected from polymers (e.g. hyaluronic acid), and the first, second and / or third compound correspond to first, second and third examples of the same polymer, but each with a different and discreet molecular weight. In some embodiments, the second compound has a molecular weight of between 100 and 500 Daltons, the first compound has a molecular weight of between 10000 and 60000 Daltons, and the third compound has a molecular weight of between 1000 and 5000 Daltons. It will be appreciated that the first compound, the second compound and any additional compounds (e.g. a third compound) may be selected from a range of substances suitable for delivery to biological tissues. For example, the first compound, the second compound and any additional compounds may be selected from cosmetic agents, vitamins, herbs, dietary supplements, humectants, active pharmaceutical ingredients, allergens, diagnostic agents, markers (e.g., coloured dyes or radiological dyes or markers), and any other compound that is desirable to introduce into a biological tissue. It will be appreciated that the coloured dyes may be any dye suitable for use with the present invention. Non-limiting examples include Fluorescein isothiocyanate-dextran, Rhodamine B isothiocyanate-Dextran and the like. It will be appreciated that in some embodiments the microneedles, and in particular the single polymeric matrix of the microneedles, may contain one or more additional agents (in addition to the first compound, the second compound and any additional compounds), such as fillers, bulking agents, buffering agents, salts, and the like. Such additional agents are well known within the art, and all such agents are contemplated for use herein. In some embodiments, the biological tissue is a tissue of a human or other mammal, including but not limited to the skin of human or other mammal. In one embodiment, the first compound, the second compound and / or any additional compounds (e.g. a third compound) may be selected from a cosmetic agent, vitamin, herb, or dietary supplement known in the art. Non-limiting examples include ascorbic acid, salicylic acid, nicotinamide, vitamin B3, niacinamide, hydroquinone, retinol, glycolic acid, lactic acid, tartaric acid, citric acid, vitis vinifera (grape) seed extract, portulaca orelacea (duckweed or little hogweed) purslane extract, madecassoside (centella asiatica, also known as Tiger Grass or gotu kola), Panax Ginseng Root Extract, Carnosine, Astragalus Membranaceus Extract, Adenosine, Tocopheyl Acetate (vitamin E), Bakuchiol, Palmitoyl Pentapeptide-4, Retinol, Polydeoxyribonucleotide, Anthemis Nobilis (chamomile) flower extract, Arbutin, Glycyrrhiza Glabra (licorice) root extract, Kojic acid, Ferulic acid, Oxidized Glutathione, Glutathione, Ascorbyl glucoside,, Camellia Sinensis (Green Tea) leaf extract, Centella Asiatica extract, magnesium ascorbyl phosphate, coumaric acid, tranexamic acid (synthetic lysine amino acid), zingiber officinale (ginger) root extract, Phoenix Dactylifera seed, Chenopodium Quinoa seed extract, kawarayomogi (Korean mugwort) leaf extract, Artemisia princeps (Japanese Mugwort / wormwood) leaf extract, olive oil or juice (also known as Olea Europaea Fruit Oil), 5-HTP (5-hydroxytryptophan), acai berry, acetyl-L-camitine, activated charcoal, aloe vera, alpha-lipoic acid, apple cider vinegar, arginine, ashitaba, ashwagandha, astaxanthin, barley, bee pollen, beta-alanine, beta-carotene, beta-glucans, biotin, bitter melon, black cherry, black cohosh, blackcurrant, black tea, branched-ahain amino acids, bromelain (bromelin), calcium, camphor, chamomile, chasteberry, chitosan, chlorella, chlorophyll, choline, chondroitin, chromium, cinnamon, citicoline, coconut water, coenzyme Q10, conjugated linoleic acid, cordyceps , cranberry, creatine, D-mannose, damiana, deer velvet, DHEA, DMSO, echinacea , EDTA, elderberry, emu Oil, evening primrose oil, fenugreek, feverfew, folic acid, forskolin, GABA (gamma-aminobutyric acid), gelatin, ginger, ginkgo biloba, ginseng, glycine, glucosamine, glucosamine sulfate, glutathione, gotu kola, green coffee, guarana, guggul, gymnema, hawthorn, hibiscus, holy basil, horny goat weed, inulin, iron, krill oil, L-carnitine, L-citrulline, L-trypotophan, lactobacillus , magnesium, magnolia , milk thistle, MSM (methylsulfonylmethane), niacin, olive, omega-3 fatty acids, oolong tea, oregano, passionflower, pectin, phenylalanine, phosphatidylserine, potassium, probiotics, progesterone, quercetin, ribose, red yeast rice, reishi mushroom, resveratrol, rosehip, saffron, SAM-e, saw palmetto, schisandra, sea buckthorn, selenium, senna , slippery elm, St. John's wort, stinging nettle, tea tree oil, theanine, tribulus terrestris , turmeric (curcumin), tyrosine, valerian, vitamin A, vitamin B12, vitamin D, vitamin K, vitamin B6 (pyridoxine), whey protein, witch hazel, xanthan gum, xylitol, yohimbe, zinc, lutein, dexpanthenol, liquorice root extract, Indian pennywort extract, ginsenosides, superoxide dismutase, acetyl hexapeptide-3, oligopeptide-68, palmitoyl tetrapeptide-7, acetylhexapeptide, bovine serum albumin and combinations thereof. In some embodiments, the first compound, the second compound and / or any