Macroporous solid rigid microneedles containing embedded particulate drug

Abstract

FIELD OF THE DISCLOSURE The present disclosure relates to microneedles and microneedle patches for transdermal drug delivery and methods of making and using same. The microneedles are porous and contain drug in the form of particles within the pores.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application is related to and claims priority to U.S. Provisional Patent Application No. 63 / 201812, filed May 13, 2021, and U.S. Provisional Patent Application No. 63 / 212586, filed June 18, 2021, which are incorporated by reference herein for all purposes.

[0002] (Statement regarding federally funded research) This invention was made with Government support under Grant No. HU0001-20-2-0014 awarded by the Department of Defense. The United States Government has certain rights in this invention. [Background technology]

[0003] FIELD OF THE DISCLOSURE This application relates generally to drug delivery systems and methods, and more particularly to automated drug delivery systems and methods.

[0004] Many systemic drugs require administration by injection, such as intravenous, intramuscular, or subcutaneous injection. This is true for certain therapeutic drugs, such as vaccines, diagnostic agents, and also for x-ray imaging, for example. Administration by injection is often required for drugs that are poorly or unpredictably absorbed by oral or other routes. This is commonly the case for macromolecular drugs, such as proteins, therapeutic monoclonal antibodies, which are degraded and not absorbed by the oral route. Some small molecule drugs, such as propranolol, morphine, vancomycin, and tetrahydrocannabinol (THC), are also poorly or erratically absorbed by the oral route. First-pass metabolism prevents oral absorption of many drugs.

[0005] Administration by injection is painful and often requires the services of a medical professional, which is expensive and inconvenient. Many drugs administered by injection are provided in aqueous formulations, which can make the drugs more unstable, require inconvenient conditions for transportation and storage, and have a short shelf life. Summary of the Invention [Problem to be solved by the invention]

[0006] To solve the above problems, there has been much attention on delivering drugs through the skin, for example, transdermally. However, transdermal administration is relatively uncommon due to technical problems. The technical problem is that the epidermis, especially its most superficial layer, the stratum corneum, is a formidable barrier to molecules that weigh more than about 500 Daltons and that have certain physicochemical properties, such as high hydrophilicity or hydrophobicity. [Means for solving the problem]

[0007] One technical approach to deliver drugs beyond the epidermis for transdermal absorption is to use drug-loaded skin-piercing microneedles. Generally, such microneedles include (1) a rigid structure with an end adapted to pierce the skin and (2) an active ingredient of the drug, typically combined with one or more excipients.

[0008] Microneedles provide a convenient transdermal delivery route that allows for long-term sustained release of drugs. Microneedles have gained attention as a way to avoid the degradation of drugs in the digestive tract, the first-pass effect in the liver, and the pain and inconvenience of intravenous injection that accompanies oral delivery. The use of microneedles also provides minimally invasive, painless, and self-administered delivery of drugs, from cosmetics to vaccinations, making them even more attractive. Manufacturing methods for microneedles include UV lithography, drawing lithography, deep X-ray lithography, micromilling, deep drilling RIE (DRIE), wet etching, and 2D and 3D printing, but there are many complexities. Efforts are being made to simplify the manufacturing method of microneedles and make the manufacturing process more cost-effective and less time-consuming.

[0009] Microneedles can be classified as solid, hollow, dissolving, tip-coalescing, and porous. Porous microneedles have a large volume of distributed pores. However, porous microneedles known in the art are fragile. In addition, it is difficult to make rigid porous microneedles that are strong enough to penetrate the skin. Furthermore, most other current microneedle technologies (e.g., hydrogel microneedles) do not have the mechanical properties for reliable and stable skin penetration. Furthermore, most microneedles can only carry a limited amount of drug. This limitation is especially problematic for drugs that require a solvent. It is also problematic for drugs that require a high absolute dose (e.g., macromolecular drugs, low-potency drugs, antibiotics). Some types of microneedles are physically or chemically incompatible with some drugs.

[0010] Thus, there is a need for an efficient and economical drug delivery system, and more specifically, there is a need for improved microneedle drug delivery systems and methods of manufacturing microneedle drug delivery systems. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 illustrates a flowable material having a drug in the form of particles, according to an embodiment of the present disclosure. [Diagram 2] FIG. 2 illustrates a mold having a cavity according to an embodiment of the present disclosure. [Diagram 3] FIG. 3 illustrates a flowable material having drug in the form of particles of FIG. 1 cast onto the mold of FIG. 2 according to an embodiment of the present disclosure. [Figure 4] FIG. 4 illustrates a schematic diagram of the hardening of a flowable material in a mold, according to an embodiment of the present disclosure. [Diagram 5] FIG. 5 shows the hardened polymeric material having microneedles after being removed from the mold according to an embodiment of the present disclosure. [Figure 6]FIG. 6 illustrates a microneedle of the hardened polymeric material of FIG. 5 according to an embodiment of the present disclosure. [Figure 7] FIG. 7 shows a bandage having an array of microneedles according to an embodiment of the present disclosure. [Figure 8a] FIG. 8a shows a microneedle in a dermal environment according to an embodiment of the present disclosure. [Figure 8b] FIG. 8b shows the diffusion of drug from the microneedles into the dermal environment according to an embodiment of the present disclosure. [Figure 9] FIG. 9 shows an array of microneedles according to the present disclosure. [Figure 10] FIG. 10 shows a scanning electron micrograph of a microneedle according to the present disclosure. [Figure 11] FIG. 11 is an enlarged view of some of the microneedles of FIG. 10 in accordance with the present disclosure. [Figure 12] FIG. 12 is a further enlarged view of a portion of the microneedle of FIG. 10 in accordance with the present disclosure. [Figure 13] FIG. 13 shows a scanning electron micrograph of a microneedle according to the present disclosure. [Figure 14] FIG. 14 shows a scanning electron micrograph of the microneedles after drug release according to the present disclosure. [Figure 15] FIG. 15 shows a schematic diagram of a drug-loaded solid matrix and the solid matrix after drug release according to an embodiment of the present disclosure. [Figure 16] FIG. 16 illustrates a bandage having a light emitter and a light sensor according to an embodiment of the present disclosure. [Figure 17] FIG. 17 is a schematic illustration of mixing two flowable materials to form a composite material, according to an embodiment of the present disclosure. [Figure 18] FIG. 18 illustrates the composite material of FIG. 17 cast onto a mold, according to an embodiment of the present disclosure. [Figure 19]FIG. 19 is a schematic illustration of placing the hardened synthetic material of FIG. 18 in an etching solution, according to an embodiment of the present disclosure. [Figure 20] FIG. 20 is a schematic diagram of the hardened composite material of FIG. 18 disposed within an etching solution, according to an embodiment of the present disclosure. [Figure 21] FIG. 21 illustrates an open-pore material in the form of microneedles, according to an embodiment of the present disclosure. [Figure 22] FIG. 22 is a schematic illustration of immersion of the open-pore material of FIG. 21 in a carrier liquid containing a particular form of drug, according to an embodiment of the present disclosure. [Figure 23] FIG. 23 is a schematic diagram similar to FIG. 22 illustrating agitation and evaporation of the carrier liquid according to an embodiment of the present disclosure. [Figure 24] FIG. 24 shows an open-pore material containing drug in the form of particles, according to an embodiment of the present disclosure. [Diagram 25] FIG. 25 shows an open-pore material containing drug in the form of particles, according to an embodiment of the present disclosure. [Figure 26a] FIG. 26a is a schematic illustration of microneedles on a thick back substrate penetrating into a subject, according to an embodiment of the present disclosure. [Figure 26b] FIG. 26b is a schematic illustration of microneedles on a thin dorsal substrate penetrating into a subject, according to an embodiment of the present disclosure. [Figure 27] FIG. 27 is a schematic diagram of creating an open-pore material by applying a gas through a resin, according to an embodiment of the present disclosure. [Figure 28a] FIG. 28a shows views at different times as the microneedle enters the dermal environment and drug is released according to an embodiment of the present disclosure. [Figure 28b] FIG. 28b shows views at different times as the microneedle enters the dermal environment and drug is released according to an embodiment of the present disclosure. [Figure 28c]FIG. 28c shows views at different times as the microneedle enters the dermal environment and drug is released according to an embodiment of the present disclosure. [Figure 29a] FIG. 29a shows flow cytometry data of CD20 positive cell fluorescence for six samples according to the present disclosure. [Figure 29b] FIG. 29b shows flow cytometry data of CD20 positive cell fluorescence for six samples according to the present disclosure. [Figure 29c] FIG. 29c shows flow cytometry data of CD20 positive cell fluorescence for six samples according to the present disclosure. [Figure 29d] FIG. 29d shows flow cytometry data of CD20 positive cell fluorescence for six samples according to the present disclosure. [Figure 29e] FIG. 29e shows flow cytometry data of CD20 positive cell fluorescence for six samples according to the present disclosure. [Fig. 29f] FIG. 29f shows flow cytometry data of CD20 positive cell fluorescence for six samples according to the present disclosure. [Figure 30a] FIG. 30a shows two patches applied to an African Green Monkey for transdermal drug delivery according to the present disclosure, and the area after removal of the patches. [Figure 30b] FIG. 30b shows flow cytometry data from animals administered two patches of rituximab daily, in accordance with the present disclosure. [Figure 30c] FIG. 30c shows B cell depletion in blood following intravenous injection and patch administration of Rituximab according to the present disclosure. [Diagram 31] FIG. 31 shows a specimen of an array of microneedles containing FITC-dextran, according to an embodiment of the present disclosure. [Diagram 32] FIG. 32 shows a specimen of an array of microneedles in a simulated dermal fluid according to an embodiment of the present disclosure. [Diagram 33]FIG. 33 shows the release data of FITC-dextran for two different formulated patches according to the present disclosure. [Figure 34a] FIG. 34a shows a schematic diagram of a method for manufacturing a microneedle mold, microneedles, and a microneedle patch according to the present disclosure. [Figure 34b] FIG. 34b shows a microneedle patch according to the present disclosure. [Figure 35a] FIG. 35a shows unmilled sulforhodamine B particles according to the present disclosure. [Figure 35b] FIG. 35b shows milled sulforhodamine B particles according to the present disclosure. [Figure 35c] FIG. 35c shows the particle size distribution of sulforhodamine B particles before and after milling according to the present disclosure. [Fig. 35d] FIG. 35d shows a microneedle made with unmilled sulforhodamine B particles according to the present disclosure (scale bar is 1 mm). [Figure 35e] FIG. 35e shows a microneedle made with milled sulforhodamine B particles according to the present disclosure (scale bar is 1 mm). [Fig. 35f] FIG. 35f shows a microneedle made of milled sulforhodamine B particles with a base structure according to the present disclosure (scale bar is 0.5 mm). [Figure 35g] FIG. 35g shows a schematic diagram of an array of microneedles with an elastic backing substrate and a solid acrylic ring in accordance with the present disclosure. [Fig. 35h] FIG. 35h is a schematic diagram of an in vitro release experiment according to the present disclosure. [Figure 35i] FIG. 35i shows the front of a dye-loaded microneedle patch according to the present disclosure. [Figure 35j] FIG. 35j shows the backside of the dye-loaded microneedle patch of FIG. 35i according to the present disclosure. [Figure 35k]FIG. 35k shows dye release from the dye-loaded microneedle patch of FIGS. 35i,j according to the present disclosure. [Figure 35l] FIG. 35l shows the release distribution of dye into gelatin from dye-loaded microneedle patches at different timestamps according to the present disclosure. [Figure 36a] FIG. 36a shows the UV-Vis spectra of different concentrations of ibuprofen in solution according to the present disclosure. [Figure 36b] FIG. 36b shows the UV-Vis spectra of different concentrations of lidocaine in solution according to the present disclosure. [Figure 36c] FIG. 36c shows the calibration curves for ibuprofen and lidocaine according to the present disclosure. [Fig. 36d] FIG. 36d is the release profile of an ibuprofen / resin microneedle patch and a lidocaine / resin microneedle patch in Dulbecco's Phosphate Buffered Saline (DPBS) according to the present disclosure, each patch having 100 microneedles. [Figure 36e] FIG. 36e shows the FTIR absorption spectrum of lidocaine powder compared to lidocaine encapsulated in microneedles in accordance with the present disclosure. [Fig. 36f] FIG. 36f shows the FTIR absorption spectrum of ibuprofen powder compared to ibuprofen encapsulated in microneedles according to the present disclosure. [Figure 37a] FIG. 37a is a photomicrograph of a tissue section of microneedle-treated pig skin in accordance with the present disclosure (scale bar, 100 micrometers). [Figure 37b] FIG. 37b shows the resin / drug surface morphology before and after release according to the present disclosure (scale bar is 200 micrometers). [Figure 37c] FIG. 37c shows a graph of the mechanical behavior of an individual microneedle containing drug and resin according to the present disclosure. [Fig. 37d]FIG. 37d is a bar graph comparing the robustness of resin / drug microneedles of the present disclosure with polyethylene glycol diacrylate (PEGDA) / drug microneedles, in accordance with the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Applicant has discovered a drug delivery system that includes one or more microneedles in which a drug is incorporated in the form of particles. When the one or more microneedles are applied to the skin of a subject, the drug diffuses through the skin and is delivered, for example, to the systemic circulation or to a desired local tissue. Without wishing to be bound by theory, in some embodiments, the solvent to aid in the diffusion of the drug is provided entirely or substantially by the interstitial fluid of the recipient subject. Thus, one of several distinguishing features of the present invention is that the drug can be optionally provided in a solid (or substantially solid) form that is compatible with solvation by the skin. Thus, the drug can be provided in a solvent-free (or substantially solvent-free) formulation, e.g., anhydrous. Thus, very large amounts of the active ingredient of the drug (i.e., drug substance) can be loaded into the microneedle (measured based on the mass of drug substance per mass of microneedle or the mass of active ingredient per volume of microneedle), e.g., 10 micrograms or more of drug substance per 35 nanoliters (the approximate volume of one microneedle). This provides several important benefits. These benefits include, for example, the ability to deliver active ingredients that could not previously be loaded in sufficient quantities onto microneedles through the microneedles, the ability to deliver high molecular weight molecules such as biologics and therapeutic monoclonal antibodies, the ability to create microneedles that may require shorter application times and / or less frequent reapplication, and the ability to obtain very high drug concentrations in the vicinity of the microneedles, thereby creating large concentration gradients and correspondingly improving drug delivery.Furthermore, the present invention optionally allows drugs to be incorporated into the microneedles in an anhydrous state.This can beneficially improve and extend the stability, such as the shelf life, of many drugs, including stability at room temperature.

