Microneedles with embedded particulate drug

Abstract

The present disclosure provides microneedles and microneedle patches for transdermal drug delivery and methods of making and using the same. The microneedles are comprised of a solid composite material comprising a polymerized / cured biocompatible polymer matrix, drug particles, and a surfactant, wherein drug particles and surfactant are dispersed throughout the polymer matrix forming an interconnected drug network extending to surfaces of the microneedle.

Description

MICRONEEDLES WITH EMBEDDED PARTICULATE DRUGCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 671,639, filed July 15, 2024, and U.S. Provisional Patent Application 63 / 711,450, filed October 24, 2024, the contents of each of which are incorporated herein by reference in their entirety.BACKGROUND

[0002] The present application generally relates to drug delivery systems and methods, and relates in particular to microneedle-type drug delivery devices, methods of fabricating them, and their use for drug delivery.

[0003] Many systemic drugs require administration by injection, e.g., intravenous, intramuscular, or subcutaneous injection. This is also true of certain therapeutic agents, e.g., vaccines, and diagnostic agents, e.g., radiographic contrast agents. Administration by injection is often required for drugs with poor or unpredictable absorption by mouth or other routes. This is typically the case with high-molecular-weight drugs, e.g., proteins and therapeutic monoclonal antibodies, because they are degraded by the oral route and not absorbed. Some low-molecular- weight drugs, such as propranolol, morphine, vancomycin, and tetrahydrocannabinol (THC), are also poorly or inconsistently absorbed by the oral route. Additionally, first-pass metabolism interferes with the oral absorption of many drugs.

[0004] Administration by injection is painful and often requires the services of a healthcare provider, which is expensive and inconvenient. Many drugs administered by injection are provided in aqueous formulations, which can render them less stable, requiring inconvenient shipping and storage conditions, and shortening shelf life.

[0005] To address the foregoing problems, there has been much interest in delivering drugs across the skin, e.g., transdermally. Transdermal administration remains relatively uncommon, however, due to a fundamental technical challenge: the epidermis — andparticularly the most superficial layer thereof, i.e., the stratum comeum — is a formidable barrier to molecules weighing more than about 500 Daltons, and those with certain physicochemical properties, e g., high hydrophilicity or hydrophobicity.

[0006] One technical approach to deliver a drug past the epidermis for transdermal absorption is to use drug-loaded, skin-penetrating microneedles. Generally, these microneedles comprise: (1) a rigid structure with an apex adapted to pierce into the skin; and (2) a drug active ingredient, typically combined with one or more excipients. Microneedles offer a convenient transdermal delivery route. Microneedles have received attention as a way to avoid degradation of drugs in the gastrointestinal tract, first-pass effects of liver metabolism associated with oral delivery, and the pain and inconvenience of intravenous injection. Also, microneedles can offer a minimally invasive, less painful, and self-administrable delivery of therapeutic, diagnostic, and cosmetic agents, as compared to subcutaneous injection. However, challenges remain in the field of microneedles. For example, porous microneedles tend to be fragile, and it has been a challenge to make hard porous microneedles that are strong enough to penetrate skin. Moreover, other types of microneedles (e.g., hydrogel microneedles) may not have mechanical properties for reliable and stable skin penetration. Additionally, most microneedles developed to date can carry only limited amounts of drug formulation. This limitation is particularly problematic for drugs requiring excipients, especially solvents. It is also problematic for drugs that require high absolute doses (e.g., high-molecular-weight drugs, low-potency drugs, antibiotics). Still further, some types of microneedles are physically or chemically incompatible with some drugs.

[0007] There remains a need, therefore, for improved microneedle drug delivery systems, and methods for fabricating microneedle drug delivery systems.SUMMARY

[0008] Described herein are microneedles for delivering a drug. The microneedles are a composite material formed from a flowable material comprising a polymerizable / curable biocompatible polymer material (e.g., biocompatible resin material), drug in particulate form, surfactant, and, optionally, cosurfactant. Thecomposite microneedles have a generally solid structure with drug particles and surfactant (and optionally, cosurfactant) dispersed throughout an insoluble (e.g., rigid) polymer matrix (e.g., polymerized biocompatible resin), forming an interconnected drug network facilitated by the surfactant and optional cosurfactant throughout the polymer matrix and extending to surfaces of the microneedles. After drug release, the spent microneedles have an open, porous structure mainly comprised of the rigid polymerized / cured polymer matrix.

[0009] The microneedle for delivering a drug may include a solid composite material comprising a polymerized / cured biocompatible polymer matrix, drug particles, and a surfactant, wherein drug particles and surfactant are dispersed throughout the polymer matrix forming an interconnected drug network extending to surfaces of the microneedle.

[0010] The polymerized / cured biocompatible polymer matrix may comprise a photocured biocompatible resin. The biocompatible resin may be a dental resin.

[0011] The drug particles may have a particle size distribution having a D(10) greater than or equal to about 500 nm, a D(50) of from about 1 pm to about 50 pm, and a D(90) less than or equal to about 100 pm, including a particle size distribution having a D(10) greater than or equal to 500 nm, a D(50) of 1 pm to 50 pm, and a D(90) less than or equal to 100 pm, including a particle size distribution having a D(10) greater than or equal to about 2 pm, a D(50) of from about 2 pm to about 25 pm, and a D(90) less than or equal to about 50 pm, including a particle size distribution having a D(10) greater than or equal to 2 pm, a D(50) of 2 pm to 25 pm, and a D(90) less than or equal to 50 pm. In some embodiments, the drug particles have a D(50) particle size of from about 100 nm to about 100 pm.

[0012] The surfactant may have an average HLB value >10, such as an average HLB value of about 12 to about 15. The surfactant may comprise one or more surfactants selected from sorbitan esters, polysorbates, cremophor, D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS), fatty acid esters, alkyl polyglycosides, and aliphatic alcohol-based non-ionic surfactants.

[0013] The microneedle may further comprise a cosurfactant dispersed throughout the polymer matrix. The cosurfactant may have an average HLB value <10, such as an average HLB value of about 2 to about 6. The cosurfactant may comprise one or more selected from propylene glycol, polyethylene glycol 12-hydroxy stearate, glycerin, isopropyl alcohol, diethylene glycol monoethyl ether, a polyethylene glycol, a castor oil derivative, an ethoxylated vegetable oil derivative, propylene glycol monocaprylate, glyceryl monooleate, oleyl alcohol, isopropyl myristate, diisopropyl adipate, ethyl oleate, and lauryl lactate. The surfactant may comprise polyoxyethylene sorbitan monooleate and the cosurfactant may comprise di ethylene glycol monoethyl ether.

[0014] The drug may be water-soluble, and may comprise one or more selected from a therapeutic agent, a prophylactic agent, a diagnostic agent, and a cosmetic agent. The drug may be an antibody (e.g., a monoclonal antibody), a therapeutic peptide or protein (e.g., Vitamin B12, liraglutide, semaglutide, tirzepatide, apelin, amylin, ibuprofen, insulin, insulin degludec), a nucleotide (e.g., DNA, RNA, including mRNA), a low- molecular weight drug (e.g., having a molecular weight less than 500 Daltons, e.g., ibuprofen), or any combination of two or more thereof. The drug may have a molecular weight greater than 500 Daltons. The drug particles may consist of the drug. The drug particles may comprise a composition comprising drug and a pharmaceutically acceptable excipient. The drug particles may comprise spray-dried drug particles. The drug particles may have a heterogenous structure, optionally wherein the drug particles have a structure selected from a core-shell structure, a liposome, a polymeric microparticle, and a lipid nanoparticle. The drug particles may be substantially solvent-free. The drug particles may be substantially water-free.

[0015] The microneedle may have an axial length of from about 0.5 mm to about 1.5 mm. The microneedle may have a hardness of from about 40 Shore A to about 90 Shore D. The tip of the microneedle may break at an applied force of greater than about 0.26 newtons, e.g., may withstand an applied force of about 0.26 newtons or greater.

[0016] The microneedle may have a tip region, a base region, and an intermediate region between the tip region and the base region, wherein the constituents or relativeamounts thereof of the solid composite material may vary from one region to another. The tip region may have a solid composite material comprising polymerized / cured biocompatible polymer matrix, drug particles, and surfactant and optional cosurfactant. The intermediate region may have a solid composite material comprising the polymerized / cured biocompatible polymer matrix. The intermediate region may additionally include surfactant and, optionally, cosurfactant. The intermediate region may optionally additionally include drug particles. If present, the percent by weight of drug particles in the solid composite material of the intermediate region may be less than a percent by weight of drug particles in the solid composite material of the tip region. The base region may have a solid composite material comprising the polymerized / cured biocompatible polymer matrix. The base region may additionally include surfactant and, optionally, cosurfactant. The base region may additionally optionally include drug particles. If present, the percent by weight of drug particles in the solid composite material of the base region may be less than a percent by weight of drug particles in the solid composite material of one or both of the tip region and the intermediate region.

[0017] After 24 hours in aqueous release media, the microneedle may release 80% or more of drug loaded therein, optionally wherein the microneedle may release 80%, 85%, 90%, 95%, 97%, or more, of drug loaded therein.