additional compounds (e.g. a third compound) is selected from a cosmetic agent, vitamin, herb, or dietary supplement selected from ascorbic acid, salicylic acid, nicotinamide, vitamin B3, niacinamide, hydroquinone, retinol, glycolic acid, lactic acid, tartaric acid, citric acid, vitis vinifera (grape) seed extract, portulaca orelacea (duckweed or little hogweed) purslane extract, madecassoside (centella asiatica, also known asTiger Grass or gotu kola), Panax Ginseng Root Extract, Carnosine, Astragalus Membranaceus Extract, Adenosine, Tocopheyl Acetate (vitamin E), Bakuchiol, Palmitoyl Pentapeptide-4, Retinol, Polydeoxyribonucleotide, Anthemis Nobilis (chamomile) flower extract, Arbutin, Glycyrrhiza Glabra (licorice) root extract, Kojic acid, Ferulic acid, Oxidized Glutathione, Glutathione, Ascorbyl glucoside, glycolic acid, Camellia Sinensis (Green Tea) leaf extract, Centella Asiatica extract, magnesium ascorbyl phosphate, coumaric acid, tranexamic acid (synthetic lysine amino acid), zingiber officinale (ginger) root extract, Phoenix Dactylifera seed, Chenopodium Quinoa seed extract, kawarayomogi (Korean mugwort) leaf extract, Artemisia princeps (Japanese Mugwort / wormwood) leaf extract, olive oil or juice (also known as Olea Europaea Fruit Oil), vitamin A, vitamin Bl2, vitamin C, vitamin D, vitamin K, whey protein, witch hazel, xanthan gum, xylitol, yohimbe, zinc, lutein, dexpanthenol, liquorice root extract, Indian pennywort extract, ginsenosides, superoxide dismutase, acetyl hexapeptide-3, oligopeptide-68, palmitoyl tetrapeptide-7, acetyl-hexapeptide, bovine serum albumin, and combinations thereof. In some embodiments, the first compound, the second compound and / or any additional compounds (e.g. a third compound) is selected from a cosmetic agent, vitamin, herb, or dietary supplement selected from ascorbic acid, salicylic acid, nicotinamide, vitamin B3, niacinamide, hydroquinone, retinol, glycolic acid, lactic acid, tartaric acid, citric acid, vitis vinifera (grape) seed extract, portulaca orelacea (duckweed or little hogweed) purslane extract, madecassoside (centella asiatica, also known as Tiger Grass or gotu kola), Panax Ginseng Root Extract, Carnosine, Astragalus Membranaceus Extract, Adenosine, Tocopheyl Acetate (vitamin E), Bakuchiol, Palmitoyl Pentapeptide-4, Retinol, Polydeoxyribonucleotide, Anthemis Nobilis (chamomile) flower extract, Arbutin, Glycyrrhiza Glabra (licorice) root extract, Kojic acid, Ferulic acid, Oxidized Glutathione, Glutathione, Ascorbyl glucoside, Camellia Sinensis (Green Tea) leaf extract, Centella Asiatica extract, magnesium ascorbyl phosphate, coumaric acid, tranexamic acid (synthetic lysine amino acid), zingiber officinale (ginger) root extract, Phoenix Dactylifera seed, Chenopodium Quinoa seed extract, kawarayomogi (Korean mugwort) leaf extract, Artemisia princeps (Japanese Mug wort / worm wood) leaf extract, olive oil or juice (also known as Olea Europaea Fruit Oil), vitamin A, vitamin B12, vitamin C, vitamin D, vitamin K, vitamin B6 (pyridoxine), whey protein, witch hazel, xanthan gum, xylitol, yohimbe, zinc, acetyl-hexapeptide, bovine serum albumin, and combinations thereof. In certain embodiments, the cosmetic agent, vitamin, herb, or dietary supplement is selected from ascorbic acid, salicylic acid, nicotinamide, hydroquinone, retinol, glycolic acid, lactic acid, tartaric acid, citric acid, acetyl-hexapeptide and combinations thereof. In certain embodiments, the second compound is a cosmetic agent, vitamin, herb, or dietary supplement, such as those described hereinabove. Thus, in certain embodiments, the second compound is selected from ascorbic acid, salicylic acid, nicotinamide, hydroquinone, retinol, glycolic acid, lactic acid, tartaric acid, citric acid and combinations thereof, and, for example, is selected from ascorbic acid, salicylic acid, nicotinamide, and combinations thereof. In some embodiments the first compound is selected from hyaluronic acid, acetylhexapeptide or bovine serum albumin. It will be appreciated that acetyl-hexapeptide suitably covers both acetyl-hexapeptide-3 and acetyl-hexapeptide-8. In some embodiments, the first compound, the second compound and / or any additional compounds (e.g. a third compound) may be a prophylactic, therapeutic, or diagnostic agent useful in medical or veterinary application. Thus, in certain embodiments, the first compound, the second compound and any additional compounds (e.g. a third compound) may be a prophylactic or therapeutic substance, which may be referred to herein as an active pharmaceutical ingredient (API). In certain embodiments, the API is selected from proteins, peptides and fragments thereof, which can be naturally occurring, synthesized or recombinantly produced. Representative examples of types of API for delivery include antibiotics, antiviral agents, analgesics, anesthetics, antihistamines, anti-inflammatory agents, anti-coagulants, allergens, vitamins, antineoplastic agents. In one embodiment, the first compound, the second compound and any additional compounds (e.g. a third compound) may be a vaccine. Non-limiting examples of suitable vaccines include vaccines for infectious diseases, therapeutic vaccines