[0013] The microneedles of the present invention also have notable physical characteristics that provide practical benefits. The size and other physical properties of the drug particles can be adjusted to alter the drug delivery characteristics of the microneedle, such as drug delivery rate. The composition and structure of the microneedle provide excellent skin penetration and structural integrity, such as rigidity or semi-rigidity, and resistance to breakage.

[0014] (Outline of the structure and manufacture of microneedles) In one embodiment, the system of the invention comprises one or more microneedles, each of which comprises a porous material that optionally comprises a drug in the form of particles that are solvent-free, substantially solvent-free, anhydrous, and / or substantially anhydrous.

[0015] In some embodiments, the porous material is formed from a flowable material (e.g., a resin, such as a polymer, that is subsequently cured to form a solid, or a flowable metal, such as an alloy, that is subsequently cooled to form a solid). In some embodiments, the flowable material is placed into a mold, which comprises one or more needle-shaped mold cavities. Solidification of the flowable material in the mold yields the microneedles of the invention. In some embodiments, the mold comprises an array of needle-shaped mold cavities in a particular geometric configuration.

[0016] (Drug particles) In some embodiments, the drug particles are combined with the flowable material to obtain a dispersion. In some embodiments, the drug particles include a solid, which is insoluble or substantially insoluble in the flowable material. Thus, in some embodiments, hydrophobic drug particles are combined with a hydrophilic flowable material. In some embodiments, hydrophilic drug particles are combined with a hydrophobic flowable material. In some embodiments, the drug is provided as droplets (or micelles, vesicles, or other aggregates of drug in a liquid phase), and the droplets (or such other aggregates) are immiscible or substantially immiscible in the flowable material. For purposes of this disclosure, the terms "immiscible" or "substantially immiscible" refer to miscibility under selected manufacturing conditions, such as temperature. Thus, two materials may be miscible for purposes of the present invention even if they are miscible under other conditions, such as high temperature or the presence of additives such as emulsifiers.

[0017] Drug particles for use in the present invention can be obtained, for example, by lyophilization, spray drying, or solvent evaporation, such as liquid emulsion, or formation of microfluid droplets followed by dehydration, to produce drug particles that are then dispersed throughout the flowable material as drug particles. In some embodiments, the size (i.e., largest dimension) of the drug particles is between 1 micrometer and 100 micrometers. In some embodiments, the size of the drug particles is between 37 micrometers and 100 micrometers. In some embodiments, the size of the drug particles is between 1 micrometer and 37 micrometers. In some embodiments, the size of the drug particles is between 500 nanometers and 1 micrometer. In some embodiments, the size of the drug particles is between 100 nanometers and 500 nanometers. In some embodiments, the size of the drug particles is between 10 nanometers and 500 nanometers. It is understood that throughout this disclosure, when the size of the drug particles is described, the particle size can optionally exist as a distribution of sizes. Thus, when a particle measurement of the particle size is provided, this measurement can represent the mean or median of the particle size distribution. Thus, in some embodiments, the median size of the drug particles is between about 1 micrometer and 100 micrometers, between about 1 micrometer and 37 micrometers, between about 500 nanometers and 1 micrometer, or between about 100 nanometers and 500 nanometers. Thus, in some embodiments, 90 percent, 95 percent, 99 percent, or 99.9 percent of the drug in the composition is between 1 micrometer and 100 micrometers, between about 1 micrometer and 37 micrometers, between about 500 nanometers and 1 micrometer, or between 100 nanometers and 500 nanometers. In the preceding paragraphs, sixteen possible pairwise combinations of ratios and particle size ranges are disclosed, each of which is disclosed herein as if individually set forth.

[0018] In some embodiments, the drug particles are solvent-free, substantially solvent-free, or made without solvent. In some embodiments, the drug particles are anhydrous, substantially anhydrous, or made without solvent. As used herein, the terms "substantially solvent-free" and "made without substantially solvent" each include, but are not limited to, compositions that contain negligible amounts of solvent, such as, for example, solvent molecules non-covalently bound to the drug particles. Similarly, as used herein, the terms "substantially solvent-free" and "made without substantially solvent" each include, but are not limited to, compositions that contain negligible amounts of water, including, for example, water present in the drug particles that are hydrates, or water passively absorbed or adsorbed from the atmosphere.

[0019] The drug particles may be homogeneous or heterogeneous. The drug particles may be physically uniform or may be composed of two or more parts. For example, the drug particles may optionally include a central core and a surface shell, and the surface shell may be selected to optimize the physical interaction between the drug particles and the flowable material, if desired. For example, the drug particles may include a central core containing an active drug ingredient surrounded by a protective shell. The protective shell may be adapted to prevent the drug from dissolving in the flowable material. Some examples include the use of a hydrophilic protective shell in a hydrophobic flowable material, the use of a hydrophobic protective shell in a hydrophilic flowable material, the use of a protective shell to prevent chemical reactions between the active drug ingredient and the flowable material, or the use of a protective shell with an absorption spectrum that protects the active drug ingredient from photodegradation, for example, during curing of the flowable material.

[0020] The drug particles can include one or more excipients, such as binders, buffers, salts, stabilizers, and / or preservatives known in the art. The mixture including the drug particles and the flowable material can also include one or more excipients, such as binders, buffers, salts, stabilizers, and / or preservatives known in the art.

[0021] The drug particles may be single drug particles or may be physical clusters of one or more drug particles containing any of the shells, excipients, or active drug ingredients described above.

[0022] The use of drugs in particulate form can be of particular interest for the delivery of high molecular weight drugs, which are typically hydrophilic and soluble in, for example, the interstitial fluid of the skin, and therefore are excellent candidates for use in certain embodiments described above.

[0023] The drug particles, or the mixture containing the drug particles and the flowable material, may be provided with one or more detectable markers known in the art. The markers may include, for example, non-toxic dyes such as fluorescein, green fluorescent protein, or radioactive compounds. Such markers are useful for monitoring drug release from the microneedles.

[0024] (Drugs used in the present invention) In some embodiments, the drug is a monoclonal antibody (e.g., rituximab), an antibody, a therapeutic peptide, a colony stimulating factor, a low molecular weight drug, an analgesic (e.g., lidocaine), another anesthetic drug, or a combination thereof. Applicants have specifically verified the operability of drug-loaded microneedles after embedding the protein rituximab, the low molecular weight lidocaine, and ibuprofen inside the microneedles (see Examples).

[0025] In some embodiments, the drug is an analgesic, an anesthetic, an anti-Alzheimer's drug, an anti-bronchial asthma drug, an anti-Parkinson's drug, an anti-allergy drug, an anti-angina drug, an anti-arrhythmic drug, an anti-arthritis drug, an anti-asthma drug, an antibacterial drug, an antibiotic, an anti-cancer drug, an anticoagulant, an antidepressant, an anti-diabetic drug, an antiemetic drug, an anti-epileptic drug, an anti-fungal drug, an anti-glaucoma drug, an anti-gout drug, an antihistamine drug, an anti-hyperprolactinemia drug, an antihypertensive drug, an anti-inflammatory drug, an anti-migraine drug, an anti-tumor drug, an anti-obesity drug, an anti-parasitic drug, an antiprotozoan drug, an antipyretic drug, an anti-psoriasis drug, an anti-psychotic drug, an antithrombotic drug, an anti-ulcer drug, an anti-viral drug, an anti-anxiety drug, a prostatic hyperplasia drug, a bronchodilator, a calcium hormone or a supplement. , cardiac stimulants, vasoactive agents, chelating agents, antidotes, chemopreventive agents, contraceptives, diuretics, dopamine agonists, gastrointestinal agents, gastroprokinetic agents, hematopoietic agents, hemophiliacs, hormones, hormone replacement therapy agents, hypnotics, hypocholesterolemic agents, antihyperlipidemic agents, immunomodulators, immunoenhancing agents, immunosuppressants, immunotherapeutic agents, lipid regulators, drugs for treating male sexual dysfunction, drugs for multiple sclerosis, muscle relaxants, neuroleptics, nootropics, anti-osteoporosis drugs, phytoestrogens, antiplatelet agents, prostaglandins, radiosensitizers for radiation therapy, muscle relaxants, sedatives, tranquilizers and stimulants, respiratory distress syndrome drugs, vasodilators, or vitamins.

[0026] In some embodiments, the microneedles of the present invention are provided loaded with a vaccine instead of a drug.