[0018] The microneedle may be prepared from a flowable material comprising a polymerizable / curable biocompatible polymer material, drug particles, and a liquid surfactant, wherein the drug particles may be dispersed in the flowable material. The flowable material may comprise from about 30 wt.% to about 70 wt.% of the polymer material, such as from about 40 wt.% to about 60 wt.% of the polymer material. The flowable material may comprise from about 1 wt.% to about 70 wt.%, or from about 5 wt.% to about 40 wt.%, of the drug particles. The flowable material may comprise from about 1 wt.% to about 35 wt.% of the liquid surfactant. The flowable material may further comprise liquid cosurfactant in an amount about 1 wt.% to about 35 wt.%. The flowable material may comprise from about 1 wt.% to about 55 wt.% of surfactant and optional cosurfactant combined.

[0019] The microneedle may be prepared by a process comprising forming a flowable mixture comprising a polymerizable / curable biocompatible polymer material, drug particles, and a liquid surfactant, wherein the drug particles are dispersed in the flowable material; forming the flowable mixture into a microneedle shape; and one or both of polymerizing and curing the flowable mixture to form the microneedle.

[0020] Forming the flowable mixture into a microneedle shape may comprise casting the flowable mixture into a microneedle-forming mold. Forming the flowable mixture into a microneedle shape may comprise 3D printing the flowable mixture into a microneedle shape.

[0021] A microneedle patch may comprise a plurality of microneedles. The plurality may be 50 or more microneedles. The plurality may be 100 or more microneedles. A microneedle patch may comprise a plurality of microneedles spaced about 0.5 mm apart, about 1 mm apart, about 2 mm apart, or any value therebetween, optionally wherein the patch may have a planar microneedle area of from about 0.5 cm2to about 100 cm2.

[0022] A microneedle patch may comprise a first plurality of microneedles comprising a first solid composite material comprising a first polymerized / cured biocompatible polymer matrix, first drug particles, a first surfactant, and, optionally, a first cosurfactant; and a second plurality of microneedles comprising a second solid composite material comprising a second polymerized / cured biocompatible polymer matrix, second drug particles, a second surfactant, and, optionally, a second cosurfactant. The first drug particles may comprise a first drug and the second drug particles may comprise a second drug the same as or different from the first drug. Additionally or alternatively, the first drug particles may have a particle size distribution having a D(10), D(50), and D(90) the same as or different from those of a particle size distribution of the second drug particles. Additionally or alternatively, the first biocompatible polymer matrix may comprise a first resin and the second biocompatible polymer matrix may comprise a second resin the same as or different from the first resin. Additionally or alternatively, the first surfactant may be the same as or different from the second surfactant. Additionally or alternatively, the first solid composite material may comprise a cosurfactant and the second solid composite material may notcomprise a cosurfactant, or the first solid composite material may comprise a first cosurfactant and the second solid composite material may comprise a second cosurfactant the same as or different from the first cosurfactant. Additionally or alternatively, a ratio by weight in the first solid composite material of the first polymerized / cured biocompatible polymer matrix, first drug particles, first surfactant and optional first cosurfactant (if present) may be the same as or different from a ratio by weight in the second solid composite material of the second polymerized / cured biocompatible polymer matrix, second drug particles, second surfactant and optional second cosurfactant (if present).

[0023] Also provided herein is a flowable material that may comprise a polymerizable / curable biocompatible polymer material, drug particles, and a liquid surfactant, wherein the drug particles are dispersed in the flowable material. The flowable material may comprise from about 30 wt.% to about 70 wt.% or from about 40 wt.% to about 60 wt.% of the polymer material. The flowable material may comprise from about 1 wt.% to about 70 wt.% or from about 5 wt.% to about 40 wt.% of the drug particles. The flowable material may comprise from about 1 wt.% to about 35 wt.% of the liquid surfactant. The flowable material may further comprise liquid cosurfactant in an amount about 1 wt.% to about 35 wt.%. The flowable material may comprise from about 1 wt.% to about 55 wt.% of surfactant and optional cosurfactant combined.

[0024] Also provided are processes for preparing a microneedle, which may comprise forming a flowable mixture comprising the polymerizable / curable biocompatible polymer material, drug particles, and liquid surfactant, wherein the drug particles are dispersed in the flowable material; forming the flowable mixture into a microneedle shape; and one or both of polymerizing and curing the flowable mixture to form the microneedle. Forming the flowable mixture into a microneedle shape may comprise 3D printing the flowable mixture into a microneedle shape. Forming the flowable mixture into a microneedle shape may comprise casting the flowable mixture onto a microneedleforming mold having a microneedle-forming cavity, and wherein one or both of polymerizing and curing the flowable mixture comprises curing the flowable mixture in the microneedle-forming cavity to obtain a solid microneedle.

[0025] In some embodiments, a process for preparing a microneedle may comprise forming a flowable mixture comprising the polymerizable / curable biocompatible polymer material, drug particles, and liquid surfactant, wherein the drug particles are dispersed in the flowable material; stretching a microneedle-forming mold having a microneedle-forming cavity beyond an original size of the mold; casting the flowable mixture onto the stretched microneedle-forming mold; permitting the stretched microneedle-forming mold to relax into an unstretched state; curing the flowable mixture in the microneedle-forming cavity to obtain a solid microneedle; and removing the solid microneedle from the mold.

[0026] In some embodiments, a process for preparing a microneedle may comprise casting a first flowable mixture onto a microneedle-forming mold having a microneedleforming cavity comprises a tip region, a base region, and, optionally, an intermediate region between the tip region and the base region, wherein the casting fills a region of the microneedle-forming cavity that comprises at least the tip region, and curing the first flowable mixture in the mold, wherein the first flowable mixture comprises the polymerizable / curable biocompatible polymer material, drug particles, and liquid surfactant and optional cosurfactant (if present), wherein the drug particles are dispersed in the flowable material; optionally, casting a second flowable mixture into an unfilled region of the microneedle-forming cavity that comprises the intermediate region, and curing the second flowable mixture in the mold, wherein the second flowable mixture comprises the polymerizable / curable biocompatible polymer material, optionally comprises the liquid surfactant, optionally comprises the cosurfactant (if present), and further optionally comprises drug particles dispersed in the flowable material; and casting a third flowable mixture into an unfilled region of the microneedle-forming cavity that comprises at least the base region, and curing the third flowable mixture in the mold, wherein the third flowable mixture comprises the polymerizable / curable biocompatible polymer material, optionally comprises the liquid surfactant and optional cosurfactant (if present), and further optionally comprises drug particles dispersed in the flowable material; and removing the solid microneedle from the mold.

[0027] In accordance with any of the foregoing processes, the process may further comprise forming a back substrate for the microneedle, such as by (i) before removing the solid microneedle from the mold, casting a second polymerizable / curable biocompatible polymer material on the microneedle mold (which may be the same as or different from the polymerizable / curable biocompatible polymer material of the flowable material, or may be the same material as the flowable material), and curing the second polymerizable / curable biocompatible polymer material to bond it to the microneedle, to thereby obtain a back substrate on the microneedle; or (ii) before curing the flowable mixture in the microneedle-forming cavity, casting a second polymerizable / curable biocompatible polymer material on the microneedle mold (which may be the same as or different from the polymerizable / curable biocompatible polymer material of the flowable material or may be the same material as the flowable material) on the microneedle mold, and curing the flowable mixture and second polymerizable / curable biocompatible polymer material, to thereby obtain a microneedle on a back substrate.

[0028] In any embodiments, the process may comprise curing the flowable mixture by photocuring, optionally by UV light, further optionally by light at a wavelength of 405 nm.

[0029] In any embodiments, the mold may comprise a plurality of microneedle-forming cavities arranged in an array, and the process may obtain a plurality of microneedles arranged in an array. The drug particles may be formulated in the flowable mixture in powder form.

[0030] In alternative embodiments, a process for preparing a microneedle may comprise forming a microneedle comprising a tip region, a base region, and, optionally, an intermediate region between the tip region and the base region by a process comprising forming the tip region by 3D printing from a flowable mixture comprising polymerizable / curable biocompatible polymer material, drug particles, and surfactant and optional cosurfactant (if present), wherein the drug particles are dispersed in the flowable material; optionally, forming the intermediate region by 3D printing from a second flowable mixture comprising the polymerizable / curable biocompatible polymer material,optionally comprising liquid surfactant and optional cosurfactant (if present), and further optionally comprising drug particles dispersed in the flowable material; and forming the base region by 3D printing from a third flowable mixture comprising the polymerizable / curable biocompatible polymer material, optionally comprising liquid surfactant and optional cosurfactant (if present), and further optionally comprising drug particles dispersed in the flowable material.BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG.l illustrates an array of microneedles according to the present disclosure.

[0032] FIG. 2 shows schematic representations of a cross-section of a microneedle as described herein before and after drug release, showing the solid composite structure comprised of insoluble (rigid) polymerized / cured polymer matrix (e.g., polymerized resin) loaded with drug in particulate form and surfactant prior to drug release, and an open, porous structure mainly comprised of insoluble (rigid) polymerized / cured polymer matrix after drug release. Liquid surfactant surrounds the solid phase drug particles and is in contact with the resin and fills any gaps between the drug particles and the resin, resulting in an interconnected network. The resulting interconnected network allows the release of all drug particles in the interconnected network, resulting in an open porous structure after drug release.