for cancers, neurological disorders, allergies, and smoking cessation or other addictions. In certain embodiments the vaccine may be a vaccine for the prevention of anthrax, cervical cancer (human papillomavirus), dengue fever, diphtheria, Ebola, hepatitis A, hepatitis B, hepatitis C, haemophilus influenzae type b (Hib), HIV / AIDS, human papillomavirus (HPV), influenza (seasonal and pandemic), Japanese encephalitis (JE), lyme disease, malaria, measles, meningococcal, monkeypox, mumps, pertussis, pneumococcal, polio, rabies, rotavirus, rubella, shingles (herpes zoster), smallpox, tetanus, typhoid, tuberculosis (TB), varicella (chickenpox), West Nile, and yellow fever. In another embodiment, the first compound, the second compound and any additional compounds (e.g. a third compound) may be a therapeutic agent. The therapeutic agent may be selected from small molecules and larger biotechnology produced or purified molecules (e.g., peptides, proteins, DNA, RNA). Examples of therapeutics include but are not limited to insulin, insulin-like growth factor, insultropin, parathyroid hormone, pramlintide acetate, growth hormone release hormone, growth hormone release factor, mecasermin, Factor VIII, Factor IX, antithrombin III, protein C, protein S, P-gluco-cerebrosidase, alglucosidase-a, laronidase, idursulphase, galsulphase, agalsidase-P, a-1 proteinase inhibitor, lactase, pancreatic enzymes, adenosine deaminase, pooled immunoglobulins, human albumin, erythropoietin, darbepoetin-a, filgrastim, pegfilgrastim, sargramostim, oprelvekin, human follicle-stimulating hormone, human chorionic gonadotropin, lutropin-a, interferon (alpha, beta, gamma), aldesleukin, alteplase, reteplase, tenecteplase, urokinase, factor Vila, drotrecogin-a, salmon calcitonin, exenatide, octreotide, dibotermin-a, recombinant human bone morphogenic protein 7, histrelin acetate, palifermin, becaplermin, trypsin, nesiritide, botulinum toxin (types A and B), collagenase, human deoxyribonuclease I, hyaluronidase, papain, 1-asparaginase, peg-asparaginase, rasburicase, lepirudin, bivalirudin, streptokinase, anistreplase, bevacizumab, cetuximab, panitumumab, alemtuzumab, rituximab, trastuzumab, abatacept, anakinra, adalimumab, etanercept, infliximab, alefacept, efalizuman, natalizumab, eculizumab, antithymocyte globulin, basiliximab, daclizumab, muromonab-CD3, omalizumab, palivizumab, enfuvirtide, abciximab, pegvisomant, crotalidene polyvalent fab (ovine), digoxin immune serum fab (ovine), ranibizumab, denileukin diftitox, ibritumomab tiuxetan, gemtuzumab ozogamicin, tositumomab, I-tositumomab, anti-rhesus (rh) immunoglobulin G, desmopressin, vasopressin, deamino [Val4, D-Arg8] arginine vasopressin, somatostatin, somatotropin, bradykinin, bleomycin sulfate, chymopapain, glucagon, epoprostenol, cholecystokinin, oxytocin, corticotropin, prostaglandin, pentigetide, thymosin alpha-1, alpha-1 antitrypsin, fentanyl, lidocaine, epinephrine, sumatriptan, benztropine mesylate, liraglutide, fondaparinux, heparin, hydromorphone, omacetaxine mepesuccinate, pramlintide acetate, thyrotropin-alpha, glycopyrrol ate, dihydroergotamine mesylate, Bortezomib, triptoreline pamaote, teduglutide, methylnaltrexone bromide, pasireotide, ondansetron hydrochloride, droperidol, triamcinolone (hex)acetonide, aripiprazole, estradiol valerate, morphine sulfate, olanzapine, methadone hydrochloride, and methotrexate. The first compound, the second compound and / or any additional compounds (e.g. a third compound) may be present in any suitable amount. In some embodiments, the first compound, the second compound and / or any additional compounds (e.g. a third compound) may each independently be present in an amount of between 0.01 % and 20% based on the weight of the polymeric matrix of the microneedle. The first compound, the second compound and / or any additional compounds (e.g. a third compound) may each independently be present in an amount of between 1 % and 15% based on the weight of the polymeric matrix of the microneedle, such as between 2 % and 12%, or such as between 5% and 12%. Single Polymeric Matrix The single polymeric matrix will be understood to be the core polymeric material from which the array of microneedles is made. The single polymeric matrix will be understood as being one continuous matrix of polymeric material extending from the base to the tip of the microneedle. That is, the single polymeric matrix is not comprised of discreet layers of polymeric materials. In certain embodiments, the microneedles of the present invention (i.e. the array of microneedles) are dissolving microneedles. Thus, in certain embodiments, the single polymeric matrix is formed of a biocompatible polymeric material that is capable of dissolving in the presence of physiological conditions within the biological tissue of an individual. In certain embodiments, the biocompatible polymeric material is one that is capable of dissolving in the presence of physiological fluids within the biological tissue of an individual. Non-limiting examples of suitable physiological fluids within the biological tissue include sweat, sebum, interstitial fluid and the like. Biocompatible polymeric materials suitable for