[0027] The microneedles of the present invention, in their finished state, comprise a rigid porous material. In some embodiments, the pores of the porous material are created by spatial exclusion imposed by the presence of drug particles dispersed in the flowable material during the manufacturing process of the microneedles. Thus, in some embodiments, the drug particles are contained within the pores of the porous material. In some embodiments, the drug particles occupy substantially all of the volume of the pores of the porous material. In some embodiments, the drug particles occupy at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.9%, or 99.99% of the volume of the pores of the porous material. In some embodiments, substantially all of the pores are occupied by the drug particles. In some embodiments, at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.9%, or 99.99% of the pores are occupied by the drug particles. In some embodiments, substantially all of the solvent accessible volume of the microneedle is occupied by drug particles. In some embodiments, at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.9%, or 99.99% of the solvent accessible volume of the microneedle is occupied by drug particles. For purposes of this disclosure, the term "solvent accessible volume" refers to the maximum volume that may be absorbed by a microneedle immersed in a suitable solvent, e.g., water.

[0028] In some embodiments, the flowable material may be a biocompatible resin. For example, Dental SG resin may be used. Other suitable types of biocompatible resins include, but are not limited to, BioMed Clear Resin (RS-F2-BMCL-01), BioMed Amber Resin (RS-F2-BMAM-01), Dental LT Clear Resin (RS-F2-DLCL-02), Surgical Guide Resin (RS-F2-SGAM-01), and Dental SG Resin (RS-F2-DGOR-01). The biocompatible resin may be light curable, i.e., may be cured to provide a hard polymer. In some embodiments, the biocompatible resin or its cured form may include species selected from chitosan, chitosan polybutylene adipate terephthalate, poly(butylene adipate-co-terephthalate), polyethylene glycol, poly(ethylene glycol) diacrylate, gelatin, gelatin methacryloyl, polyvinyl alcohol, silk, and combinations thereof. Other materials used to fabricate the porous microneedles may include, but are not limited to, polylactic acid (PLA), polyvinyl alcohol (PVA), poly(ethylene glycol diacrylate) (PEGDA), or UV-curable polymers.

[0029] In some embodiments, the porous material is initially obtained without drug particles, and then the drug particles are introduced into the porous material. Essentially, the porous material can be known in the art (polymers including PLGA, PVA, PDMS, acrylics, and hydrogels including PEG gelatin, chitosan), or the porous material can be created by the combination of a sacrificial material and a flowable material, where the two materials are immiscible or insoluble (as can be the case in the phase of the sacrificial material). Once the flowable material has solidified, the sacrificial material can be selectively removed, for example by chemical means, to obtain a porous material with open pores. Drug particles can then be formed within the porous material, for example, by immersing the porous material in a carrier liquid containing the drug, followed by evaporation or sublimation of the carrier liquid, leaving the drug particles within the porous material. In some embodiments, the drug can be water-soluble and the porous material can be hydrophobic, or the drug can be lipid-soluble and the porous material can be hydrophilic. For purposes of this disclosure, the term "sacrificial material" refers to a material that is used during a manufacturing process or part thereof, for example to provide a void or cavity, but that is removed prior to obtaining the final product.

[0030] Whether the pores are created by spatial exclusion imposed by the presence of drug particles dispersed within the flowable material, or the pores are initially obtained without any drug particles, the pores should be interconnected such that all or substantially all of the drug particles are accessible to external solvents such as interstitial fluid, This accessibility is sometimes referred to herein as making the pores open or drug available.

[0031] (Microneedle structure) Disclosed herein is a new class of microneedles, specifically referred to as macro-porous rigid (macro-POSH) microneedles. Macro-POSH microneedles are rigid microneedles with a highly porous structure with micro / nano-sized pores, which can facilitate loading of very large amounts of drugs into the microneedles. At the same time, the macro-POSH microneedles disclosed herein have excellent structural properties. The fabricated microneedles have a high Young's modulus (estimated to be 1000 times that of human skin), making them resistant to breakage, and can effectively penetrate various types of skin without breakage. The microneedles can form and maintain a very sharp tip (see examples).

[0032] Figure 9 shows an array of microneedles according to one embodiment of the invention, and Figure 10 shows a scanning electron micrograph of a portion of a microneedle according to one embodiment of the invention prior to drug release. Figure 11 shows a close-up of some of the microneedles of Figure 10, and Figure 12 shows a further close-up of a portion of the microneedles of Figure 10.

[0033] The size of the microneedle pores may be correlated with the size of the drug powder loaded into the microneedles. The size of the pores may have any dimension from nanoscale to microscale. For example, the pores may have a diameter ranging from about 100 nanometers to about 40 micrometers. In one particular embodiment, a drug particle having a size of about 6 micrometers provides a pore size of about 6 micrometers. In some embodiments, the pores may range from about 100 nanometers to 100 micrometers in the largest dimension. In some embodiments, the pores may range from about 10 micrometers to 100 micrometers. In some embodiments, the pores may range from about 1 micrometer to 100 micrometers. In some embodiments, the pores may range from about 500 nanometers to 10 micrometers. In some embodiments, the pores may range from about 500 nanometers to 50 micrometers.

[0034] In some embodiments, the axial length of the microneedle (i.e., the length measured from the tip [i.e., the sharp point] to the base) is between 0.5 mm and 10 mm. In some embodiments, the axial length is between 0.5 mm and 8 mm. In some embodiments, the axial length is between 0.5 mm and 6 mm. In some embodiments, the axial length is between 0.5 mm and 5 mm. In some embodiments, the axial length is between 0.5 mm and 4 mm. In some embodiments, the axial length is between 0.5 mm and 3 mm. In some embodiments, the axial length is between 0.5 mm and 2 mm. In some embodiments, the axial length is between 0.5 mm and 1.5 mm. In some embodiments, the axial length is between 0.5 mm and 1 mm. In some embodiments, the axial length is between 1 mm and 1.5 mm. In some embodiments, the axial length is between 0.75 mm and 1 mm. In some embodiments, the axial length is between 1 mm and 1.25 mm. In some embodiments, the axial length is between 0.8 mm and 1.2 mm. In some embodiments, the axial length is between 0.9 mm and 1.1 mm. In some embodiments, the axial length is between 0.1 mm and 1 mm. In some embodiments, the axial length is between 0.1 mm and 0.75 mm. In some embodiments, the axial length is between 0.1 mm and 0.5 mm.

[0035] (back substrate) A material attached to the base of one or more microneedles for support purposes, such as to provide an adhesive supportive backing and / or to arrange the microneedles in an array, is referred to herein as a backing substrate. In some embodiments, the backing substrate may be or include a thin elastic (FIG. 26B). In some embodiments, the backing substrate may be or include a flexible adhesive. In some embodiments, the backing substrate may be or include a woven material. In some embodiments, the backing substrate may be or include a film. In some embodiments, the backing substrate may be or include a bandage or dressing. In some embodiments, the backing substrate may be or include a biodegradable material. In some embodiments, the backing substrate may function as an intermediate adhesive to a larger patch for clinical applications. In some embodiments, the backing substrate may be a continuation of the same porous material that makes up the microneedles (FIG. 5). In some embodiments, the backing substrate may be a secondary drug-loaded material, including a drug-loaded porous material.

[0036] A polymer that forms a strong bond with the microneedles may be used as the material forming the backing substrate. The material used to form the backing substrate may be rigid or flexible depending on the application. Suitable flexible materials include, but are not limited to, paper, fabric, polyetheretherketone (PEEK), polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polytetrafluoroethylene (PTFE), parylene, and polyimide. Elastic and flexible resins may be used (e.g., Elastic 50A Resin (Part Number: FLELCL01), Flexible 80A Resin (Part Number: FLFL8001)). UV-curable resins may be used, for example, when conformability, flexibility, and elasticity are required for the microneedle patch. For applications requiring a rigid backing substrate, hard resins may be used. Suitable examples of hard resins include, but are not limited to, Surgical Guide Resin (Part Number: FLSGAM01).

[0037] In some embodiments where the backing substrate is planar or substantially planar, the "planar area" of the patch may be calculated as the area of ​​the patch in the plane defined by the backing substrate. In some such embodiments, the "planar area of ​​the microneedles" of the patch may be calculated as the area of ​​a regular or irregular polygon, defined as the polygon with the largest area that (1) lies in the plane of the backing substrate and (2) is circumscribed by the locus of all straight lines connecting all the microneedles in pairs. Without wishing to modify the geometric definition above, more simply stated, the planar area of ​​the microneedles is the area defined by the perimeter of the microneedles on the patch. In some embodiments, the planar area of ​​the patch is about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 16, 18, 20, 24, 25, 27, 28, 30, 32, 33, 35, 36, 40, 42, 45, 48, 50, 55, 56, 60, 63, 64, 65, 70, 72, 75, 80, 81, 85, 90, 95, 99, 100, 105, 110, 120, 121, 125, 130, 135, 140, 144, 145, 150, 160, 170, 180, 190, 200, 210, 215, 220, or 225 cm. 2 It is. In some embodiments, the planar area of ​​the microneedles of the patch is about 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 16, 18, 20, 24, 25, 27, 28, 30, 32, 33, 35, 36, 40, 42, 45, 48, 50, 55, 56, 60, 63, 64, 65, 70, 72, 75, 80, 81, 85, 90, 95, 99, 100, 105, 110, 120, 121, 125, 130, 135, 140, 144, 145, 150, 160, 170, 180, 190, 200, 210, 215, 220, 225 cm 2 In some embodiments, the planar area of ​​the patch is about 0.1 to 1, 1 to 5, 1 to 10, 5 to 10, 10 to 20, 10 to 100, 20 to 50, 50 to 100, 100 to 150, 150 to 200, or 200 to 250 cm. 2In some embodiments, the planar area of ​​the microneedles of the patch is between about 0.1 to 1, 0.5 to 100, 1 to 5, 1 to 10, 5 to 10, 10 to 20, 10 to 100, 20 to 50, 50 to 100, 100 to 150, 150 to 200, or 200 to 250 cm. 2 , is between.

[0038] (Microneedle manufacturing) One example of the process for making the microneedles of the present invention is shown in Figures 1 to 6. Figure 1 shows a flowable material 10, such as a resin, in which a drug 12 in the form of particles is dispersed (schematically better seen in the enlarged area of ​​Figure 1). The material 10 is cast into a mold 14 having a cavity 16, shown in Figure 2. As shown in Figure 3, the material 10 with the drug 12 fills the cavity. The drug may be provided in the form of particles, such as a powder. The combination of the flowable material and the drug in the form of particles or in dissolved form is referred to herein as a cast paste or a cast solution, respectively. It has further been discovered that when a form of particles is used, the finer the powder, the less resin is needed to create a usable cast paste that results in a porous material with mechanical properties robust enough to achieve penetration and removal of the microneedle into the dermis layer without breaking (see paragraph

[0080] in the Examples). As an example, for powders with particles of 10 microns or larger, drug powder and resin can be mixed in a 1:1 (w / w) ratio to create a pourable paste with robust mechanical properties when hardened. By reducing the particle size (e.g., from 10 microns to 1-5 microns, which can translate to longer grinding times or optimized spray drying methods), drug powder and resin can be mixed in ratios of 2:1, 3:1, 4:1, 5:1, and even 6:1 (w / w-drug / resin) to allow the microneedle to remain rigid enough to effectively penetrate the skin and maintain structural integrity such that it is not damaged during application, wearing, and removal from the skin, without overall loss of mechanical properties. This means that fine drug particles, leading to even finer drug particles, can allow for a much larger loading dose for a given volume of microneedle.

[0039] Referring to FIG. 4, the material 10 with drug particles 12 within the mold 14 can be cured using, for example, thermal or electromagnetic energy 16, such as UV or visible light. Referring to FIG. 5, the cured polymeric material 20, still containing drug particles 22, can then be removed from the mold while retaining the needle-like shape 22 from the mold cavity. FIG. 6 diagrammatically illustrates that the cured polymeric material 20 of each of the needles 22 contains insoluble (immiscible) drug particles 12 within the cured polymeric material 20. The cured polymeric material has a hardness of at least about Shore A40. In some embodiments, the hardness of the cured polymeric material is between Shore A40 and Shore D90. In some embodiments, the hardness of the cured polymeric material is between Shore D40 and Shore D80. In some embodiments, the hardness of the cured polymeric material is between Shore A60 and Shore D80. In some embodiments, the hardness of the cured polymeric material is between Shore A60 and Shore A100. In some embodiments, the hardness of the cured polymeric material is at least about Shore D80.