[0033] FIG. 3 shows schematic representations of a cross-section of a comparison microneedle before and after drug release, showing a solid composite structure comprised of insoluble (rigid) polymerize / cured polymer (e.g., polymerized resin) loaded with drug in particulate form (but no surfactant) before and after drug release. Compared to FIG. 2, drug release from the comparison microneedle is incomplete. During release, the particles that will not be reached by solvent (such as water or interstitial fluid) (e.g., particles that do not occupy a solvent accessible volume) are trapped inside the resin matrix and will not be released, thereby remaining trapped inside the insoluble polymerized / cured polymer (i.e., resin) matrix.

[0034] FIG. 4 illustrates a flowable material 10 as described herein (e.g., including an unpolymerized polymerizable / curable biocompatible polymeric material, surfactant and, optionally, cosurfactant) with a drug in particulate form 12 dispersed therein.

[0035] FIG. 5 illustrates a mold 14 having cavities 16.

[0036] FIG. 6 illustrates flowable material 10 with the drug in particulate form 12 of FIG. 4 cast onto mold 14 of FIG. 5.

[0037] FIG. 7 shows a schematic representation of curing the flowable material 10 with the drug in particulate form 12 of FIG. 4 cast onto mold 14 of FIG. 5.

[0038] FIG. 8 illustrates a cured polymeric material (e g., a polymerized resin) 20 comprising drug in particulate form 12 having microneedle structures 22 after removal from the mold.

[0039] FIG. 9 illustrates a microneedle 22 comprised of cured polymeric material (e.g., a polymerized resin) 20 comprising drug in particulate form 12.

[0040] FIG. 10 illustrates a bandage 30 having an array of microneedles 22 and adhesive areas 32.

[0041] FIG. 11 is a schematic representation of methods for fabricating a microneedle mold 100, microneedles 102, and a microneedle patch 104 as disclosed herein.

[0042] FIG. 12A illustrates a microneedle 22 in a dermal environment.

[0043] FIG. 12B illustrates diffusion of drug from cured polymeric material 20 comprising drug in particulate form 12 of microneedle 22 into a dermal environment.

[0044] FIGS. 13A-13C are scanning electron microscopy (SEM) images of outer surfaces of a vitamin Bl 2-containing microneedle as described herein before drug release, showing a generally solid and non-porous surface.

[0045] FIGS. 14A-14C are SEM images of a cross-section of a broken vitamin B12- containing microneedle as described herein before drug release, showing a generally solid, non-porous internal structure.

[0046] FIGS. 15A-15C are SEM images of outer surfaces of a vitamin B 12-containing microneedle as described herein after one hour of drug release, showing pores evenly dispersed across the surface.

[0047] FIGS. 16A-16C are SEM images of a cross-section of a broken vitamin B 12- containing microneedle as described herein after one hour of drug release, showing deep pores evenly distributed throughout the internal structure.

[0048] FIG. 17 is a graph of the serum concentration (pg / ml) vs. time curve for vitamin B12 delivered by a microneedle array as described herein (■) as compared to subcutaneous injection (•), in a human study described herein. The dashed lines show the target plasma concentration.

[0049] FIG. 18A is an SEM image of an outer surface (side wall) of a semaglutide- containing microneedle as described herein before drug release, showing a generally solid, non-porous surface.

[0050] FIGS. 18B-18C are SEM images of a cross-section of a broken semaglutide- containing microneedle as described herein before drug release, showing a generally solid, non-porous internal structure.

[0051] FIG. 19A is an SEM image of an outer surface of a semaglutide-containing microneedle as described herein after one hour of drug release, showing pores evenly dispersed across the surface.

[0052] FIGS. 19B-19C are SEM images of a cross-section of a broken semaglutide- containing microneedle as described herein after one hour of drug release, showing deep pores evenly distributed throughout the internal structure. The spheres visible in the images are believed to be drug particles.

[0053] FIG. 20 is a graph of the serum concentration (pM) vs. time curve for semaglutide delivered by a microneedle array as described herein (■) as compared to subcutaneous injection (•), in an animal study described herein.

[0054] FIGS. 21A-21F are SEM images of outer surfaces of a comparison ibuprofen microneedle before (A, C, D) and after (B, E, F) drug release.

[0055] FIG. 22 is a graph showing release kinetics of two different drugs, pyr-Apelin-13 and semaglutide, formulated in different microneedles of the same microneedle patch.

[0056] FIG. 23 is a graph showing release kinetics of two different drugs, insulin degludec and liraglutide, formulated in the same microneedles of the same microneedle patch.DETAILED DESCRIPTIONDefinitions

[0057] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which the present disclosure pertains, unless otherwise defined.

[0058] As used herein, the singular forms "a," "an," and "the" and the like designate both the singular and the plural, unless expressly stated to designate the singular only.

[0059] As used herein, the term "about" means that the stated parameter is not limited to the exact number stated. As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term. As used herein, ranges are to be construed as shorthand for each and every value falling within the range, and each separate value should be understood to be expressly disclosed herein.

[0060] "Subject" as used herein includes any mammal. In any embodiments described herein, the subject is human.Overview

[0061] Described herein are improved microneedle drug delivery systems wherein a drug is incorporated into the microneedle in particulate form. When one or more of the microneedles is applied to the skin of a subject, the drug is released from the microneedles, e.g., the drug particles dissolve and / or are dispersed in interstitial fluids, and particles contained within the microneedles (e.g., on and / or beneath the surfaces of the microneedles, within the polymer matrix) travel (e.g., diffuse) through a network of channels in the microneedles out of the microneedles into the skin and are delivered, e.g., to the systemic circulation or desired local tissues. As discussed below and illustrated in the examples, the disclosed microneedles may offer advantages over microneedles known in the art, such as improved strength, increased drug release, and greater drug loading (if desired), which in turn leads to greater drug absorption by the patient and greater therapeutic index. FIG. 1 illustrates an array of microneedles as disclosed here.

[0062] As described in more detail below, the disclosed microneedles are a composite material formed from a flowable material comprising a polymerizable / curable biocompatible polymer material (e.g., biocompatible resin material), drug in particulate form, surfactant, and, optionally, cosurfactant. The composite microneedles have a generally solid structure, with drug particles and surfactant (and optionally, cosurfactant) dispersed throughout an insoluble (e.g., rigid) polymerized / cured polymer matrix (e.g., polymerized biocompatible resin) forming an interconnected network of drug particles facilitated by the surfactant (and optionally, cosurfactant) throughout the polymer matrix and extending to surfaces of the microneedles. After drug release, the spent microneedles have an open, porous structure mainly comprised of the rigid polymerized / cured polymer matrix (e.g., polymerized biocompatible resin). While the discussion that follows focuses on microneedles formed from a flowable material as described herein, it should be understood that the disclosed flowable material can be used to prepare other drugcontaining structures, such as by filling the disclosed flowable material into a mold for a different structure or using the disclosed flowable material as an “ink” in 3D printing to form any desired structure (including microneedles). Thus, unless otherwise expressly stated or required by the context, use of the term “microneedle” as used should be understood to be representative of such other structures.

[0063] As used herein, surfactants and cosurfactants refer to amphiphilic molecules, with surfactants being components that reduce surface energy, and cosurfactants being components that act at the interface of hydrophilic and hydrophobic materials by reducing the interfacial tension. Without being bound by theory, it is believed the surfactant (and optional cosurfactant) may play several different roles that improve the properties of the microneedles.

[0064] For example, the surfactant (and optional cosurfactant) may promote interconnectedness of the drug network throughout the polymer matrix extending to the surface of the microneedles, which also promotes drug release as discussed in more detail below. In this context, it is believed surfactant (and optional cosurfactant) may surround the solid drug particles, filling any gaps between the particles and promoting an interconnected network of drug particles, as illustrated in FIG. 2, left panel. Additionally, surfactant (and optional cosurfactant) may facilitate wetting of solid surfaces. Without being bound by theory, the surfactant (and optional cosurfactant) may also promote mechanical strength, e.g., by filling gaps between drug particles and between drug particles and polymer matrix.

[0065] Further, surfactant (and optional cosurfactant) may reduce surface energy between solid drug particles and release media (e.g., interstitial fluid of the recipient subject), facilitating release (e.g., dissolution and / or dispersion) of solid drug particles into release media for diffusion out of the microneedles and drug delivery. For example, the surfactant may reduce surface energy of the solid drug particles at the interface of release media and the polymer matrix, promoting faster and complete release of the drug into release media, and the optional cosurfactant may reduce interfacial tension at interfaces of drug particles and release media. Still further, the surfactant (and optional cosurfactant) may enhance drug solubilization in the interstitial fluid of the recipient subject that also promotes greater drug release from the microneedles during use.