preparing dissolving microneedles are well known within the art, and all such materials are contemplated for use herein. In certain embodiments, the single polymeric matrix is formed of hyaluronic acid, sodium hyaluronate, polyvinyl alcohol, carboxymethyl cellulose, polyvinylpyrrolidone, poly(lactic-co-glycolic acid), chitosan, hydroxypropyl methylcellulose, polyethylene glycol, gelatin, polycaprolactone and combinations thereof. Thus, the single polymeric matrix may be formed of hyaluronic acid, sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone and combinations thereof. That is, the single polymeric matrix may be formed of hyaluronic acid. In certain embodiments, the single polymeric matrix may be formed of a polymeric material with a specific (average) molecular weight (e.g. hyaluronic acid with a molecular weight of 200,000 Da) and the microneedle device may further comprise a compound (e.g. the first compound) of the same polymeric material with a different (average) molecular weight (e.g. hyaluronic acid with a molecular weight of 50,000 Da). In some embodiments, the single polymeric matrix may be formed of a polymeric material with a specific (average) molecular weight (e.g. hyaluronic acid with a molecular weight of 200,000 Da) and the microneedle device may further comprise a first compound of the same polymeric material with a different (average) molecular weight (e.g. hyaluronic acid with a molecular weight of 50,000 Da), and a second compound selected from ascorbic acid, salicylic acid, nicotinamide, hydroquinone, retinol, glycolic acid, lactic acid, tartaric acid, citric acid and combinations thereof. In some embodiments, the single polymeric matrix may be formed of hyaluronic acid with an (average) molecular weight of between 100,000 Da and 1,000,000 Da (e.g. hyaluronic acid with a molecular weight of between 200,000 Da) and: the first compound selected from hyaluronic acid (e.g. hyaluronic acid with a molecular weight of 50,000 Da), acetyl-hexapeptide or bovine serum albumin; and the second compound selected from ascorbic acid, salicylic acid, nicotinamide, hydroquinone, retinol, glycolic acid, lactic acid, tartaric acid, citric acid and combinations thereof. Base The base forms the foundation of the microneedle array. The base may form a substantially planar sheet or region, having a certain thickness, and one side of the base connect to the array of microneedles. In some embodiments, the base may protrude into the microneedle itself, as is common within the field of microneedle devices. The base may be non-toxic, and does not cause irritation to the biological tissue (e g. skin) upon contact. The base may have a thickness of between 5 to 10000 microns (pm), such as from 5 to 5000 microns (pm), or such as from 50 to 5000 microns (pm), or such as from 50 to 2000 microns, or such as from 100 to 3000 microns (pm), or such as from 100 to 1000 microns (pm) It will be appreciated that the base may be formed from any suitable material that is compatible with and / or known for use in preparing bases for microneedle arrays. Many such materials are known within the art, and all such materials are contemplated for use herein. Thus, the base may be formed from a woven material, non-woven material, a polymer, a synthetic fabric, a natural fabric, different kinds of paper, a hydrocolloid and a combination thereof. Non-limiting examples of suitable materials from which the base may be formed include polydimethylsiloxane (PDMS), acrylic, styrene-methyl methacrylate copolymers, ethylene / acrylic acid, acrylonitrile-butadiene-styrene (ABS), ABS / polycarbonate, AB S / polysulfone, ABS / polyvinyl chloride, ethylene propylene, ethylene vinyl acetate (EVA), nylons (including nylon 6, nylon 6 / 6, nylon 6 / 6-6, nylon 6 / 9, nylon 6 / 10, nylon 6 / 12, nylon 11 and nylon 12), polyacrylate, polybutylene terephthalate (PBT), polycarbonate, polyethylene terephthalate (PET), polyethylene (including low density, linear low density, high density, cross-linked and ultra-high molecular weight grades), polypropylene homopolymer, polypropylene copolymers, polyolefins, polystyrene (including general purpose and high impact grades), polytetrafluoroethylene (PTFE), ethylene-tetrafluoroethylene (ETFE), polyvinyl fluoride (PVF), polyvinylidene fluoride (PVDF), polychlorotrifluoroethylene (PCTFE), polyethylene-chlorotrifluoroethylene (ECTFE), polymethyl methacrylate (PMMA), silicon styrene-acrylonitrile (SAN), elastomers, metal oxides, plastics, foams, paper-based materials, foil-based materials and glass, or any combination thereof. In certain embodiments, the base is formed from one or more polymers that are not readily dissolvable under physiological conditions. In certain embodiments, the base is formed from a non-woven material, such as paper. In some embodiments, the base is formed from a polymer, such as polydimethylsiloxane (PDMS). In some embodiments, the base may be in direct contact with the array of microneedles. In other embodiments, one or more other layers may be interposed between the base and the microneedles. For example, one or more separation layers may be interposed between the base and the microneedles. A separation