[0040] According to various aspects, the present invention provides a method for manufacturing a drug-loaded microneedle according to various aspects of the present invention. As disclosed in International Publication No. WO 2019 / 203888, published on October 24, 2019, a mold can be formed using cross-over line (COL) laser lithography to create a microneedle that combines the benefits of both hard and soft microneedles. The entire disclosure of that publication is incorporated herein by reference.

[0041] FIG. 7 shows an array of such microneedles 22 (which can be viewed as needle-like shapes or protrusions) used in conjunction with a bandage 30 that includes adhesive regions 32 .

[0042] Compared to the state of the art, these microneedles offer unprecedented drug loading capacity. In some embodiments, the drug loading capacity can be picogram to milligram scale per microneedle or picogram to gram scale per patch. Such microneedles also provide reliable skin penetration. It is important to prepare the drug-loaded dosing paste through an inventive dry emulsification of the drug in powder form with a biocompatible resin (solvent-free or substantially solvent-free). Usually, the dried drug powder does not dissolve in the resin. By controlling the particle size of the drug powder (to less than 10 μm) and mixing it with a biocompatible solvent-free pre-hardening liquid, for example of class IIa (long-life biocompatible resin with high resistance to fracture), in a 1:1 (w / w) ratio, it is possible to create a dosing paste, which is a paste-like diffusion that can be cast into a mold. In certain embodiments, the resin is USP Class VI. Casting and hardening such a paste creates a porous material. Pores in the matrix of hard cured resin are formed completely or substantially due to spatial exclusion imposed by the presence of drug particles, and the pores make all or substantially all of the drug particles accessible to external solvents such as interstitial fluid.

[0043] Controlling the size of particles not only affects the drug loading capacity, but also has a clear impact on the delivery rate of the drug (see Figure 33). Introducing this kind of control based on particle size is a very important discovery in moving towards a controlled and sustained, efficient and economical drug delivery system (e.g., as a disposable patch without electronic circuitry). This also leads to the possibility of including varying the size of a given drug particle to improve or tailor the drug release profile, with or without any additional modifiers.

[0044] Turning to FIG. 34a, several methods of manufacturing a microneedle mold 100, microneedles 102, and microneedle patches 104 according to the present disclosure are shown. Manufacturing of the microneedle mold 100 begins with laser cutting one or more microneedle-shaped recesses 106 in a first material using a cross-over line (COL) manufacturing procedure (WO 2019 / 203888) to provide a first mold 108. A second material may be dispensed into the first mold 108 to fill the microneedle-shaped recesses 106 with the second material. Subsequent curing of the second material may provide a second mold 110 having one or more microneedles 112 formed in the microneedle-shaped recesses 106. The cured second mold 110 may be removed from the first mold 108, and a surface of the cured second mold 110 may be subjected to a plasma treatment to activate the surfaces of the microneedles 112. A release layer may be applied to the plasma treated surface of the cured second mold 110. In one embodiment, the release layer may be a silane layer applied by treatment with trichloro(1H,1H,2H,2H-perfluorooctyl)silane. Following application of the silane layer, a third material may be cast onto the surface of the cured second mold 110 and the third material may be cured to provide a microneedle mold 110 having microneedle forming cavities 114. The microneedle mold 100 may be removed from the cured second mold 110. In one embodiment, the first material is an acrylic sheet, the second material is a silicone elastomer such as polydimethylsiloxane (PDMS), and the third material is a superelastic silicone rubber such as EcoFlex®.

[0045] With continued reference to FIG. 34a, a method of manufacturing the microneedles 102 and microneedle patches 104 is disclosed. The use of a superelastic microneedle mold 100 can stretch the microneedle mold 100 to facilitate embedding the highly viscous drug / biocompatible resin mixture into the mold 100. Additionally, the use of a superelastic mold can significantly reduce the manufacturing time of the microneedles by avoiding the step of pulling a vacuum to embed the embedding paste into the small microneedle-forming cavities of the mold. As shown in FIG. 34a, the microneedle mold 100 can be stretched beyond its original dimensions to expand the size of the microneedle-forming cavities 114. A drug and biocompatible resin mixture 116 can be injected into the microneedle mold 100 such that the mixture 116 fills the expanded microneedle-forming cavities 114. The drug in the mixture 116 can be in the form of solid particles. In some embodiments, the size of the drug particles is between about 1 and 100 micrometers in their largest dimension. In some embodiments, the size of the drug particles is between about 37 and 100 micrometers in their largest dimension. In some embodiments, the size of the drug particles is between about 1 micrometer and 37 micrometers in their largest dimension. In some embodiments, the size of the drug particles is between about 500 nanometers and 1 micrometer in their largest dimension. In some embodiments, the size of the drug particles is between about 100 nanometers and 500 nanometers in their largest dimension. In some embodiments, the size of the drug particles is between about 10 nanometers and 500 nanometers in their largest dimension.

[0046] The microneedle mold 100 can be shrunk to its original size and the biocompatible resin can be cured to provide the microneedles 102. In some embodiments, the biocompatible resin can be photocured by exposure to ultraviolet light. In one embodiment, the biocompatible resin is photocured by exposure to 405 nanometer light. The resulting microneedles 102 can be solid and porous with the drug embedded in the pores of the microneedles 102.

[0047] As shown in Figure 34a, an elastic polymer 118 can be dispensed into the microneedle mold 100 to cover the microneedles 102 and provide an elastic backing substrate 120. The elastic polymer 118 can be cured to provide a microneedle patch 104 having an elastic backing substrate 120 bonded to the microneedles 102. In some embodiments, the elastic polymer can be photocured by exposure to ultraviolet light. The microneedle patch 104 can be removed from the microneedle mold 100.

[0048] The use of a hard polymer for the microneedles 102 and an elastic polymer for the backing substrate 120 provides both the benefits of a stiff and rigid microneedle with guaranteed tissue insertion and the benefits of a soft elastic backing substrate. The tips of the microneedles are robust and can resist breakage upon application of forces up to about 0.26 N (Newtons). This provides a four-fold safety margin over the force required to reliably insert into the skin with the same microneedle geometry (0.058 N per needle). The conformal backing substrate 120 can be configured to conformally fit the curvature of the skin at any body site in order to apply the microneedle patch 104 to any body site.

[0049] Macroporous metallic microneedles may also be provided. Here, a microneedle mold capable of handling molten metal may be produced. The mold may be made of clay, ceramic, or any material capable of maintaining its shape in the presence of molten metal. A molten mixture of two different metals, for example metal X and metal Y (gold / silver, zinc / copper, silver / zinc, iron / titanium, or any possible alloy mixture), is introduced to create a metallic microneedle. The metallic microneedle is placed in an etchant (metal X etchant) of one of the alloy metals to etch the metal (metal X). For example, if an iron / titanium microneedle is formed, then the composite is placed in an iron etchant to etch the iron, leaving behind a porous form of titanium (the pores are the spaces where the iron was). This allows the creation of very stiff and highly porous metallic microneedles for a variety of transcutaneous and in situ sensing applications. To use it as a drug delivery device, a dissolved form of the drug can be dried onto the microneedle, or a fine drug powder can be pressed into the microneedle to load the pores of the needle with drug particles.

[0050] FIG. 17 shows at 50 two flowable materials 52, 54, which may be different resins or different metals, in liquid or molten form. When the materials 52, 54 are metals, they may be any of gold, silver, carbon, iron, copper, brass, bronze, titanium, beryllium, aluminum, tin and zinc, and alloys thereof. The materials 52, 54 are mixed together to form a composite material 56, for example mixed by a mixer 58. The materials 52, 54 are selected such that they form a heterogeneous mixture that is immiscible but can be mixed to form small droplets (i.e. less than 5 micrometers in diameter). One of the materials is selected to be sacrificial. Referring to FIG. 18, the composite material 56 is then placed into a mold 60 (e.g., a mold such as that formed in International Publication No. WO 2019 / 203888, again published October 24, 2019, the entire disclosure of which is incorporated herein by reference).

[0051] The loaded composite material is then cooled or otherwise hardened (e.g., to a hardness of at least about Shore D20), and, referring to Figs. 19 and 20, it is placed in an etchant 64 and preferably agitated as shown at 66 to remove the sacrificial material (e.g., 54). The materials 52, 54 are selected such that they are immiscible but capable of being broken down (e.g., agitated) into smaller pieces, respectively, so that the removal of the sacrificial material is designed (by mixing and volume selection of the materials) to leave a number of open pores in the remaining material (e.g., 52). Since the etchant must flow into the sacrificial material, the pores are interconnected or in fluid communication with each other. For the purposes of this disclosure, two compartments are "in fluid communication" when fluid can flow or diffuse from one compartment to the other. Fluid communication can be tested, for example, by filling the compartments with a fluid such as water, placing a dye or marker in the first compartment, and sampling the second compartment to confirm the presence of the dye or marker that indicates diffusion between the compartments.

[0052] FIG. 21 shows the resulting apertured material 68 as formed in the shape of microneedles 70. The resulting apertured material 68 is then immersed in a carrier liquid 72 containing a high concentration of drug 74 (not dissolved) in particulate form as shown in the enlarged view of FIG. 22. In some embodiments, the drug 74 is immersed in the carrier liquid 72 and then regains particulate form after evaporation of the carrier liquid. The level of immersion of the apertures may be controlled to limit the amount of material (e.g., only the microneedles) that is immersed in the carrier liquid. This limits the amount and location of drug that is placed within the apertures, for example, the drug is limited to only being placed within the microneedles or only within the tips of the microneedles. The drug particles can have a size of less than about 100 micrometers in a maximum dimension, or even less than 20 micrometers in a maximum dimension. In some embodiments, the drug particles have a size of less than 1 micrometer in a maximum dimension. In some embodiments, the drug particles have a size of 100 nanometers in a maximum dimension. The carrier liquid 72 with the drug 74 is then agitated (as shown at 76) against the apertured material 68 to cause a desired amount of drug 74 in the carrier liquid 72 to flow into the openings. With reference to Figure 23, once the desired amount of drug has flowed into the openings, the carrier liquid is evaporated using, for example, a fan or blower 78. The apertured material 68, now containing the drug in particulate form, is then removed leaving behind residual drug 74 which can be recovered and reused, as shown in Figure 24. Figure 25 shows the apertured material 68 with drug 74 in particulate form within the composition.

[0053] In a further embodiment, a material having open pores is created through injecting gas bubbles (or bubble-forming gas) through the resin or liquid metal prior to casting and cooling or hardening. For example, FIG. 27 shows at 80 a resin or liquid metal 82 to which a gas 84 (e.g., nitrogen) is provided via a valve 86. The gas (and the viscosity of the resin or liquid metal 82) can be selected such that a substantial portion 88 of the gas remains within the resin or liquid metal 82 (e.g., in the form of bubbles) and remains at a sufficient density to obtain a material having open pores. The gas-filled material 82 is then cast into a mold, cooled or hardened, and filled with drug particles as described above.

[0054] In one aspect, the present disclosure provides a method of manufacturing a microneedle for transdermal drug delivery, which may include stretching a microneedle mold having at least one microneedle forming cavity to expand a size of the at least one microneedle forming cavity, depositing a mixture of a drug and a biocompatible resin onto the microneedle mold, the mixture being arranged to fill the expanded microneedle forming cavity, the drug being in the form of solid particles and having a particle size of 10 nanometers to 100 micrometers, allowing the microneedle mold to shrink to its original size, curing the mixture within the microneedle forming cavity to provide a microneedle, the microneedle being solid and porous, the drug being embedded within the pores of the microneedle, and removing the microneedle from the microneedle mold.