[0066] As illustrated in the examples, composite microneedles formulated with a surfactant (and, optionally, a cosurfactant) as described herein demonstrate improved strength and significantly greater drug release than composite microneedles formulated without a surfactant and cosurfactant. Without being bound by theory, the surfactant (and optional cosurfactant) may contribute to improved strength by reducing voids in the microneedlestructure, e.g., by filling any gaps between solid drug particles and / or interstices between solid drug particles and the insoluble polymer matrix and / or by inhibiting the formation of large aggregates of drug particles. Also without being bound by theory, the surfactant (and optional cosurfactant) may contribute to improved drug delivery by several mechanisms of action, such as by promoting interconnectedness of the drug network formed throughout the polymer matrix and extending to the surface of the microneedles and / or by promoting release (e.g., dissolution and / or dispersion) of solid drug particles into interstitial fluid for diffusion out of the microneedle structure. Formation of an interconnected drug network throughout the microneedle structure promotes drug release because, in use, drug particles distributed throughout the microneedles are able to be exposed to interstitial fluid and hence able to release (e.g., dissolve and / or disperse) into the fluid and travel (e.g., diffuse) out of the microneedles, e.g., through channels formed by released drug particles, as illustrated in FIG. 2, right panel. In contrast, microneedles formed without a surfactant and cosurfactant as described herein demonstrate low drug release, undermining their use in therapeutic applications. This may be because while drug particles present on the surface of such microneedles may release, drug particles within the core of such microneedle structures may be trapped within the polymer matrix and not releasable, as illustrated in FIG. 3, left and right panels.

[0067] Thus, the composite microneedles disclosed herein have an interconnected drug network throughout the microneedle structure extending to the surface facilitated by the surfactant (and optionally, cosurfactant) that results in the formation of channels as drug particles are released into interstitial fluid, which in turn permits interstitial fluid (or other release media) to reach internal regions of the microneedles, such that drug particles located throughout the microneedle structure are able to be released into the fluid and travel (e.g., diffuse) out of the microneedle for drug delivery. Additionally, as also noted above, the surfactant (and optional cosurfactant) are believed to aid hydration / wetting of the microneedles and / or drug particles and solubilization or dispersion of the drug particles in release media (in vitro or interstitial fluid in vivo , which also promotes release (e.g., dissolution or dispersion) and delivery of the drug. As noted above, since the composite microneedles are a composite of polymer matrix, drug particles, surfactant, and optionalcosurfactant, as the drug particles are released, the microneedle structure becomes porous with pores and channels formed where drug particles (and surfactant and optional cosurfactant) previously were present, allowing release media (e.g., in vitro release media or interstitial fluid in vivo) to penetrate deeper within the microneedle structure, promoting release of additional drug particles, and thereby forming channels throughout the microneedles for drug release. For example, when first contacted with fluid release media (e.g., interstitial fluid), drug particles on the surface of the microneedle will release into the surrounding fluid. As these particles are released, voids appear in their locations, creating pores and channels through which fluid penetrates further into the microneedle structure. Release of additional drug particles leads to the formation of additional pores and channels throughout the microneedle structure, and further release and diffusion of additional drug particles out of the microneedle structure. With time, complete or nearcomplete release and delivery of drug may occur. Eventually, the spent microneedles have an open, porous structure devoid (or nearly devoid) of drug, as all or nearly all the drug has been released and traveled out of the microneedles and been delivered into the skin. Thus, the interconnected network of drug particles, which is facilitated by the surfactant (and optional cosurfactant), enables a more complete drug delivery process. In some embodiments, the microneedles disclosed herein are able to release about 80% or more of the drug loaded therein, including 80%, 85%, 90%, 95%, 97%, or more. For example, microneedles as disclosed herein may be able to release about 80% or more of the drug loaded therein, including 80%, 85%, 90%, 95%, 97%, or more, within a predetermined time period in release media or within a predetermined time period in place in skin, such as, for example, from within about 1 hour to within about 24 hours (or longer), including within about 1 hour, within about 3 hours, within about 6 hours, within about 9 hours, within about 12 hours, within about 15 hours, within about 18 hours, within about 21 hours, or within about 24 hours (or longer), or any time period therebetween.

[0068] As illustrated in FIG. 2 and seen in FIGS. 13A-13C, 14A-14C, and 18A-18C, the composite microneedles as described herein are solid and substantially non-porous prior to release of the drug. After drug release, the microneedles have pores formed throughout the microneedle structure. See FIGS. 15A-15C, 19A-19C. The pore structure indicates that themicroneedles are formed with a dispersion of drug particles throughout the microneedle structure. The pore structure also indicates the formation of channels throughout the microneedle structure that permit drug to be released from throughout the microneedle structure, not just at or near the surface.

[0069] In some embodiments, the pores formed in the microneedle structure after drug release may be smaller than 2 pm in diameter, in which case they also may act as a filter for bacteria, e.g., they may retain any bacteria present within the microneedle structure and prevent bacteria from being delivered into the skin, e.g., prevent any bacteria from getting into the subject. For example, in some embodiments, the pores formed after drug release may have a diameter on the order of 100 nm, or less. Thus, in effect, in some embodiments microneedles as described herein may have self-sterilizing properties with regard to the substances released from the microneedle into the subject.

[0070] In biological systems (e.g., in vivo), drug release from the microneedle may be promoted further through interactions between the surfactant and cosurfactant and biological barriers that alter the concentration gradient, thereby providing another driving force for drug diffusion out of the microneedle.

[0071] As discussed in more detail below, in some embodiments, the fluid to support diffusion of drug out of the microneedles is provided, either totally or substantially, by interstitial fluid of the recipient subject. Thus, the drug can be optionally provided in a solid (or substantially solid) form that is adapted for solvation by the skin, e.g., by interstitial fluid. Thus, the drug can be formulated without (or substantially without) a solvent, e.g., without water. Thus, relatively large amounts of drug substance can be loaded into a microneedle as described herein (as measured on the basis of drug substance mass per microneedle mass, or active ingredient mass per microneedle volume), for example 20 micrograms or more of drug substance per 70 nanoliter (which may be a typical approximate volume of one microneedle). This confers several crucial benefits, e.g., the ability to deliver active ingredients by microneedle that hitherto could not be loaded in sufficient amount on a microneedle; the ability to deliver high-molecular-weight molecules, e.g., biologies, e.g., therapeutic monoclonal antibodies, or other agents having a molecular weight greater than about 500Daltons; the ability to create microneedle patches that can require shorter application time and / or less frequent reapplication; and the ability to obtain very high drug concentrations in the vicinity of the microneedle(s), thereby creating a high concentration gradient and correspondingly improved drug delivery. Furthermore, the ability for drug to be incorporated into a microneedle without solvents (e.g., without water) can beneficially increase and extend the stability, e.g., shelf life, of the microneedle devices, including stability at room temperature and manufacturing yield. Moreover, as discussed in detail throughout, the interconnected network of drug particles, which is facilitated by the surfactant (and optional cosurfactant), enables complete or near complete release of the drug particles from the microneedles. Among other features, the ability to achieve one or both of high drug loading and complete drug release are advantageous properties of the microneedles disclosed herein that offer significant advantages over the state of the art.

[0072] The microneedles disclosed herein also possess remarkable physical characteristics that confer practical benefits. The size and other physical properties of the drug particles can be modulated to change the microneedles’ drug delivery characteristics, e.g., drug delivery rate. The composition and structure of the microneedles described herein provide excellent penetration into skin as well as structural integrity, e.g., rigidity or semi-rigidity and resistance to breakage, as discussed in more detail below.Overview of Microneedle Structure and Fabrication

[0073] The microneedles described herein are a composite material formed from a flowable material comprising a polymerizable / curable biocompatible polymer material (e.g., biocompatible resin material), drug in particulate form (also referred to herein as “drug particles”), surfactant, and, optionally, cosurfactant. The composite microneedles have a generally solid structure, with drug particles and surfactant (and optional cosurfactant) dispersed throughout an insoluble (e.g., rigid) polymerized / cured polymer matrix (e.g., polymerized biocompatible resin) forming an interconnected network of drug particles facilitated by the surfactant (and optionally, cosurfactant) throughout the rigid polymerized / cured polymer matrix and extending to surfaces of the microneedles. Afterdrug release, the spent microneedles have an open, porous structure mainly comprised of the rigid polymerized / cured polymer matrix (e.g., polymerized biocompatible resin).

[0074] The microneedles typically are formed from a flowable material comprising a polymerizable / curable biocompatible polymer material (e.g., biocompatible resin material). As used herein, the term “polymerizable / curable biocompatible polymer material” refers to a biocompatible polymer material that can be hardened by polymerization and / or curing, and includes (but is not limited to) biocompatible synthetic resin materials, such as dental resins as illustrated below, or natural resin materials, as also discussed below. For example, as discussed in more detail below, in some embodiments, the flowable material may be cast onto a mold comprising one or more needle-shaped mold cavities. Curing of the flowable material in the mold yields the microneedle(s). In some embodiments, the mold comprises an array of needle-shaped mold cavities in a specific geometric configuration. Alternatively, as noted above, in some embodiments, the flowable material may be used as “ink” for 3D printing of any desired structure, including microneedles or implantable devices.