layer may be understood as being a layer which dissolves (rapidly) upon contact with physiological conditions. Dissolution of the separation layer will be understood as occurring more quickly than the microneedle arrays (e.g. the single polymeric matrix), allowing the microneedle arrays (e.g. the single polymeric matrix) to remain embedded within the biological tissue of a subject while the base is removed. Suitable materials for such separation layers are well-known within the art, and all such materials are contemplated for use herein. A non-limiting list of materials from which the separation layer may be made include polyvinyl alcohol (PVA) and / or polyvinyl pyrrolidone (PVP). In some embodiments, the base may contain an adhesive layer (e.g. adhesive ring) to allow for adhesion to the biological tissue (e.g. skin) when the microneedle device is in use. Suitable materials for such adhesive layers (e.g. silicon adhesive rings) are well-known within the art, and all such materials are contemplated for use herein. The Process of the Invention According to a second aspect of the invention, there is provided a process for preparing a microneedle device, wherein the microneedle device comprises a base and an array of microneedles on one side of the base, said process comprising the steps of: • adding a first composition into a mould for an array of microneedles, which composition comprises at least one polymer or polymerizable monomer capable of forming a polymer matrix, a first compound and a second compound which differ in their molecular weights; • centrifuging the mould containing the first composition; • optionally curing the first composition directly after the step of centrifugation to form the array of microneedles; and • adding a base to the array of microneedles. Features of the microneedle devices, such as the first and second compounds and their molecular weights, are as set out above. The microneedle device is suitable for administration of two or more compounds into a biological tissue. It will also be appreciated that the at least one polymer or polymerizable monomers capable of forming a polymer matrix may be any polymer mentioned above as examples of the single polymeric matrix, or any monomer capable of forming said polymers. In certain embodiments, the first compound and the second compound are not polymerizable compounds. It will also be understood that the first composition may further comprise one or more additional compounds (e.g. a third compound), in accordance with the first aspect described hereinabove. Features of the one or more additional compounds (e.g. a third compound) are set out above. The step of centrifuging the moulds may be carried out using any centrifugation conditions suitable for achieving differential distribution of the first, second and optionally one or more additional compounds based on their molecular weights within the microneedles. The skilled person will be able to select suitable centrifugation conditions based on the nature of the first compositions (e.g. the nature of the first and second compounds and polymer matrix). In certain embodiments, the step of centrifuging the mould is carried out at a centrifugation speed of at least 3000 RPM, such as at least 3500 RPM, or at least 4000 RPM. Here, it will be understood that RPM refers to revolutions per minute. In some embodiments, the step of centrifuging the moulds is carried out at a centrifugation speed of between 3000 RPM and 10000 RPM, such as between 3500 RPM and 8000 RPM, or between 4000 RPM and 6000 RPM. In certain embodiments, the step of centrifuging the mould is carried out at using a Relative Centrifuge Force (RCF) of greater than 1500 g, such as greater than 1800 g, or greater than 1900 g. In some embodiments, the step of centrifuging the mould is carried out using a Relative Centrifuge Force (RCF) of between 1500 g and 6000 g, such as between 1500 g and 5500 g, or between 1700 g and 5000 g, or between 1800 g and 4500 g, and or between 1800 g and 4000 g. The step of centrifuging the mould may be conducted for any suitable duration. The step of centrifuging the moulds, for example, may be carried out for a duration of between 2 minutes and 120 minutes, such as between 2 minutes and 60 minutes, or between 2 minutes and 30 minutes, or between 2 minutes and 20 minutes, or between 2 minutes and 15 minutes, or between 3 minutes and 10 minutes. The step of centrifuging the mould may also be conducted at any suitable temperature. In certain embodiments, the step of centrifuging the moulds is carried out at a temperature of between 10 °C and 40 °C, such as 20°C to 30 °C. In some embodiments, there may be an optional additional step of drying the mould before the step of adding a base to the array of microneedles. Any suitable technique may be used to dry the moulds, such as those described hereinbelow. Methods for adding a base to an array of microneedles are well known in the art, and all such methods are contemplated for use herein. It will also be appreciated that the base may be added either before the microneedles are removed from the mould or after the microneedles are removed from the mould. In some embodiments, the