[0055] In one aspect, the present disclosure provides a method of manufacturing a microneedle patch for transdermal drug delivery, which may include stretching a microneedle mold having microneedle-forming cavities beyond the original dimensions of the microneedle mold, casting a mixture of a drug and a biocompatible resin onto the microneedle mold, the mixture being such that it fills the microneedle-forming cavities, the drug being in the form of solid particles and having a particle size of 10 nanometers to 100 micrometers, allowing the microneedle mold to shrink to the original dimensions of the microneedle mold, curing the mixture in the microneedle-forming cavities to provide microneedles, the microneedles being solid and porous, the drug being embedded within the pores of the microneedles, casting an elastic polymer into the microneedle mold, curing the elastic polymer to bond the elastic polymer to the microneedles to provide the microneedle patch, and removing the microneedle patch from the mold.

[0056] The methods described herein may also include further steps relating to the manufacture of the microneedle mold. Such further steps may include: That is, the method may include the steps of laser cutting one or more microneedle-shaped depressions in a first material to provide a first mold; depositing a second material onto the first mold to fill the one or more microneedle-shaped depressions with a second material; hardening the second material to provide a second mold having one or more microneedles formed within each of the one or more microneedle-shaped depressions; removing the hardened second material from the first mold; plasma treating a surface of the hardened second mold having the one or more microneedles; applying a release layer to the surface of the hardened second mold; depositing a third material onto the surface of the hardened second mold; hardening the third material to provide the microneedle mold having the microneedle-forming cavities; and removing the microneedle mold from the hardened second mold. The laser cutting step may include using a pattern of crossover lines. The first material may be an acrylic sheet, the second material may be a silicone elastomer, and the third material may be a superelastic silicone rubber. The applying a release layer may include silanizing a surface of the cured silicone elastomer. The silanization may be performed using (1H,1H,2H,2H-perfluorooctyl)silane.

[0057] The methods described herein may also include additional method steps related to creating a mixture of a biocompatible resin and a drug. Such additional steps may include grinding the drug into fine particles having a particle size of 10 nanometers to 100 micrometers, and mixing the ground drug and the biocompatible resin in a 1:1 ratio to provide a dosing paste.

[0058] The curing step of the methods described herein may be accomplished by any curing method understood by one of ordinary skill in the polymer art, including, but not limited to, photocuring via exposure to curing radiation, such as ultraviolet light and / or light having a wavelength of 405 nm.

[0059] The mixture of drug and biocompatible resin, a dosing paste, can have a 1:1 ratio of drug and biocompatible resin. The mixture can be a paste. The mixture can be an emulsified homogenous mixture.

[0060] (Use and implementation of microneedles) 8A and 8B show microneedles 22 with drug 12 in the form of particles within a porous, hardened polymeric material 20, where the microneedles 22 are applied to the skin and extend through the epidermal layer 34, into the dermal layer 36, and optionally into the subdermal layer 38. According to various embodiments, the drug may be entirely within the porous, hardened polymeric material, or the drug may be contained solely within the microneedles. Over time, as illustrated in connection with FIG. 8B, more drug diffuses into the dermal environment.

[0061] Drug particles that were not initially in direct contact with the environment outside the microneedle structure become available within the microneedle as adjacent drug particles are dissolved by external solvents, such as the interstitial fluid of the skin. Upon drug release and dissolution, the used microneedle becomes a highly porous structure with voids (where the pores are occupied by, for example, water, solvent, or gas). In essence, a rigid microneedle is provided that can penetrate the skin while having a clinically significant drug loading capacity. In some cases, the drug is water-soluble and the porous material is hydrophobic, or in other cases, the drug is lipid-soluble and the porous material is hydrophilic.

[0062] Over time (e.g., about 10 minutes, 15 minutes, 30 minutes, 1 hour, several hours, 7 hours, 8 hours, 10 hours, 12 hours, 24 hours, 2 days, 3 days, 5 days, 7 days, 14 days, 21 days, or 30 days), the microneedles can release the drug into the dermal environment. FIG. 31 shows a specimen with an array of microneedles (e.g., 10×10 or 20×20, 1×20, or 5×14) in a simulated dermal fluid consisting of 10% gelatin from porcine skin mixed with PBS. With reference to FIG. 32, the microneedles can include fluorescein isothiocyanate-dextran (FITC-dextran) and can be provided through a water-impermeable paraffin membrane to the 10% gelatin from porcine skin under simulation. The release rate of the drug can decrease over time, however, some amount of discharge can still be provided even after 2 hours.

[0063] In some embodiments, the drug-loaded microneedle array patch (FIG. 7) may be applied to the skin for less than 1 minute. In some embodiments, the drug-loaded microneedle array patch may be applied to the skin for about 1 to 5 minutes. In some embodiments, the drug-loaded microneedle array patch may be applied to the skin for about 5 to 30 minutes. In some embodiments, the drug-loaded microneedle array patch may be applied to the skin for about 30 to 60 minutes. In some embodiments, the drug-loaded microneedle array patch may be applied to the skin for about 1 to 8 hours. In some embodiments, the drug-loaded microneedle array patch may be applied to the skin for about 4 to 8 hours. In some embodiments, the drug-loaded microneedle array patch may be applied to the skin for about 8 to 12 hours. In some embodiments, the drug-loaded microneedle array patch may be applied to the skin for about 6 to 10 hours. In some embodiments, the drug-loaded microneedle array patch may be applied to the skin for about 12 to 24 hours. In some embodiments, the drug-loaded microneedle array patch may be applied to the skin for about 1 to 24 hours. In some embodiments, the drug-loaded microneedle array patch may be applied at night and removed the following morning. In some embodiments, the drug-loaded microneedle array patch may be applied to the skin for about 1 to 7 days. In some embodiments, the drug-loaded microneedle array patch may be applied to the skin for about 7 to 14 days. In some embodiments, the drug-loaded microneedle array patch may be applied to the skin for about 14 to 21 days. In some embodiments, patches of drug-loaded microneedle arrays may be applied to the skin for about 21 to 28 days.

[0064] Due to the customizable nature of the manufacturing process described herein above (and additionally in WO 2019 / 203888), the geometry of the array of at least one microneedle can take on a variety of shapes and sizes. This is important for use cases, as the patch of the array of microneedles can be designed to conform at a specific location on the patient's body depending on the indication and the desired location for delivery. In some embodiments, the array can be a thin, long strip (e.g., 1×100 or 2×200 microneedles) for example to deliver a drug along a patient's limb. In some embodiments, the array can be arranged in a circle, with a central region lacking microneedles, for example to deliver a drug around a patient's joint. In some embodiments, the array of microneedles can be in the form of a identifiable shape that meets commercial marketing needs, such as a smiley face or a company logo.

[0065] When the microneedle is introduced into a solvent-rich environment, some of the drug will dissolve and diffuse into the surrounding environment. This dissolution / diffusion process continues until all or substantially all of the drug within the interconnected pores of the porous material is released into the surrounding environment. Now, for this to work, the drug and resin must be immiscible. The choice of resin for making the porous material should be one that is hydrophobic in nature and therefore works most efficiently with water-soluble drugs such as peptides, proteins, and monoclonal antibodies. It has been shown that the rate of drug release can be easily tuned by controlling the particle size of the drug dried powder. The size of the drug particles can be precisely controlled, for example, using vibration-based miniature mills or spray drying methods.

[0066] Figure 13 shows a scanning electron micrograph of a portion of a microneedle of one embodiment of the present invention after drug release (top left). A close-up of the microneedle after drug release is shown on the right, and a further close-up of the microneedle is shown on the bottom left side of Figure 13. It can be seen that certain (larger) areas are empty (dark) after drug dissolution and release. Figure 14 shows a further close-up of the tip of the microneedle after drug release.

[0067] 28A-28C show diagrams of different times when a microneedle (e.g., any of the microneedles discussed above) enters the dermal environment and drug is released from the material having openings. In particular, the microneedle can penetrate the stratum corneum and epidermis into the dermis, providing drug release to the epidermis, dermis, and subcutaneous tissue regions, allowing drug delivery to Langerhans cells, the surface vascular plexus, lymphatic vessels, dendritic cells, and the deep vascular plexus.

[0068] The manufacturing process described above can be used to optimize the mechanics of the microneedle patch, including the mechanical and geometric properties of the backing substrate, as well as the shape of the microneedles, to achieve maximum penetration efficiency. In some embodiments, the microneedles are securely assembled onto a thin, transparent, elastic backing substrate by using an elastic resin that is compatible with the polymer forming the microneedles. In some embodiments, the backing substrate is further attached to a layer of adhesive. In some embodiments, the combination of the backing substrate and the thin adhesive is about 100 micrometers in thickness. As a result of having a thin and flexible adhesive patch, the patch adheres firmly to the skin surface and is very conformable. The thin substrate also greatly aids in the penetration of the microneedles compared to thick substrates (thickness greater than about 1 millimeter). In this way, the force is transferred directly to the microneedles (rather than diffusing into the backing substrate), and each individual microneedle can receive the force to achieve effective penetration.

[0069] By utilizing the use of a thin, flexible backing substrate, the microneedle arrays of macro POSH microneedles described herein can avoid the "bed of nails" principle, which states that distributing a force simultaneously across multiple points of a given area can lead to very poor penetration of the dermis layer, despite the use of sharp objects. To avoid the resistance of the bed of nails and ensure consistent and effective penetration of the skin, a thin, flexible patch can be used to apply localized forces to individual microneedles simultaneously.

[0070] Figure 15 shows a schematic of a solid matrix, e.g., a polymer, loaded with a drug, and the solid matrix after drug release. With reference to Figure 16, a bandage 40 having an adhesive 42 according to a further embodiment of the invention may include one or more light emitters 44 and one or more light sensors 46. The light sensors 46 may further be visible through the bandage so that the user can know when the drug has been completely released from the bandage.

[0071] Figure 26A shows that a set of microneedles on a thick backing substrate may penetrate unevenly into the subject's body in uneven areas. This problem can be solved as shown in Figure 26B. A set of microneedles on a thin (flexible) backing substrate is adapted to conform to the uneven areas and provide a much more uniform penetration into the subject's body.

[0072] (Other uses) The microneedles and microneedle patches described herein may be useful for application and drug delivery across anatomical structures and membranes other than the skin, such as mucous membranes (of the mouth, inside the cheek, tongue, nose), gums, conjunctiva, sclera, retina, ear canal, eardrum, epithelial cells (e.g., of the gastrointestinal tract, respiratory tract, vagina, uterine, follicular, urethral), serous membranes, and the lining of arteries or veins.

[0073] The microneedles disclosed herein may also find application in veterinary medicine, for example in pets and farm animals, and particularly in mammals.

[0074] (Monitoring possible systems) Furthermore, the system may be able to track the release of drug from the microneedles since the optical properties of the needles change once the drug diffuses out of them (note that in cases where the drug to resin ratio is large - even a 1:1 ratio - the microneedles are optically translucent after fabrication, but once the drug is released from the microneedles, the porosity in the structure increases significantly so that the microneedles appear optically opaque (they may appear whitish, yellowish, etc., depending on the resin used to make them). This large change in optical properties can be easily used to track the amount of drug released from the patch to the skin over time, thus allowing real-time digital tracking of the dosage received by the patient. A light sensor and optional light source may be used to monitor the drug discharge by measuring the light transmittance or light reflectance of one or more microneedles.