[0075] Drug Particles The microneedles described herein can be prepared with any drug, such as any drug suitable for subcutaneous or transdermal delivery via a microneedle. Typically, the drug is in a solid particulate form, also referred to herein as “drug particles.” It should be understood that the term “drug particles” as used herein includes particles that comprise other components in addition to the drug (e.g., in addition to the active pharmaceutical ingredient), such as one or more formulation components e.g., one or more pharmaceutically acceptable excipients. Nevertheless, in some embodiments, the drug particles consist of the drug.

[0076] Drug particles for use in the microneedles described herein can be obtained from a liquid drug formulation, for example, by spray drying, lyophilization, or liquid emulsion or microfluidic drop generation followed by solvent evaporation, e.g., dehydration, to create solid drug particles. In some embodiments, the drug particles comprise spray-dried drug particles. Drug particles for use in the microneedles described herein may be obtained directlyfrom a commercial source, such as a commercial supplier of active pharmaceutical ingredients (APIs).

[0077] In the context of the present disclosure, particle size characterization of the drug particles can be a quality control step, as it can significantly influence one or more performance characteristics, as discussed elsewhere herein. In the pharmaceutical industry, particle size characterization is typically achieved by measuring particle size distribution (PSD) of a relevant sample (e.g., a batch of drug particles being formulated). Typical measurements many include D(10), D(50), and D(90), which represent percentile values: D(10) is the particle diameter below which 10% of the sample lies, D(50) — also called the median particle size — indicates the midpoint where 50% of the sample is smaller and 50% is larger (and is sometimes informally referred to as the “mean” or “average”), and D(90) marks the diameter below which 90% of the sample lies. These measurements may be obtained using laser diffraction (LD), a technique that analyzes light scattering patterns to determine particle size distribution. Other quality control techniques may include microscopy methods — such as optical microscopy or scanning electron microscopy (SEM) — which may be employed to visually assess particle morphology, detect aggregates, and confirm uniformity. Drug particles having submicron or nanoparticle sizes may be assessed using dynamic light scattering (DLS) to provide sensitive measurements of hydrodynamic diameters in suspension.

[0078] Throughout this disclosure, where the size of a drug particle is described, it is to be understood that particulate size can optionally exist as distribution of sizes, e.g., that the formulated drug particles may have a size distribution. (In some instances, this may result in different size pores in the microneedle structure after use (see, e.g., FIG. 19)). Thus, where a particular measure of particle size is provided, this measure can represent the mean or median of a distribution of particle sizes, depending on the characterization method and particle size distribution. As used herein, “particle size” refers to the D(50) particle size as determined using laser diffraction, unless otherwise stated. As used herein, “particle size distribution” refers to the particle size distribution of a given sample of drug particles (e.g., a batch of drug particles being formulated, or the drug particles present in a given microneedle or microneedle patch), and may be defined with reference to D(10), D(50), and D(90), asdetermined using laser diffraction, unless otherwise stated. The particle size (e.g., D(50)) or particle size distribution (e.g., DIO, D(50), and D(90)) of commercially sourced drug particles may be stated on a Certification of Analysis or otherwise provided by the supplier. Drug particle size may be accurately controlled using, for example, a vibration based-mini mill, or a spray drying method.

[0079] In some embodiments, the drug particles have a D(50) particle size of from about 100 nm to about 100 pm, including from about 500 nm to about 100 pm. The drug particles may have a D(50) particle size of from about 5 pm to about 50 pm. The drug particles may have a D(50) particle size of from about 1 pm to about 20 pm. In particular embodiments, drug particles have a D(50) particle size of 50 pm or less, such as from about 1 pm to about 50 pm, or about 5 pm to about 50 pm. In other particular embodiments, drug particles have a D(50) particle size of 20 pm or less, such as from about 1 pm to about 20 pm, or about 5 pm to about 20 pm.

[0080] The drug particles may have a particle size distribution having a D(10) greater than or equal to about 500 nm, a D(50) of from about 1 pm to about 50 pm, and a D(90) less than or equal to about 100 pm, including a particle size distribution having a D(10) greater than or equal to 500 nm, a D(50) of 1 pm to 50 pm, and a D(90) less than or equal to 100 pm. The drug particles may have a particle size distribution having aD(10) greater than or equal to about 2 pm, a D(50) of from about 2 pm to about 25 pm, and a D(90) less than or equal to about 25 pm, including a particle size distribution having a D(10) greater than or equal to 2 pm, a D(50) of 2 pm to 25 pm, and a D(90) less than or equal to 50 pm.

[0081] The target particle size of the drug particles may vary with the size of the microneedle, with larger particle sizes being possible with larger microneedles. In some embodiments, the median size of a drug particle is between about 1 and 200 pm, between about 1 pm and 150 pm, between about 1 pm and 100 pm, or between about 1 pm and 50 pm. In some embodiments, 90 %, 95 %, 99 %, or 99.9% of drug particles in a composition have a median size between about 1 and 200 pm, between about 1 pm and 150 pm, between about 1 pm and 100 pm, or between about 1 pm and 50 pm (in the foregoing clause, 16possible pairwise combinations of a percentage and particle size range are disclosed, each combination of which is disclosed herein as though individually recited). In some embodiments the size (i.e., largest dimension) of a drug particle (e.g., a spray-dried drug particle) is between about 500 nm and 200 pm, or about 1 pm and 150 pm. In some embodiments the size of a drug particle is between about 37 and 125 pm. In some embodiments the size of a drug particle is between about 1 pm and 100 pm. In some embodiments the size of a drug particle is between about 1 pm and 50 pm. In some embodiments the size of a drug particle is less than 125 pm. In some embodiments the size of a drug particle is less than 38 pm. In some embodiments, the size of the drug particles is about 10 pm or less, optionally, about 5 pm or less.

[0082] As discussed in more detail below, the particle size of the drug particles may affect drug-loading capabilities, with smaller particle size permitting and / or requiring greater drugloading. Additionally, the particle size of the drug particles may impact the drug delivery rate and the release kinetics. Thus the particle size of the drug particles offers another mode for controlling drug delivery from the microneedles described herein (e.g., along with the relative amount of drug particles formulated in the flowable material). This also leads to the possibility of including drug particles of various, defined particle sizes to modulate the drug release profile.

[0083] In some embodiments, the drug particles are solvent-free, substantially solvent- free, or made without solvent. In some embodiments, the drug particles are water-free, substantially water-free, or made without water. As used herein, “substantially solvent-free” and “made without solvent” each include, without limitation, compositions that include negligible amounts of solvent, e.g., solvent molecules noncovalently bound to a drug particle. Likewise, as used herein, “substantially water-free” and “made without water” each include, without limitation, compositions that include negligible amounts of water, e.g., water present in a drug particle that is a hydrate, or water passively absorbed or adsorbed from the atmosphere. For example, drug particles that are solvent-free or substantially solvent-free may be obtained by methods that include spray drying or lyophilization. For example, a residual water content of drug particles may be less than about 3 wt.%, less than 2 wt.%, or less than about 1 wt.%. For example, hygroscopic drugs may have a water content of less than about1 wt.% and non-hygroscopic drugs may have a water content of less than about 3 wt.%. Lyophilized drug particles may have a water content of less than about 1 wt.%. Spray -dried drug particles may have a water content of less than 3 wt.%.

[0084] A drug particle can be homogeneous or heterogeneous, e.g., can have a homogenous or heterogenous structure. A drug particle can be physically uniform or can consist of two or more parts. For example, a drug particle can optionally comprise a central core and a superficial shell; and the superficial shell can, if desired, be selected to optimize physical interactions between the drug particle and the flowable material. For example, the drug particle can comprise a central core containing a drug active ingredient surrounded by a protective shell. The protective shell can be adapted to prevent dissolution of the drug in the flowable material. Some examples include: use of a hydrophilic protective shell in a hydrophobic flowable material; use of a hydrophobic protective shell in a hydrophilic flowable material; use of a protective shell to prevent a chemical reaction between the drug active ingredient and the flowable material; or use of a protective shell that possesses an absorbance spectrum that protects the drug active material from photodegradation, e.g., during curing of the flowable material. Other examples of heterogeneous drug particles include liposomes, polymeric microparticles, and lipid nanoparticles.

[0085] A drug particle can be a single drug particle or a physical cluster of one or more drug particles, including any one or more of the aforementioned homogeneous or heterogeneous drug particles having the same or different components, including the same or different drugs.

[0086] As noted above, a drug particle can comprise one or more pharmaceutically acceptable excipients, e.g., one or more binders, buffers, salts, stabilizers, preservatives and the like. Additionally or alternatively, the flowable material can further comprise one or more excipients, e.g., one or more binders, buffers, salts, stabilizers, preservatives, and the like.

[0087] The use of a particulate form of drug can be of special interest for the delivery of high-molecular-weight drugs. These drugs are typically soluble in interstitial fluid, e.g., of the skin; thus, they are excellent candidates for use in certain embodiments of the present disclosure.