base may be added to the array of microneedles by laminating the microneedle array with one or more of the materials capable of forming a base described hereinabove, such as a non-woven material (e.g. paper). In certain embodiments, the step of adding the base to the array of microneedles comprises the following steps: • adding a second composition capable of forming a base to the mould, which composition comprises at least one polymer or polymerizable monomer capable of forming a base; • optionally curing the second composition; and • drying the mould to prepare the microneedle device. It will also be appreciated that the at least one polymer or polymerizable monomer capable of forming a base may be any polymer mentioned above as examples of the base, or any monomer capable of forming said polymers. Thus, in certain embodiments, the present invention provides a process for preparing a microneedle device suitable for administration of two or more compounds into a biological tissue, wherein the microneedle device comprises a base and an array of microneedles on one side of the base, said process comprising the steps of: • adding a first composition into a mould for an array of microneedles, which composition comprises at least one polymer or polymerizable monomer capable of forming a polymer matrix, a first compound and a second compound which differ in their molecular weights; • centrifuging the mould containing the first composition; • optionally curing the first composition directly after the step of centrifugation; • optionally adding a second composition capable of forming a base to the mould, which composition comprises at least one polymer or polymerizable monomer capable of forming a base; • optionally curing the second composition; and • drying the mould to prepare the microneedle device. It will be appreciated that the step of curing the first composition, and optionally the second composition, may be conducted using any suitable curing method known in the art. Such curing methods are well known within the art, and all such methods are contemplated for use herein. In certain embodiments, the step of curing the first composition, and optionally the second composition, is conducted by allowing the composition(s) to stand at a temperature of between 20 °C and 100 °C and at a pressure of between 0.01 and 1.01 bar for between 30 minutes and 48 hours. In some embodiments, step of curing the first composition, and optionally the second composition, is conducted by allowing the composition(s) to stand in an atmosphere of inert gas (e.g. an atmosphere of nitrogen, argon, neon, helium and the like). It will be appreciated that the step of curing the first composition, and optionally the second composition, may be conducted at any suitable humidity. In certain embodiments, the step of curing the first composition, and optionally the second composition, is conducted at a relative humidity of between 20% and 90%, such as between 30% and 80%, or between 40% and 60%. The step of curing the first composition, and optionally the second composition, may be conducted by allowing the composition(s) to stand at atmospheric pressure (1.01 bar) at a temperature of between 20 °C and 60 ° for between 30 minutes and 24 hours. Thus, the step of curing the first composition, and optionally the second composition, may be conducted by allowing the composition(s) to stand at atmospheric pressure (1.01 bar) at a temperature of between 20 °C and 60 ° and a relative humidity of between 30% and 80% (e.g. 50%) for between 30 minutes and 24 hours. The step of drying the mould may be conducted at any suitable temperature and for any suitable duration. The step of drying the mould may be conducted at a temperature of between 20 °C and 100 °C for a duration of between 1 hour and 48 hours. Thus, the step of drying the moulds may be conducted at a temperature of between 20 °C and 80 °C for a duration of between 1 hour and 36 hours. The step of drying the moulds may also be conducted at a temperature of between 20 °C and 50 °C for a duration of between 1 hour and 24 hours. The step of drying the moulds may further be conducted at a temperature of between 20 °C and 40 °C for a duration of between 6 hours and 24 hours. The step of drying the moulds may also be conducted at a temperature of between 20 °C and 40 °C (e.g. between 20 °C and 25°C) for a duration of between 12 hours and 24 hours. It will be appreciated that the first composition may comprise one or more solvents. Nonlimiting examples of suitable solvents include aqueous solvents (e.g. water), alcohols (e.g. ethanol), di oxanes (e.g. 1,2-di oxane), n-methylprryolidine and furans (e.g. tetrahydrofuran). The solvent may therefore be an aqueous solvent (e.g. water). It will be appreciated that the first composition may comprise any suitable amounts of the at least one polymer or polymerizable monomer capable of forming a polymer matrix, the first compound and the second compound, and the skilled person will be able to readily choose the amount of each compound to use based on both their common general knowledge and the intended properties of the microneedle device. In certain embodiments, the first composition