[0075] As mentioned above, the microneedles may carry a marker that is released into the patient's body along with the drug. A sample from the patient, such as a blood or urine sample, can be tested for the marker. The skin, including the application site, can be tested for the marker. Other structures, such as the eye or superficial blood vessels, can also be tested for the marker. EXAMPLES

[0076] (Microneedle manufacturing procedure) A crossover line (COL) manufacturing procedure was used to fabricate the microneedle patch as shown in FIG. 34a. A CO2 laser (Boss LS-1416, Boss Laser, LLC, Sanford, FL, USA) was used to create a negative volume on a Clear Scratch- and UV- Resistant Cast Acrylic Sheet (Part No. 8560K359, McMaster-Carr, Princeton, NJ, USA). The engraved acrylic mold was cleaned with isopropanol and distilled water to remove dust and other foreign matter from the surface and the engraved side. Excess moisture on the surface was removed using a nitrogen gun. The mold was then dried in an atmospheric oven at 80 degrees Celsius for 30 minutes. Polydimethylsiloxane (PDMS) (Dow Sylgard® 184 Silicone Elastomer, Dow Silicones Corporation, Midland, MI, USA) was then cast onto the acrylic sheet. The cast sheet was degassed and then cured in an oven at 80°C for 2 hours. After the PDMS curing was complete, the PDMS microneedles were peeled off from the acrylic sheet and treated with oxygen plasma to activate the surface of the PDMS microneedles. The PDMS microneedles were then silanized with trichloro(1H,1H,2H,2H-perfluorooctyl)silane (SKU: 448931-10G, MilliporeSigma, Burlington, MA, USA) overnight under vacuum in a desiccator. Ecoflex® 00-50 (Smooth-on, Incorporated, Macungie, PA, USA) was dispensed in a 1:1 ratio onto the silanized PDMS microneedles and then cured at room temperature. The silane layer creates a barrier between the PDMS microneedles and the Ecoflex mold, preventing them from bonding and facilitating peeling.The resulting Ecoflex mold is very flexible and stretchable, and can be stretched to about three times its original size. Obtaining a stretchable mold allows the fabrication of microneedle patches in a much shorter time. The final Ecoflex mold can be used to create microneedles made of various polymers. Drug solutions or powders can be poured into the stretched mold. Here, we introduce a new paste consisting of biocompatible resin and drug (see Drug-Loaded Microneedles). The Ecoflex mold is stretched, and the resin / drug paste is poured into the stretched Ecoflex mold. The mold is then placed in rest mode, and the excess drug paste is removed from the mold surface. The paste embedded in the Ecoflex mold is then photocured by exposure to 405 nm light. After the paste is cured, a thin layer of elastic polymer is poured onto the mold surface as a backing matrix, and cured under UV light to harden the backing matrix. Finally, the microneedles with the substrate were peeled off from the mold with the needles bonded to the back substrate. Referring to Fig. 34b, a conformable and flexible 6cm x 20cm microneedle patch was prepared. Microneedle patches can be manufactured in any form and shape according to this procedure. This method provides high drug loading capacity and drugs can be dispersed without the need for cryogenic cooling.

[0077] Dye-loaded microneedle patches for in vitro release To visually demonstrate the in vitro release of the microneedles, a resin / pigment paste was prepared. Biocompatible resin (Dental SG) from Formlabs (Somerville, MA, USA) and Sulforhodamine B (SKU: 230162-5G, MilliporeSigma, Burlington, MA, USA) were used as the pigment. Due to the small size of the microneedles, the pigment particles were ground into fine particles of smaller size. The encapsulation of unmilled and milled pigment in the microneedles was compared by preparing microneedles with both unmilled and milled Sulforhodamine B particles. The unmilled and milled particles of pigment are shown in Figures 35a and 35b, respectively, and the size distribution of the unmilled and milled pigment is shown in Figure 35c. On average, the unmilled and milled pigment particles had a particle size of about 50 micrometers and 6 micrometers, respectively. As shown in Figure 35d, the ungrounded pigment particles showed a low degree of encapsulation in the microneedles due to the large size of the pigment particles. Meanwhile, improved pigment encapsulation was observed with smaller ground pigment particles (see Figures 35e and 35f). Figure 35f shows a pigment-loaded microneedle with a star-shaped base structure for more robustness and rigidity. Figure 35g shows a schematic diagram of a microneedle patch prepared for in vitro pigment release experiment. A solid acrylic ring was added to the outer periphery of the substrate so that the microneedle patch could be easily held and applied (see Figure 35g). The in vitro pigment release experiment is shown diagrammatically in Figure 35h. A 10% gelatin (MilliporeSigma pig skin gelatin, SKU: G2500-1KG) solution was prepared as a model tissue and poured into a petri dish. It was then placed in a refrigerator for 20 minutes for further solidification. A thin layer of parafilm (Parafilm®, Amcor, Zurich, Switzerland) was then used as a skin model to cover the gelatin solution in the dish.The top and bottom sides of the prepared dye-loaded microneedle patch are shown in Figures 35i and 35j. After inserting the microneedle patch into the parafilm-covered gelatin, visible release of the dye into the gelatin solution occurs (see Figure 35l). Figure 35k shows the release of the dye after 10 minutes.

[0078] (Drug-loaded microneedles) Lidocaine and ibuprofen are drugs used for pain relief. These drugs were selected to prepare a pain relief patch. First, the in vitro release profiles of lidocaine and ibuprofen were investigated to verify their dispersion mechanisms. Then, experiments were conducted to determine whether the cured resin and drug (lidocaine or ibuprofen) maintained the characteristics of lidocaine and ibuprofen and whether their respective properties were unchanged. FTIR spectroscopy measurements were performed on the cured resin / drug to investigate whether lidocaine and ibuprofen maintained their respective properties. Furthermore, the mechanical properties of the drug-loaded microneedles were investigated.

[0079] In Vitro Drug Release of Microneedles with Lidocaine and Ibuprofen For in vitro drug release experiments, ibuprofen sodium salt (SKU: I1892) and lidocaine hydrochloride monohydrate (SKU: L5647) purchased from MilliporeSigma (Burlington, MA, USA) were used. The concentrations of ibuprofen and lidocaine were detected by UV-Vis spectroscopy at 222 nm and 263 nm, respectively. Various concentrations of ibuprofen and lidocaine were prepared by dissolution in Dulbecco's Phosphate Buffered Saline (DPBS) (SKU: 59331C from MilliporeSigma). The absorbance peaks at 222 nm and 263 nm, respectively, for ibuprofen and lidocaine were detected using an Evolution 220 UV-Vis spectrometer from Thermo Fisher Scientific, Inc. (Waltham, MA, USA). As shown in Figures 36a and 36b, solutions of ibuprofen and lidocaine were swept at wavelengths of 190-300 nm and 254-300 nm, respectively, for various concentrations. Calibration curves for ibuprofen and lidocaine are shown in Figure 36c. Ibuprofen sodium salt and lidocaine hydrochloride monohydrate were ground in a Chulux grinder (four blades) for 3 minutes to produce finer particles. The fine particles of ibuprofen and lidocaine were then mixed with biocompatible resin in a 1:1 ratio. Microneedle patches were then fabricated by the method described in the section "Fabrication procedure of microneedle mold". Each microneedle patch had 100 microneedles. Several petri dishes containing DPBS (one petri dish for each time stamp) were placed in an incubator at 37 degrees Celsius. At each time stamp, the patch was transferred to a new petri dish containing DPBS. As shown in Figure 36d, the release profile indicates that each patch (containing 100 microneedles) releases approximately 1 milligram of drug in the DPBS solution.

[0080] In Vitro Drug Release of Macromolecules and Modulation of Release Profiles Based on Particle Size FIG. 31 shows microneedles containing FITC-dextran (49 kDa), which may be delivered, for example, through a water-impermeable paraffin membrane into 10% gelatin from simulated porcine skin. FIG. 32 shows a specimen with an array of microneedles (e.g., 10×10) in simulated dermal fluid. FIG. 33 shows the cumulative release of FITC-dextran for two different molded patches. By reducing the particle size (to the limit), the drug release rate and the overall amount of drug release can be increased or adjusted. Adjusting the rate and profile of drug release can be important to remain in the therapeutic window for a long period of time and obtain better clinical results for a given drug.

[0081] (Interaction between polymers and drugs: FTIR spectroscopy) FTIR spectroscopy was used to evaluate possible changes in the encapsulated drug during the manufacturing process. A Nicolet 6700 (Thermo Scientific®, Waltham, MA, USA) equipped with a Smart™ iTX ATR accessory with a diamond crystal was used. The Fourier transform infrared attenuated total reflectance (FTIR-ATR) spectrum showed the following characteristic peaks for lidocaine: NH group at 3450 cm; -1 and 3385 cm -1 and the amide C=O group stretches at 1655 cm -1 The stretching at 1655 cm associated with the C=O group of the amide -1 A clear increase in the intensity of the peaks at 3450, 3400, and 3200 cm was observed (see FIG. 36e). In FTIR, an increase in peak intensity usually reflects an increase in the amount (per unit volume) of functional groups associated with a molecular bond, while a shift in peak position usually reflects a change in the hybridization state or electron distribution of the molecular bond. Thus, the decrease in the intensity of the amide C=O group in the lidocaine / resin sample was attributed to the decrease in the ratio of lidocaine in the sample. Confirming the FTIR with the manufacturer's data sheet for lidocaine hydrochloride monohydrate, as seen in our data in FIG. 36e, there is a clear increase in the intensity of the peaks at 3450, 3400, and 3200 cm.-1 Furthermore, the FTIR spectrum of ibuprofen / resin showed no shift in peak position (see Figure 36f). -1 and 3400 cm -1 The peaks in Fig. 1 were assigned to the stretching vibrations of the C=O group and the OH group, respectively. These FTIR observations confirmed that the chemical structures of lidocaine and ibuprofen remained unchanged during the manufacturing process.

[0082] (Histological examination, surface morphology, and mechanical behavior) To confirm the insertion of the microneedle into the skin, a histological examination was performed. For the histological examination, skin from a 4-month-old Yorkshire pig was used. The skin was shaved and cut using a 10# scalpel blade and placed in a specimen container filled with sterile 0.9% saline. A microneedle patch was inserted into the skin using thumb pressure. The microneedle patch was peeled off shortly after application. The photomicrograph in Figure 37a is from an H&E (hematoxylin & eosin) stained tissue section fixed in 10% neutral formalin. The histological examination showed that the microneedle penetrated the skin by about 600 micrometers, as shown in Figure 37a. As shown in other similar studies, the penetration depth of the microneedle into the skin was shorter than the entire length of the microneedle, which is due to the deformation of the skin, which is highly elastic. The mixture of the resin and the drug creates holes and cavities, as shown in Figure 37b. The drug is released after administration of the microneedle, leaving behind an empty cavity. The porous microneedles of the present disclosure show high robustness due to the high tensile strength of the resin (73 megapascals (MPs)). The mechanical behavior of individual resin / drug microneedles is shown in FIG. 37c. Compression tests were performed using Instron (Norwood, Massachusetts, USA). The tips of these microneedles began to break at a force of 0.26 N per needle. Previous experiments showed that this provides a four-fold safety margin over the force required for skin insertion with microneedles of this geometry (0.058 N per needle). The resin / drug microneedles of the present disclosure were compared to polyethylene glycol diacrylate (PEGDA)-based microneedles. PEGDA microneedles have shown strong mechanical properties in previous studies to easily penetrate the skin. Here, we confirm the high robustness of the resin / drug microneedles of the present disclosure in comparison to PEGDA-based microneedles (see Figure 37d).PEGDA microneedles were prepared using a 500 mg per milliliter drug solution and PEGDA with a molecular weight of 575 (MilliporeSigma SKU: 437441-500ML) mixed with 1% photoinitiator (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (MilliporeSigma SKU: 410896-10G)). The drug solution and PEGDA solution were mixed in a 4:1 (v / v) ratio. The prepared solution was added to a microneedle mold and crosslinked by UV light irradiation at a wavelength of 365 nm.