[0088] In some embodiments, the drug particle comprises one or more detectable markers, such as any biocompatible detectable marker, e.g., a nontoxic dye such as fluorescein, green fluorescent protein, or a radioactive compound. Such embodiments are useful, for example, for detecting and / or monitoring drug distribution in the microneedle and drug release from the microneedle. Additionally or alternatively, such embodiments may be useful for quality control purposes, e.g., to ensure drug particles are distributed throughout the microneedle.Exemplary Drugs

[0089] The microneedles described herein can be prepared with any one or more drugs. As used herein, the term “drug” is used broadly to refer to any substance that may be administered transdermally for any desired effect, and includes therapeutic agents, prophylactic agents, diagnostic agents, and cosmetic agents.

[0090] The microneedles described herein are suitable for use with drugs with a high molecular weight (e.g., greater than 500 Daltons), which traditionally are hard to effectively deliver transdermally, but also are useful for drugs with a lower molecular weight. Indeed, the microneedles described herein can achieve multi-milligram transdermal delivery of large molecule drugs, including drugs having a molecular weight greater than 4000 Daltons (e.g., liraglutide, semaglutide, tirzepatide, etc.). This is demonstrated in the examples below, which are believed to be the first report of multi-milligram transdermal delivery of large molecule drugs.

[0091] As noted above, the microneedles described herein can be prepared with any one or more drugs. The microneedles described herein are suitable for use with drugs that are poorly soluble in water, which traditionally may not have been administered transdermally because of their poor solubility. This is because effective drug delivery and therapeutic efficacy generally requires that the drug be solubilized. However, by formulating drugs with poor aqueous solubility with a surfactant (and optional cosurfactant) as disclosed herein, chemical interactions take place through H-bonding and / or hydrophobic interaction, leading to complexation between the drug and surfactant, which facilitates wetting of the drug in an aqueous environment (e.g., interstitial fluid) by lowering surface energy and thereby increasing solubility of drug. As discussed herein, in some embodiments, the use of acosurfactant as disclosed herein enhances performance of the surfactant(s) and reduces the interfacial tension at the interface of different materials.

[0092] In some embodiments, the drug is an antibody (e.g., a monoclonal antibody), a therapeutic peptide or protein, a nucleotide (e.g., DNA, RNA, including mRNA), a low- molecular weight drug (e.g., having a molecular weight less than 500 Daltons), or any combination of any two or more thereof. In some embodiments, the drug is ibuprofen. In some embodiments, the drug is or includes a GLP 1 -receptor agonist (e.g., liraglutide, semaglutide, tirzepatide). In some embodiments, the drug is or includes apelin (e.g., [Pyrl]apelin-13, apelin-36, apelin-17, apelin-13). In some embodiments, the drug is or includes Vitamin B12. In some embodiments, the drug is or includes ibuprofen. In some embodiments, the drug is or includes amylin. In some embodiments, the drug is or includes insulin (including insulin degludec).

[0093] In some embodiments, the drug is or includes an analgesic, anesthetic, antiAlzheimer's agent, anti-asthma agent, anti -Parkinson’s agent, antiallergic, antianginal, antiarrhythmic, antiarthritic, antiasthmatic, antibacterial, antibiotic, anticancer, anticoagulant, anti-depressant, antidiabetic, antiemetic, antiepileptic, antifungal, antiglaucoma, anti-gout, antihistamine, antihyperprolactinemia, antihypertensive, anti-inflammatory, anti-migraine, anti-neoplastic, antiobesity, antiparasitic, anti -protozoal, anti-pyretic, antipsoriatic, antipsychotic, antithrombotic, antiulcer, antiviral, anxiolytic, benign prostatic hypertrophy, bronchodilator, calcium hormone or supplement, cardiotonic, cardiovascular agent, chelator, antidote, chemopreventive agent, contraception, diuretic, dopaminergic agent, gastrointestinal agent, gastroprokinetic, hematopoiesis, hemophilia, hormone, hormone replacement therapy, hypnotic, hypocholesterolemic, hypolipidemic, immunomodulator, immunostimulant, immunosuppressant, immunotherapy, lipid regulating agent, male sexual dysfunction medication, multiple sclerosis, muscle relaxant, neuroleptic, nootropic, anti-osteoportic, phytoestrogen, platelet aggregation inhibitor, prostaglandin, radioenhancer for radiotherapy, muscle relaxant, sedative, tranquilizer, and stimulant, respiratory distress syndrome, vasodilator, or vitamin, or any combination of any two or more thereof.

[0094] In some embodiments the drug is or includes a vaccine antigen or an antibody useful for passive immunization, or any combination of any two or more thereof.

[0095] In embodiments comprising more than one drug, two or more drugs may be formulated together in the same microneedle formulation (such that one microneedle contains the two or more drugs) or different drugs may be formulated in different microneedle formulations used to prepare a single microneedle patch (such that one set of microneedles contains Drug(s) A and another set of microneedles contains Drug(s) B, etc.). In either case, the drugs may be formulated to exhibit the same or different release profiles, for example, by independently varying one or more of the relative amount of drug, drug particle size, identity of other components, and relative amounts of other components.Microneedle Formulations

[0096] The microneedles described herein are formed from a polymerizable / curable biocompatible polymeric material (e.g., biocompatible resin material), drug in particulate form, and surfactant (and, optionally, cosurfactant), which may initially be prepared as a flowable material (also referred to below as a “casting paste”) that may be cast into microneedle molds or used as a 3D printing ink, and then hardened (e.g., cured), to form microneedles that have a generally solid structure with drug particles and surfactant (and optionally, cosurfactant) dispersed throughout an insoluble (e.g., rigid) polymerized / cured polymer matrix (e.g., polymerized biocompatible resin), forming an interconnected drug network facilitated by the surfactant and optional cosurfactant throughout the polymer matrix and extending to surfaces of the microneedles.

[0097] As used herein, the term “flowable polymerizable / curable biocompatible polymer material” refers to a flowable polymeric material that is amenable to one or both of polymerization and curing to form a rigid material, such as through one or more of polymerization and crosslinking of its constituents. In some embodiments, the flowable polymerizable / curable biocompatible polymer material is a polymerizable / curable biocompatible resin material that is converted to a generally solid (e.g., rigid) material by polymerization and / or curing, such as by photocuring. Thus, in some embodiments, thepolymerizable / curable biocompatible polymeric material is a material that is initially in a flowable state and can be polymerized / cured (such as by photocuring) to arrive at a generally solid (e.g., rigid) As used herein, the term “polymerized / cured biocompatible polymer material” refers to the biocompatible polymer material in its polymerized / cured (e.g., rigid) state.

[0098] In some embodiments, the polymerizable / curable biocompatible polymeric material is a Class I resin material. In some embodiments, the polymerizable / curable biocompatible polymeric material is a Class Ila resin material (e.g., having long-term biocompatibility with high resistance to fracture). In some embodiments, the polymerizable / curable biocompatible polymeric material is a USP Class VI resin.

[0099] For example, a dental resin may be used. For example, suitable dental resins include synthetic resins comprising one or more of the following components: bis- glycidyl methacrylate (Bis-GMA), ethoxylated bisphenol A (EO-BPA), butyl acrylate (BA), 2-ethylhexyl acrylate (2 -EHA), glacial acrylic acid (GAA), methyl methacrylate (MMA), ethyl methacrylate (EMA), hydroxyethyl methacrylate (HEMA), triethylene glycol dimethacrylate (TEGDMA), urethane dimethacrylate (UDMA). Suitable resins may further include one or more other components, such as a filler material such as silica, a flowing agent such as dimethylglyoxime, and / or a photoinitiator. An example dental resin is Dental SG resin (NextDent). Other suitable types of curable biocompatible resins include, but are not limited to, Ortho Rigid (NextDent), 2000-MW Series Medical adhesive (DyMax), BioMed Clear Resin (FormLab), Biomed Amber Resin (FormLab), Dental LT Clear Resin (FormLab), Surgical Guide Resin (FormLab), and Dental SG resin (FormLab). In some embodiments, the biocompatible resin material comprises one or more selected from chitosan, chitosan polybutylene adipate terephthalate, poly(butylene adipate-co-terephthalate), polyethylene glycol, poly(ethylene glycol) diacrylate, gelatin, gelatin methacryloyl, polyvinyl alcohol, and silk. Other materials that may be used to fabricate the microneedles may include, but are not limited to, polylactic acid (PLA), polyvinyl alcohol (PVA), poly(ethylene glycol diacrylate) (PEGDA), and polymers curable by ultraviolet radiation.

[0100] As noted above, the flowable material (e.g., casting paste) also includes a surfactant and, optionally, a cosurfactant. The surfactant(s) and cosurfactant(s) may be selected to have an average hydrophilic-lipophilic balance (HLB) value selected to improve one or more properties such as drug loading, delivery / distribution, and release kinetics of the drug being formulated. In this regard, because drugs have varying levels of hydrophilicity and hydrophobicity, the HLB values of the surfactant(s) and, optionally, cosurfactant(s) can be selected and tailored for the drug(s) being formulated. Based on HLB values, surfactants are classified into hydrophilic (HLB >10) and hydrophobic (HLB 1-10) surfactants. Hydrophilic surfactants can reduce the surface tension in aqueous systems, while hydrophobic surfactants have more affinity for nonaqueous systems. As noted above, in embodiments disclosed herein, the microneedle formulations may include a blend of high and low HLB value surfactant(s) and, optionally, cosurfactant(s) to improve drug solubilization and interfacial tension. While not wanting to be bound by theory, the addition of an optional cosurfactant is believed to decrease the blending stress at the interface by accumulating at the interfacial layer.