comprises between 10 % and 50 % of the at least one polymer or polymerizable monomer capable of forming a polymer matrix based on the total weight of the first composition. The first composition may comprise between 15% and 45 % of the at least one polymer or polymerizable monomer capable of forming a polymer matrix based on the total weight of the first composition. Thus, the first composition may comprise between 20% and 40 % of the at least one polymer or polymerizable monomer capable of forming a polymer matrix based on the total weight of the first composition. That is, the first composition may comprise between 25% and 35 % (e.g. 30 %) of the at least one polymer or polymerizable monomer capable of forming a polymer matrix based on the total weight of the first composition. In certain embodiments, the first composition comprises between 0.1 % and 30 % of each of the first and the second compound based on the total weight of the first composition. The first composition may comprise between 1 % and 20 % of each of the first and the second compound based on the total weight of the first composition. Thus, the first composition may comprise between 2 % and 15 % of each of the first and the second compound based on the total weight of the first composition. That is, the first composition may comprise between 5 % and 10 % of each of the first and the second compound based on the total weight of the first composition. It will be appreciated that the total weight of the first composition referred to above includes the weight (mass) of the solvent used to prepare the first composition. Other Features Each and every compatible combination of the embodiments described above is explicitly disclosed herein, as if each and every combination was individually and explicitly recited. Various further aspects and embodiments of the invention will be apparent to those skilled in the art in view of the present disclosure. “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, “A and / or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually herein. Unless context dictates otherwise, the descriptions and definitions of the features set out above are not limited to any particular aspect or embodiment of the invention and apply equally to all aspects and embodiments which are described. Examples Certain aspects and embodiments of the invention will now be illustrated by way of example and with reference to the figures described above. Example 1 Preparation of PDMS microneedle moulds. First, PDMS microneedle moulds were prepared by taking a preformed microneedle male master mould insert and covering the insert with degassed liquid polydimethylsiloxane (PDMS). The PDMS was then cured under ambient conditions (1 atmosphere and circa. 25 °C) before being removed from the preformed male master mould to form a female PDMS mould. The preformed microneedle male mould insert contained a 6x6 array of microneedle protrusions and was prepared using routine and well-known micro-injection moulding methodology that is commonly used to create such microneedle moulds. Moulds comprising different array sizes (e.g. other than 6x6) may also be used. Each microneedle female mould comprises microdepressions with a base diameter of 400 pm and a height of 700 pm. Preparation of the homogenous gel First, a homogenous mixture of 42.6 wt% ethyl-alcohol (Sigma 459836), 0.4 wt% Fluorescein isothiocyanate-dextran (Sigma FD2000S), 0.4 wt% Rhodamine B isothiocyanate-Dextran (Sigma R8881), 24.6 wt% Polyvinylpyrrolidone (PVP) (Sigma 234257) and 32 wt% ‘Reverse Osmosis’ water was prepared using the following protocol. The PVP and ethyl-alcohol were mixed at room temperature, in a 25 ml plastic test tube, using a vortex mixer for 1 minute. Next, Fluorescein isothiocyanate-dextran and Rhodamine B isothiocyanate-Dextran were added, and the resulting mixture was mixed via vortex mixer for a further 1 minute, until homogenous. The Reverse Osmosis water was then added and mixed again via vortex mixer for 1 minute, until a fully homogenous gel was created. The approximate molecular weights of the reagents used were as followed: • PVP Molecular Weight = 29,000 Daltons • Fluorescein isothiocyanate-dextran Molecular Weight = 2,000,000 Daltons • Rhodamine B isothiocyanate-Dextran Molecular Weight = 10,000 Daltons Preparation of the microneedles Approximately 1 gram of the homogenous gel prepared as described above was dropped onto the polydimethyl siloxane (PDMS) female microneedle mould described above. The gel-loaded mould was then subject to 5,580 g centrifugal force (5,500 rpm) for 20 minutes, within a “Thermo Scientific Megafuge 16” Centrifuge. The gel-loaded female mould was then removed from the centrifuge and left to air-dry overnight, in ambient conditions. The microneedle array was then extracted from the female PDMS mould with tweezers, 5 resulting in the gradient microneedle array depicted in Figures 3 to 5. Figures 3 to 5 depict white-light microscopy images of the prepared microneedles take using a Keyence VHX-7000 series microscope, with El00 lens and illustrate the differential distribution of the fluorescent dextran molecules within the microneedle arrays. 10