[0083] In Vitro Bioassay to Evaluate the Efficacy of Monoclonal Antibodies after Microneedle Patch Manufacturing To evaluate the efficacy of therapies delivered through microneedles in an in vitro model, a whole blood assay was performed using rituximab (RTX) as the drug. Rituximab is a chimeric monoclonal antibody against the protein CD20, which is found primarily on the surface of immune system B cells. When rituximab binds to this protein, it triggers cell death via complement-dependent cytotoxicity (CDC). RTX is a good model to evaluate mAb delivery mechanisms, primarily due to clear pharmacodynamic outcomes such as depletion of CD20-positive B cells in whole blood. Microneedle patches with five different amounts of RTX and a fixed polymer-drug ratio were incubated in freshly drawn human blood in a 24-well plate. CD20-positive and CD19-positive cells were quantified in each well using flow cytometry. Figure 29 shows the CD20-positive fluorescence of six samples. CD20-positive cells are present in the left samples (a) to (c), but absent in the right samples (d) to (f). The conditions were as follows: (a) buffy coat and serum not exposed to microneedles (MN) and before incubation, (b) blood not exposed to MN and after 4 hours of incubation, (c) blood exposed to inactive MN and after incubation, (d) blood after incubation with 1 MN (20 μg RTX), (e) blood after incubation with 5 MN (100 μg RTX), (f) blood after incubation with 200 MN (4 mg RTX). Thus, CD20 positive cells were present in blood samples (a) to (c) that were not treated with RTX-loaded MN. Conversely, CD20 positive cells were depleted from blood samples (d) to (f) that were treated with 1, 5, or 200 MN. Compared to the control experiment, the RTX-loaded microneedle patch showed a dramatic reduction in CD20 positive and CD19 positive counts.

[0084] The results demonstrate that (1) in vitro analysis using fresh blood can be used to evaluate the pharmacodynamics of different forms of microneedle patches, (2) RTX-loaded microneedle patches induce the expected pharmacodynamic effect of B cell depletion, and (3) RTX activity is retained after completion of the manufacturing process of the microneedle patches.

[0085] In vivo delivery of rituximab to non-human primates A primate in vivo study was conducted to compare the systemic pharmacodynamic effects of rituximab (RTX) after intravenous (IV) delivery and after microneedle-mediated transdermal delivery in African green monkeys. Figure 30 (a) shows two applied patches and the area after removal of the patch containing the monoclonal antibody in transdermal delivery. The pharmacodynamic effects were quantified by measuring circulating B cells by flow cytometry (all these graphs were generated by cytometry), using rituximab as a compound that is a tool to evaluate the capabilities of novel microneedle formulations and delivery techniques and achieve systemic bioavailability of macromolecules (e.g., monoclonal antibodies) after transdermal delivery. Rituximab administration, both IV and TD, caused B cell depletion. However, the most significant blood B cell depletion was observed one week after IV administration. Daily administration of two patches of RTX-loaded microneedles also showed significant depletion (up to 81%). This is shown in FIG. 30(c). FIG. 30(b) shows flow cytometry data from animals receiving two patches daily, showing significant B cell depletion from baseline by day 7 (lower right quadrant). Depletion over time for two patches administered for 0, 1, 7, 14, and 21 days is shown in FIG. 29.

Claims

1. A microneedle for delivering a drug, the microneedle comprising: a solid porous material having a plurality of pores; The tip and a drug in the form of particles, The drug is contained within the pores.

2. The microneedle of claim 1 , wherein the drug is substantially solvent-free or substantially anhydrous.

3. 3. The microneedle of claim 1, wherein more than 90% of the pores or the volume of the pores is occupied by at least one drug particle.

4. The microneedle of claim 3 , wherein greater than 99.9% of the pores or the volume of the pores is occupied by at least one drug particle.

5. The microneedle of claim 1 , wherein the porous material is a hardened polymeric material.

6. 3. The microneedle of claim 1, wherein the axial length of the microneedle is between about 0.5 mm and 1.5 mm.

7. The microneedle according to claim 1 , wherein the hardness of the porous material is between Shore A40 and Shore D90.

8. A device for delivering a drug, said device comprising two or more microneedles according to any one of claims 1 to 2.

9. The device of claim 8 , further comprising a supportive backing material.

10. The device of claim 9 , further comprising an adhesive.

11. 1. A microneedle drug delivery system for drug delivery via interstitial fluid mediated diffusion, the microneedle drug delivery system comprising a drug in the form of particles within a porous material.

12. The microneedle drug delivery system of claim 11 , wherein the porous material is a hardened polymeric material.

13. The microneedle drug delivery system of claim 11 , wherein the cured polymeric material is cured with electromagnetic radiation.

14. 12. The microneedle drug delivery system of claim 11, wherein the porous material comprises a metal selected from the group consisting of gold, silver, carbon, iron, copper, brass, bronze, titanium, beryllium, aluminum, tin and zinc, and alloys and combinations thereof.

15. The microneedle drug delivery system of claim 11 , wherein the porous material comprises a plurality of needle-like protrusions.

16. The microneedle drug delivery system of claim 15 , wherein the plurality of needle-shaped protrusions are arranged in a row.

17. The microneedle drug delivery system of claim 15 , wherein each of the needle-shaped protrusions is less than 2 mm in its greatest dimension.

18. The microneedle drug delivery system of claim 11 , wherein the porous material has a hardness of at least about Shore A40 or at least about Shore B90.

19. The microneedle drug delivery system of claim 11 , wherein the porous material comprises a plurality of open pores.

20. The microneedle drug delivery system of claim 19 , wherein the apertures are interconnected.

21. The microneedle drug delivery system of claim 19 , wherein the apertures are in fluid communication with each other.

22. The microneedle drug delivery system of claim 11 , wherein the particles are in the form of a powder.

23. 23. The microneedle drug delivery system of claim 22, wherein the powder comprises particles having a size of less than about 100 micrometers in a maximum dimension.

24. 23. The microneedle drug delivery system of claim 22, wherein the powder comprises particles having a size of less than about 20 micrometers in a maximum dimension.

25. The microneedle drug delivery system of claim 11 , wherein the drug in particulate form is water-soluble or liposoluble.

26. 26. The microneedle drug delivery system of claim 25, wherein the cured polymeric material is hydrophobic or hydrophilic.

27. The microneedle drug delivery system of claim 11 , wherein the porous material is formed from at least one resin.

28. The microneedle drug delivery system of claim 27, wherein at least one of the resins is sacrificial.

29. The microneedle drug delivery system of claim 27, wherein the drug is in the form of particles and the at least one resin forms a colloid.

30. The microneedle drug delivery system of claim 27, wherein the drug is in particulate form and the at least one resin is immiscible.

31. The microneedle drug delivery system of claim 11 , wherein the system comprises a plurality of needle-like protrusions and a bandage.

32. 32. The microneedle drug delivery system of claim 31, wherein the bandage comprises a sensor for determining the amount of drug contained in the bandage.

33. 1. A time-controlled drug delivery system, comprising: The time-controlled drug delivery system further comprises: A time-controlled drug delivery system comprising a drug in the form of particles within the pores of the porous material such that the drug in the form of particles can dissolve and diffuse when the porous material is exposed to a dermal environment containing interstitial fluid.

34. 34. The time-controlled drug delivery system of claim 33, wherein the porous material is hardened.

35. 34. The time-controlled drug delivery system of claim 33, wherein the porous material comprises a metal selected from the group consisting of gold, silver, carbon, iron, copper, brass, bronze, titanium, beryllium, aluminum, tin and zinc, and alloys and combinations thereof.

36. 34. The time-controlled drug delivery system of claim 33, wherein the porous material is formed as a plurality of needle-like protrusions.

37. 37. The time-controlled drug delivery system of claim 36, wherein the plurality of needle-shaped protrusions are arranged in a row.

38. 37. The time-controlled drug delivery system of claim 36, wherein each of said needle-shaped protrusions is less than about 2 mm in its greatest dimension.

39. 34. The time-controlled drug delivery system of claim 33, wherein the porous material has a hardness of at least about Shore A40.

40. 34. The time-controlled drug delivery system of claim 33, wherein the porous material comprises a plurality of open pores.

41. 41. The time-controlled drug delivery system of claim 40, wherein the plurality of apertures are interconnected.

42. 41. The time-controlled drug delivery system of claim 40, wherein the plurality of apertures are in fluid communication with each other.

43. 34. The time-controlled drug delivery system of claim 33, wherein the particles are in the form of a powder.

44. 44. The time-controlled drug delivery system of claim 43, wherein the powder comprises particles having a size of less than about 100 micrometers in a greatest dimension.

45. 34. The time-controlled drug delivery system of claim 33, wherein the powder comprises particles having a size of less than about 20 micrometers in a greatest dimension.

46. 34. The time-controlled drug delivery system of claim 33, wherein the drug in particulate form is water-soluble or liposoluble.

47. 47. The time-controlled drug delivery system of claim 46, wherein the porous material is hydrophobic or hydrophilic.

48. 34. The time-controlled drug delivery system of claim 33, wherein the porous material is hydrophilic.

49. 34. The time-controlled drug delivery system of claim 33, wherein the porous material is formed from at least one resin.

50. The time-controlled drug delivery system of claim 49, wherein at least one resin is sacrificial.

51. The time-controlled drug delivery system of claim 49, wherein the drug is in the form of particles and the at least one resin forms a colloid.

52. The time-controlled drug delivery system of claim 49, wherein the drug is in particulate form and the at least one resin is immiscible.

53. 34. The time-controlled drug delivery system of claim 33, wherein the system comprises a plurality of needle-like protrusions on a bandage for attachment to the skin.

54. 54. A time-controlled drug delivery system according to claim 53, wherein the bandage comprises a sensor for determining the amount of drug contained in the bandage.

55. 1. A method of making a composition for drug delivery, the method comprising: Providing a drug in the form of particles; mixing said drug in particulate form with a resin material; forming said drug and said resin material in the form of intermixed particles.

56. 56. The method of claim 55, wherein said forming said drug and said resin material in the form of intermixed particles comprises casting said resin material into a mold.

57. The method of claim 55, wherein the drug is in the form of particles and the resin material and the particles are immiscible.

58. 56. The method of claim 55, further comprising curing the resin material to provide a hardened composition.

59. 60. The method of claim 58, wherein the curing comprises using electromagnetic radiation.

60. 60. The method of claim 58, wherein the cured composition has a hardness of at least Shore A 40.

61. 60. The method of claim 58, wherein the hardened composition is porous and comprises a plurality of open pores.

62. 62. The method of claim 61, wherein the plurality of apertures are interconnected.

63. 62. The method of claim 61, wherein the plurality of apertures are in fluid communication with one another.

64. 59. The method of claim 58, wherein the drug, when in particulate form, is water soluble.

65. 65. The method of claim 64, wherein the cured composition is hydrophobic.

66. 59. The method of claim 58, wherein the drug, when in particulate form, is lipid soluble.

67. 67. The method of claim 66, wherein the cured composition is hydrophilic.

68. 56. The method of claim 55, wherein said forming said drug and said resin material in the form of intermixed particles comprises forming them as a plurality of needle-like projections.

69. 59. The method of claim 58, wherein the plurality of needle-like projections are arranged in a row.

70. 59. The method of claim 58, wherein each of the needle-shaped projections is less than about 2 mm in its greatest dimension.

71. 56. The method of claim 55, wherein the particulate form is a powder.

72. 72. The method of claim 71, wherein the powder comprises particles having a size of less than about 100 micrometers in a largest dimension.

73. 72. The method of claim 71, wherein the powder comprises particles having a size of less than about 20 micrometers in a largest dimension.