[0101] The surfactant typically is an amphiphilic liquid at 35°C, and may be a nonionic hydrophilic liquid surfactant. The non-ionic hydrophilic liquid surfactant preferably has an average HLB value >10 (including an average HLB value of about 12 to about 15). Nonionic hydrophilic surfactants include, but are not limited to, sorbitan esters (e.g., Span 20, Span 40, and Span 80), , polysorbates (e.g., polyoxyethylene sorbitan monooleate, TWEEN® 20, TWEEN® 40, TWEEN® 60, or TWEEN® 80), cremophor, D-u-tocopheryl polyethylene glycol succinate (Vitamin E TPGS), fatty acid esters (e g., cetyl alcohol and steryl alcohol), alkyl polyglycosides such as an alkyl polyglucoside, aliphatic alcohol- based non-ionic surfactants such as aliphatic alcohol ethoxylates, and siloxane polyalkyleneoxide copolymers (e.g., SILWET™ L-7604). The surfactant may be a combination of two or more surfactants.

[0102] The surfactant(s) may be present in the flowable material in any suitable amount to achieve the effects disclosed herein. For example, the surfactant(s) may be present in the flowable material in an amount of about 1 wt.% to about 35 wt.%, or any value therebetween, including from about 1 wt.% to about 15 wt.%, or any value therebetween, based on the total weight of the flowable material. This includes about 1wt.%, 2 wt.%, 3 wt.%, 4 wt.%, 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, 9 wt.%, 10 wt.%, 11 wt.%, 12 wt.%, 13 wt.%, 14 wt.%, 15 wt.%, and any value therebetween, all based on the total weight of the flowable material. In some embodiments, the surfactant (e.g., one or more surfactants) is present in the flowable material in an amount of about 3 wt.% to about 10 wt.%, or about 4 wt.% to about 10 wt.%, or about 5 wt.% to about 10 wt.%, based on the total weight of the flowable material. In some embodiments, the surfactant (e.g., one or more surfactants) is present in the flowable material in an amount up to about 35 wt.%, including about 32 wt.%, based on the total weight of the flowable material. For example, a greater amount of surfactant may be used when the drug is difficult to formulate, e.g., where the drug exhibits a low aqueous solubility. In general, the upper limit on the relative amount of surfactant (and optional cosurfactant) may be dictated by the need for an amount of polymerizable / curable polymeric material that will form a microneedle with required / desired structural properties, as discussed below.

[0103] The decision to use an optional cosurfactant in the microneedle formulation may depend on the drug being formulated. For example, a cosurfactant (also known in the art as a cosolvent) may be used when the drug exhibits low aqueous solubility, such as to enhance solubilization and bioavailability of the drug. Additionally, cosurfactants may improve the stability and efficacy of the formulation under various conditions. The presence of a cosurfactant may also be advantageous in situations where it can modify interfacial properties and improve the overall performance of the surfactant system. When used, the cosurfactant is typically selected for its compatibility with the surfactant(s) to ensure formulation stability and efficacy. The cosurfactant may be a non-ionic lipophilic cosurfactant. The non-ionic lipophilic cosurfactant preferably has an average HLB value <10 (including an average HLB value of about 2 to about 6). Suitable non-ionic lipophilic cosurfactants include, but are not limited to, propylene glycol, glycerin, isopropyl alcohol, diethylene glycol monoethyl ether (e.g., TRANSCUTOL® HP purified EP / NF, TRANSCUTOL® P), polyethylene glycols (e.g., PEG200, PEG400, PEG600), polyethylene glycol 12-hydroxystearate (Solutol HS15), castor oil derivatives including PEG-40 hydrogenated castor oil, ethoxylated vegetable oil derivatives (e.g., PEG-conjugated vegetable oils), propylene glycol monocaprylate (e.g., CAPRYOL™ PGMC type I NF), glyceryl monooleate (GMO), oleyl alcohol, isopropylmyristate (IPM), diisopropyl adipate, ethyl oleate, and lauryl lactate. The cosurfactant may be a combination of two or more cosurfactants.

[0104] When a surfactant and cosurfactant are used, any suitable combination of surfactant and cosurfactant as disclosed herein may be used, such as one or more of the foregoing surfactants and one or more of the foregoing cosurfactants. For example, the surfactant may comprise a sorbitan ester (e.g., polyoxyethylene sorbitan monooleate, TWEEN® 20, TWEEN® 40, TWEEN® 60, or TWEEN" 80) and the cosurfactant may comprise propylene glycol, glycerin, isopropyl alcohol, diethylene glycol monoethyl ether (e.g., TRANSCUTOL® HP purified EP / NF, TRANSCUTOL® P), a polyethylene glycol, Solutol HS15, a castor oil derivative, an ethoxylated vegetable oil derivative, propylene glycol monocaprylate (e.g., CAPRYOL™ PGMC type I NF), glyceryl monooleate (GMO), oleyl alcohol, isopropyl myristate (IPM), diisopropyl adipate, ethyl oleate, or lauryl lactate. For example, a sorbitan ester may be used with a polyethylene glycol and / or a di ethylene glycol monoethyl ether. For example, the surfactant may be TWEEN® 80 and the cosurfactant TRANSCUTOL® HP.

[0105] In another example surfactant / cosurfactant combination, the surfactant may comprise a polysorbate and the cosurfactant may comprise propylene glycol, glycerin, isopropyl alcohol, diethylene glycol monoethyl ether (e.g., TRANSCUTOL® HP purified EP / NF, TRANSCUTOL® P), a polyethylene glycol, Solutol HS15, a castor oil derivative, an ethoxylated vegetable oil derivative, propylene glycol monocaprylate (e.g., CAPRYOL™ PGMC type I NF), glyceryl monooleate (GMO), oleyl alcohol, isopropyl myristate (IPM), diisopropyl adipate, ethyl oleate, or lauryl lactate. For example, a polysorbate may be used with a polyethylene glycol and / or a diethylene glycol monoethyl ether

[0106] In another example surfactant / cosurfactant combination, the surfactant may comprise a cremophor and the cosurfactant may comprise propylene glycol, glycerin, isopropyl alcohol, diethylene glycol monoethyl ether (e.g., TRANSCUTOL® HP purified EP / NF, TRANSCUTOL® P), a polyethylene glycol, Solutol HS15, a castor oil derivative, an ethoxylated vegetable oil derivative, propylene glycol monocaprylate (e.g.,CAPRYOL™ PGMC type I NF), glyceryl monooleate (GMO), oleyl alcohol, isopropyl myristate (TPM), diisopropyl adipate, ethyl oleate, or lauryl lactate. For example, a cremophor may be used with a polyethylene glycol, propylene glycol, and / or Solutol HS15.

[0107] In another example surfactant / co surfactant combination, the surfactant may comprise an alkyl polyglucoside and the cosurfactant may comprise propylene glycol, glycerin, isopropyl alcohol, diethylene glycol monoethyl ether (e.g., TRANSCUTOL® HP purified EP / NF, TRANSCUTOL® P), a polyethylene glycol, Solutol HS15, a castor oil derivative, an ethoxylated vegetable oil derivative, propylene glycol monocaprylate (e.g., CAPRYOL™ PGMC type I NF), glyceryl monooleate (GMO), oleyl alcohol, isopropyl myristate (IPM), diisopropyl adipate, ethyl oleate, or lauryl lactate.

[0108] In another example surfactant / cosurfactant combination, the surfactant may comprise Vitamin E TPGS and the cosurfactant may comprise diethylene glycol monoethyl ether and / or Solutol HS 15.

[0109] In specific embodiments, the surfactant is or comprises polyoxyethylene sorbitan monooleate, such as TWEEN® 80. In specific embodiments, the cosurfactant is or comprises diethylene glycol monoethyl ether, such as TRANSCUTOL® HP. In further specific embodiments, the surfactant is polyoxyethylene sorbitan monooleate, such as TWEEN® 80, and the cosurfactant is diethylene glycol monoethyl ether, such as TRANSCUTOL® HP.

[0110] The cosurfactant(s) may be present in the flowable material in any suitable amount to achieve the desired effect(s). For example, the cosurfactant(s) may be present in the flowable material in an amount of about 1 wt.% to about 35 wt.%, or any value therebetween, including from about 1 wt.% to about 15 wt.%, or any value therebetween, based on the total weight of the flowable material. This includes about 1 wt.%, 2 wt.%, 3 wt.%, 4 wt.%, 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, 9 wt.%, 10 wt.%, 11 wt.%, 12 wt.%, 13 wt.%, 14 wt.%, 15 wt.%, and any value therebetween, based on the total weight of the flowable material. In some embodiments, the cosurfactant (e.g., one or more co surfactants) is present in the flowable material in an amount of about 1 wt.% to about8 wt.%, or about 2 wt.% to about 6 wt.%, based on the total weight of the flowable material. Tn some embodiments, the cosurfactant (e.g., one or more cosurfactants) is present in the flowable material in an amount up to about 35 wt.%, including about 32 wt.%, based on the total weight of the flowable material. For example, a greater amount of cosurfactant may be used when the drug is difficult to formulate, e.g., where the drug exhibits a low aqueous solubility. As noted above, in general, the upper limit on the relative amount of surfactant and optional cosurfactant may be dictated by the need for an amount of polymerizable / curable polymeric material that will form a microneedle with required / desired structural properties, as discussed below.