Claims

1. A microneedle device comprising:a base; andan array of microneedles on one side of the base, where a microneedle extends to a tip from the base, andwherein at least one, such as each, microneedle:is a single polymeric matrix, containing a first compound and a second compound, and the first compound has a molecular weight that differs from the second compound; andthe first and second compounds are differentially distributed between the tip and the base.

2. The microneedle device according to claim 1, wherein the first compound has a higher molecular weight than the second compound, and the concentration of the first compound is higher towards the tip relative to the concentration of the second compound.

3. The microneedle device according to claim 1 or claim 2, wherein the first compound has a molecular weight that is 50 Daltons or more than a molecular weight of the second compound, such as 100 Daltons or more than the molecular weight of the second compound, or such as 200 Daltons or more than the molecular weight of the second compound, or such as 500 Daltons or more than the molecular weight of the second compound, or such as 1000 Daltons or more than the molecular weight of the second compound, or such as 2000 Daltons or more than the molecular weight of the second compound, or such as 10000 Daltons or more than the molecular weight of the second compound.

4. The microneedle device according to any one of claims 1 to 3, wherein the single polymeric matrix is formed of hyaluronic acid, sodium hyaluronate, polyvinyl alcohol, carboxymethyl cellulose, polyvinylpyrrolidone, poly(lactic-co-glycolic acid), chitosan,hydroxypropyl methylcellulose, polyethylene glycol, gelatin, polycaprolactone, and combinations thereof, for example the single polymeric matrix is formed of hyaluronic acid, sodium hyaluronate, polyvinyl alcohol and combinations thereof.

5. The microneedle device according to any one of claims 1 to 4, wherein the second compound has a molecular weight of between 100 and 500 Daltons and the first compound has a molecular weight of between 10000 and 60000 Daltons.

6. The microneedle device according to any one of claims 1 to 5, wherein the microneedle further comprises a third compound, having a molecular weight between the molecular weights of the first and second compounds.

7. The microneedle device according to claim 6, wherein the first compound has a higher molecular weight than the second and third compounds, and the third compound has a higher molecular weight than the second compound, and the concentration of the first compound is higher towards the tip relative to the concentration of the second and third compounds, and the concentration of the second compound is higher towards the base relative to the concentration of the first and third compounds.

8. The microneedle device according to claim 6 or claim 7, wherein the second compound has a molecular weight of between 100 and 500 Daltons, the first compound has a molecular weight of between 10000 and 60000 Daltons, and the third compound has a molecular weight of between 1000 and 5000 Daltons.

9. The microneedle device according to any one of claims 1 to 8, wherein the second compound is selected from ascorbic acid, salicylic acid, nicotinamide, hydroquinone, retinol, glycolic acid, lactic acid, tartaric acid, citric acid and combinations thereof.

10. The microneedle device according to any one of claims 1 to 9, wherein the first compound is selected from hyaluronic acid, acetyl-hexapeptide or bovine serum albumin.

11. A process for preparing a microneedle device, wherein the microneedle device comprises a base and an array of microneedles on one side of the base, said process comprising the steps of:• adding a first composition into a mould for an array of microneedles, which composition comprises at least one polymer or polymerizable monomer capable of forming a polymer matrix, a first compound and a second compound which differ in their molecular weights;• centrifuging the mould containing the first composition;• optionally curing the first composition directly after the step of centrifugation to form the array of microneedles; and• adding a base to the array of microneedles..

12. A process according to claim 11, wherein the first compound has a molecular weight that is 100 Daltons more than the second compound, such as at least 200 Daltons, or such as at least 500 Daltons, or such as 1000 Daltons, or such as 2000 Daltons, or such as 10000 Daltons.

13. A process according to claim 11 or claim 12, wherein the at least one polymer or polymerizable monomer comprises at least one polymer or polymerizable monomer selected from hyaluronic acid, sodium hyaluronate, polyvinyl alcohol, carboxymethyl cellulose, polyvinylpyrrolidone, poly(lactic-co-glycolic acid), chitosan, hydroxypropyl methylcellulose, polyethylene glycol, gelatin, polycaprolactone, or any monomer thereof.

14. A process according to any one of claims 11 to 13, wherein the step of centrifuging the mould is carried out at a centrifugation speed of at least 3500 RPM, such as at least 3800 RPM, or such as at least 4000 RPM.

15. A process according to any one of claims 11 to 14, wherein the step of centrifuging the mould is carried out at using a Relative Centrifuge Force (RCF) of greater than 1500 g, such as greater than 1800 g, or such as greater than 1900 g.

16. A process according to any one of claims 11 to 15, wherein the step of centrifuging the mould is carried out at using a Relative Centrifuge Force (RCF) of between 1500 g and 6000 g, such as between 1700 g and 5000 g, or such as between 1800 g and 4000 g.

17. A process according to any one of claims 11 to 16, wherein the step of centrifuging the mould is carried out for a duration of between 2 minutes and 120 minutes, such as between 2 minutes and 60 minutes, or such as between 2 minutes and 30 minutes, or such as between 2 minutes and 20 minutes, or such as between 2 minutes and 15 minutes, or such as between 3 minutes and 10 minutes.

18. A process according to any one of claims 11 to 17, wherein the step of drying the mould is conducted at a temperature of between 20 °C and 100 °C (e.g. 20 °C and 50 °C) for a duration of between 1 hour and 24 hours (e.g. 12 to 18 hours).

19. A process according to any one of claims 11 to 18, wherein the step of adding the base to the array of microneedles comprises the following steps:• adding a second composition capable of forming a base to the mould, which composition comprises at least one polymer or polymerizable monomer capable of forming a base;• optionally curing the second composition; and drying the mould to prepare the microneedle device20. A microneedle device for administration of two or more compounds into a biological tissue prepared according to the process defined in any one of claims 11 to 19.

21. Use of a microneedle device according to any one of claims 1 to 10 or 20 for administration of two or more compounds into a biological tissue of a subject.

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