74. 56. The method of claim 55, wherein mixing the drug in particulate form with a resin material occurs prior to forming the drug in particulate form and the resin material together.

75. 56. The method of claim 55, wherein mixing the drug in particulate form with a resin material occurs after forming the drug in particulate form and the resin material intermixed.

76. 1. A method of making a compound for drug delivery, the method comprising: providing a drug in the form of particles; forming a malleable material; providing openings in the formed malleable material; and depositing the drug in the form of particles within the formed malleable material.

77. 77. The method of claim 76, wherein the malleable material comprises a plurality of resins.

78. 78. The method of claim 77, further comprising sacrificing at least one of the resins to form the aperture.

79. 80. The method of claim 78, wherein a plurality of said apertures are interconnected.

80. 80. The method of claim 78, wherein a plurality of said apertures are in fluid communication with one another.

81. 77. The method of claim 76, wherein the malleable material comprises a metal selected from the group consisting of gold, silver, carbon, iron, copper, brass, bronze, titanium, beryllium, aluminum, tin, and zinc, and alloys and combinations thereof.

82. 77. The method of claim 76, wherein the formed malleable material has a hardness of at least about Shore B80.

83. 77. The method of claim 76, wherein forming the malleable material comprises forming a plurality of needle-like projections.

84. 84. The method of claim 83, wherein the plurality of needle-like projections are arranged in a row.

85. 84. The method of claim 83, wherein each of the plurality of needle-shaped projections is less than about 2 mm in its greatest dimension.

86. 84. The method of claim 83, wherein the particulate form is a powder.

87. 87. The method of claim 86, wherein the powder comprises particles having a size of less than about 100 micrometers in a largest dimension.

88. 87. The method of claim 86, wherein the powder comprises particles having a size of less than about 20 micrometers in a largest dimension.

89. 77. The method of claim 76, wherein the drug in particulate form is water soluble.

90. 77. The method of claim 76, wherein the drug in particulate form is lipid soluble.

91. 1. A method of providing a time-controlled drug delivery system, the method comprising: Providing a porous material having open pores; providing a drug in the form of particles within the open pores of the porous material; and allowing the porous material to contact a dermal environment containing interstitial fluid, such that the drug in particulate form contacts the interstitial fluid and causes dissolution of the drug into the interstitial fluid.

92. 92. The method of claim 91, wherein the porous material is a polymeric material that is hardened with electromagnetic radiation.

93. 92. The method of claim 91, wherein the porous material comprises a metal selected from the group consisting of gold, silver, carbon, iron, copper, brass, bronze, titanium, beryllium, aluminum, tin, and zinc, and alloys and combinations thereof.

94. 92. The method of claim 91, wherein the porous material is formed as a plurality of needle-like protrusions.

95. 95. The method of claim 94, wherein the plurality of needle-like projections are arranged in a row.

96. 95. The method of claim 94, wherein each of the needle-shaped projections is less than about 2 mm in its greatest dimension.

97. 92. The method of claim 91, wherein the porous material has a hardness of at least Shore A40.

98. 92. The method of claim 91, wherein the porous material comprises a plurality of open pores.

99. 100. The method of claim 98, wherein the plurality of apertures are interconnected.

100. 100. The method of claim 98, wherein the plurality of apertures are in fluid communication with one another.

101. 92. The method of claim 91, wherein the particles are in the form of a powder.

102. 102. The method of claim 101, wherein the powder comprises particles having a size of less than about 100 micrometers in a greatest dimension.

103. 103. The method of claim 102, wherein the powder comprises particles having a size of less than about 20 micrometers in a largest dimension.

104. 92. The method of claim 91, wherein the drug in particulate form is water-soluble or lipid-soluble.

105. 105. The method of claim 104, wherein the porous material is hydrophobic or hydrophilic.

106. 92. The method of claim 91, wherein the porous material is formed from a resin.

107. 107. The method of claim 106, wherein the drug and the resin are immiscible when in particulate form.

108. 1. A method for manufacturing a microneedle for transdermal drug delivery, the method comprising: Providing a microneedle mold with a full-sized microneedle forming cavity; stretching the microneedle mold to expand the size of the microneedle forming cavity; casting a mixture of a drug and a biocompatible resin onto the microneedle mold, the mixture being adapted to fill the enlarged microneedle forming cavities, the drug being in the form of solid particles and having a particle size of 10 nanometers to 100 micrometers; allowing the microneedle mold to shrink such that the microneedle forming cavities resume their original dimensions; hardening the mixture within the microneedle forming cavity to provide a solid, porous microneedle, the drug being embedded within the pores of the microneedle; and and removing the microneedle from the microneedle mold.

109. The method includes introducing an elastic polymer into the microneedle mold; 109. The method of claim 108, further comprising curing the elastomeric polymer to bond the elastomeric polymer to the microneedles.

110. 110. The method of claim 108 or 109, wherein the microneedle mold comprises a plurality of microneedle forming cavities and the method provides a plurality of solid, porous microneedles.

111. 109. The method of claim 108, wherein curing the elastomeric polymer comprises photocuring the elastomeric polymer by exposing it to ultraviolet light.

112. The method further includes manufacturing the microneedle mold by a process, the process comprising: laser cutting one or more microneedle shaped depressions in a first material to provide a first mold; casting a second material onto the first mold to fill the one or more microneedle-shaped cavities with the second material; curing the second material to provide a second mold having one or more microneedles formed within each of the one or more microneedle-shaped depressions; removing the hardened second material from the first mold; plasma treating the hardened second mold surface having the one or more microneedles; applying a release layer to the surface of the hardened second mold; casting a third material onto the surface of the hardened second mold; curing the third material to provide the microneedle mold having the microneedle forming cavity; and removing the microneedle mold from the hardened second mold.

113. 113. The method of claim 112, wherein laser cutting the one or more microneedle-shaped depressions in the first material comprises laser cutting each of the one or more microneedle-shaped depressions with a pattern of crossover lines.

114. 113. The method of claim 112, wherein the first material is an acrylic sheet, the second material is a silicone elastomer, and the third material is a superelastic silicone rubber.

115. 113. The method of claim 112, wherein applying the release layer comprises silanizing the surface of the cured silicone elastomer with trichloro(1H,1H,2H,2H-perfluorooctyl)silane.

116. 110. The method of claim 109, wherein the microneedle patch comprises at least 100 of said microneedles.

117. The microneedle patch is about 0.5 cm ２ About 100 cm from ２ The method of claim 109, wherein the microneedle has a planar area of

118. 56. The method of claim 55, wherein the mixture is a 1:1 mixture of the drug and the biocompatible resin.

119. 56. The method of claim 55, wherein the mixture is in the form of a paste.

120. 56. The method of claim 55, wherein the mixture is an emulsified homogenous mixture of the biocompatible resin and the drug.

121. The method of claim 55, wherein the biocompatible resin comprises a light-curable hard polymer.

122. 56. The method of claim 55, wherein the biocompatible resin comprises a polymer selected from the group consisting of chitosan, chitosan polybutylene adipate terephthalate, poly(butylene adipate-co-terephthalate), polyethylene glycol, poly(ethylene glycol) diacrylate, gelatin, gelatin methacryloyl, polyvinyl alcohol, and silk.

123. The method further includes, prior to introducing the mixture, preparing the mixture of the biocompatible resin and the drug by a process, the process comprising: grinding the drug into fine particles having a particle size of 1 micrometer to 100 micrometers; mixing the ground drug and the biocompatible resin in a 1:1 ratio to provide a viscous paste; 56. The method of claim 55, further comprising:

124. 56. The method of claim 55, wherein curing the mixture comprises photocuring the mixture by exposure to ultraviolet light.

125. 56. The method of claim 55, wherein curing the mixture comprises photocuring the mixture by exposure to 405 nm light.

126. 56. The method of claim 55, wherein the microneedles are macro-porous solid rigid (macro-POSH) microneedles.

127. 56. The method of claim 55, wherein the drug is one of ibuprofen and lidocaine.

128. 56. The method of claim 55, wherein the drug is one of ibuprofen sodium salt and lidocaine hydrochloride.

129. A microneedle for transdermal drug delivery, said microneedle comprising: a microneedle body formed of a hardened biocompatible resin and having a hole; and a drug in the form of particles embedded in the pores of the microneedle body, the microneedle having sufficient mechanical strength to penetrate the epidermis of human skin, and the drug having a particle size of 10 nanometers to 100 micrometers.

130. The microneedle of claim 129, wherein the microneedle body comprises a 1:1 mixture of the biocompatible resin and the drug.

131. The microneedle of claim 129 or 130, wherein the biocompatible resin comprises a photocurable hard polymer.

132. The microneedle of any one of claims 129 to 130, wherein the biocompatible resin comprises a polymer selected from the group consisting of chitosan, chitosan polybutylene adipate terephthalate, poly(butylene adipate-co-terephthalate), polyethylene glycol, polyethylene glycol diacrylate, gelatin, gelatin methacryloyl, polyvinyl alcohol, silk fibroin, and combinations thereof.

133. 131. The microneedle of any one of claims 129 to 130, wherein the drug is one of ibuprofen and lidocaine.

134. 131. The microneedle of any one of claims 129 to 130, wherein the tip of the microneedle is resistant to breakage against an applied force of up to about 0.26 Newtons.

135. A microneedle as claimed in any one of claims 129 to 130, wherein the microneedle body is porous having pores with a pore size between 100 nanometers and 40 micrometers.

136. 131. The microneedle of any one of claims 129 to 130, wherein the microneedle is a macroporous solid rigid (macroPOSH) microneedle.

137. 1. A microneedle patch for transdermal drug delivery, comprising: a porous microneedle formed from a hardened biocompatible resin and having microparticles of a drug embedded within the pores of the microneedle, the microneedle having sufficient mechanical strength to penetrate the epidermis of the skin without damaging it; A microneedle patch comprising a conformal backing substrate coupled to the microneedles.

138. The microneedle patch of claim 137, wherein the porous microneedles are formed from a 1:1 mixture of the biocompatible resin and the drug.

139. The microneedle patch of claim 137, wherein the biocompatible resin comprises a photocurable hard polymer.

140. The microneedle patch of any one of claims 137 to 139, wherein the biocompatible resin comprises a polymer selected from the group consisting of chitosan, chitosan polybutylene adipate terephthalate, poly(butylene adipate-co-terephthalate), polyethylene glycol, polyethylene glycol diacrylate, gelatin, gelatin methacryloyl, polyvinyl alcohol, and silk.

141. 140. The microneedle patch of any one of claims 137 to 139, wherein the drug is one of ibuprofen and lidocaine.

142. 140. The microneedle patch of any one of claims 137 to 139, wherein the tips of the microneedles break upon an applied force of approximately 0.26 Newtons.

143. The microneedle patch of any one of claims 137 to 139, wherein the conformal backing substrate is made of an elastic polymer.

144. A microneedle patch according to any one of claims 137 to 139, wherein the conformable backing substrate is configured to conformably fit to the curvature of the skin of any body part.

145. The microneedle patch of any one of claims 137 to 139, wherein the microneedle patch comprises a plurality of porous microneedles.

146. 140. The microneedle patch of any one of claims 137 to 139, wherein the microneedle patch comprises at least 100 solid, porous microneedles.

147. The microneedle patch is about 0.5 cm ２ About 100cm from ２ 140. The microneedle patch of any one of claims 137 to 139, having a microneedle planar area of.

148. 140. The microneedle patch of any one of claims 137 to 139, wherein the porous microneedles are macroporous having pores with pore sizes between 100 nanometers and 40 micrometers.

149. 140. The microneedle patch of any one of claims 137 to 139, wherein the porous microneedles are macroporous solid rigid (macroPOSH) microneedles.

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