[0111] The weight ratio of surfactant to cosurfactant (when used) may be selected to achieve a desired effect. In some embodiments, the weight ratio of surfactant to cosurfactant is from about 1 :8 to about 8: 1, or any value therebetween, including from about 1 :4 to about 4: 1, about 1 :2 to about 2: 1, and about 1 : 1, or any value therebetween. The relative amount of surfactant and cosurfactant may be selected based on the properties of the drug or drug particles being formulated.

[0112] As noted above, in general, the upper limit on the relative amount of drug, surfactant and optional cosurfactant may be dictated by the need for an amount of polymerizable / curable polymeric material that will form a microneedle with required / desired structural properties. Tn general, the flowable material (casting paste) may comprise polymerizable / curable polymeric material in an amount from about 30 wt.% to about 70 wt.%, including from about 40 wt.% to about 60 wt.%, with the balance of the flowable material being comprised of drug particles, surfactant, optional cosurfactant, and any other optional components disclosed above. For example, the flowable material may include the polymerizable / curable polymeric material (e.g., unpolymerized resin material) in an amount of about 30 wt.%, about 40 wt.%, about 50 wt.%, about 55 wt.%, about 60 wt.%, about 65 wt.%, about 70 wt.%, or any value therebetween. Conversely, in general, the flowable material (casting paste) may comprise drug particles in an amount up to about 70 wt.%, up to about 60 wt.%, up to about 50 wt.%, or up to about 40 wt.%, such as from about lwt.% to about 70 wt.%, or from about 5 wt.% to about 40 wt.%, or any value therebetween, including about 1 wt.%, about 2wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 10 wt.%, about 15 wt.%, about 20 wt.%, about 25 wt.%, about 30 wt.%, about 35 wt.%, about 40 wt.%, about 45 wt.%, about 50 wt.%, about 55 wt.%, about 60 wt.%, about 65 wt.%, about 70 wt.%, or any value therebetween. Thus, in some embodiments, the ratio of polymerizable / curable polymeric material to drug particles in the flowable material is from about 4:1 to about 1 :4, including from about 3.5: 1 to about 1 :3.5, including about 1: 1. It should be understood, however, that in some embodiments, the relative amount of drug particles can be greater. For example, drug particles with a smaller particle size generally can be formulated in a higher relative amount (based on weight), because they occupy less volume than drug particles with a smaller particle size. For similar reasons, a greater amount (by weight) of drug particles with a smaller particle size may be required to achieve a flowable mixture (casting paste) of a desired viscosity to form microneedles having an interconnected drug network as described herein.

[0113] As discussed above, the amount of surfactant and optional cosurfactant may depend on the properties of the drug (or drug particle) being formulated. In some embodiments, the total amount of both surfactant and optional cosurfactant ranges from 1% to 55 wt.%, based on the total weight of the flowable material. In some embodiments, the total amount of both surfactant and optional cosurfactant is about 33% wt.%, about 35% wt.%, about 40% wt.%, about 45% wt.%, about 50% wt.%, or about 55% wt.%, all based on the total weight of the flowable material. In specific embodiments, a ratio of polymerizable / curable polymeric material to drug to surfactant to cosurfactant is about 6:4: 1 : 1, about 6:6: 1:1, about 3: 1 :0.25:2, about 10:6:2:2, about 9:7:2:2, or about 8:7:2.5:2.5, or about 8: 1 : 11 (surfactant and optional cosurfactant combined). In specific embodiments, a ratio of polymerizable / curable polymeric material to drug to surfactant is about 6:3 :0.5. In specific embodiments, a ratio of polymerizable / curable polymeric material to drug to surfactant to cosurfactant is about 6:6: 1 : 1 and the drug particles have a particle size distribution having a D(10) greater than or equal to about 2 pm, a D(50) of from about 2 pm to about 25 pm, and a D(90) less than or equal to about 25 pm, including a particle size distribution having a D(10) greater than or equal to 2 pm, a D(50) of 2 pm to 25 pm, and a D(90) less than or equal to 50 pm.

[0114] In some embodiments, to fabricate the microneedles, drug particles are combined with (e.g., blended with) other components of the flowable material to obtain a dispersion (e.g., a casting paste). In some embodiments, the drug particles are insoluble or substantially insoluble in the flowable material. In some embodiments, the drug particles are formulated in the flowable material in a solid state, but may dissolve or partially dissolve in the flowable material. In some embodiments, the drug particles are hydrophilic and the flowable material is hydrophobic.Microneedle Structure

[0115] As noted above, once formed, the microneedles described herein comprise a generally solid composite material comprised of insoluble (e.g. rigid) polymerized / cured polymeric material (e.g., polymerized resin), drug in particulate form, and surfactant (and, optionally, cosurfactant). In the formed microneedles (e.g., after polymerizing / curing), the surfactant (and optional cosurfactant) may be in a liquid state in the microneedle structure. In the formed microneedles (e.g., after polymerizing / curing), the drug particles may be in a dry state in the microneedle structure.

[0116] The microneedle formulations described herein provide formability and shape replication properties that are advantageous in the preparation of microneedles. As noted above, in some embodiments, surfactant (e.g., liquid surfactant) (and, optionally, cosurfactant) may essentially fill all gaps between the solid drug particles and and / or interstices between solid drug particles and the insoluble polymer matrix. Thus, in some embodiments, substantially all of the solvent-accessible volume of the microneedle is occupied by drug particles, surfactant, and, optionally, cosurfactant. For purposes of this disclosure, “solvent-accessible volume” refers the maximum volume of a suitable solvent, e.g., water or interstitial fluid, absorbed by a microneedle immersed in that solvent.

[0117] The fabricated microneedles are resistant to breakage, such as having a high Young's modulus (10 to 1000 times higher than human skin) and can effectively penetrate a variety of skin types without breaking. For example, the fabricated microneedles may have a Young’s modulus of about 1 GPa to about 2 GPa (e.g., 1.1 GPa, 1.2 GPa, 1.3 GPa, 1.4 GPa, 1.5 GPa, 1.6 GPa, 1.7 GPa, 1.8 GPa, or 1.9 GPa).

[0118] The hardness of the microneedles is derived from the mechanical properties of the polymerized biocompatible material (e.g., polymerized resin) and the inclusion of solid drug particles (e.g., dry particles) within the polymerized polymer matrix, which promotes rigidity and hardness for effective skin penetration, e.g., for resistance to breakage during skin penetration. The fabricated microneedles may have a hardness of at least about 40 Shore A. In some embodiments the hardness of the fabricated microneedles is between 40 Shore A and 90 Shore D. In some embodiments the hardness of the fabricated microneedles is between 20 Shore D and 80 Shore D. In some embodiments the hardness of the fabricated microneedles is between 30 Shore A and 80 Shore D. In some embodiments the hardness of the fabricated microneedles is between 40 Shore A and 60 Shore A. In some embodiments the hardness of the fabricated microneedles is at least about 50 Shore D, providing resistance to deformation.

[0119] FIG. 1 shows an array of microneedles in accordance with an aspect of the present disclosure. The microneedles can form and maintain an exceptionally sharp tip. In some embodiments, the fabricated microneedles maintain a tip radius of less than 5 pm, providing effective skin penetration without substantial microneedle damage. The use of drug particles of a fine particle size (e.g., with a particle size distribution having a D(50) less than 5 pm) and the flowability of the flowable mixture (casting paste) facilitates excellent shape reproduction from the mold, resulting in microneedle that is an almost exact copy of the mold with a sharp tip. In this regard, flowability of the casting paste can be controlled by adjusting the drug particle size and the polymeric material (e.g., resin) mixing ratio.

[0120] In some embodiments, the axial length of the microneedle (i.e., as measured from the apex [i.e., sharp point] to the base) 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. Insome 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. Tn some embodiments, the axial length is between 0.1 mm and 0.5 mm.Back Substrate

[0121] The microneedles may have a material attached to the base(s) of one or more microneedles for supportive purposes, e.g., to provide an adhesive backing and / or to position multiple microneedles in an array, herein referred to as the back substrate. In some embodiments, the back substrate can be, or can comprise, a thin support, such as a thin elastic material. In some embodiments, the back substrate can be, or can comprise, a flexible adhesive. In some embodiments, the back substrate can be, or can comprise, a woven material. In some embodiments, the back substrate can be, or can comprise, a film. In some embodiments, the back substrate can be, or can comprise, a bandage or dressing. In some embodiments, the back substrate can be, or can comprise, a biodegradable material. In some embodiments the back substrate can act as an intermediate adhesive to a larger patch for clinical application. In some aspects, the material used to form the back substrate is or includes any polymerizable / curable biocompatible polymer material as described herein for use in a flowable mixture used to form microneedles (e.g., any polymerizable / curable biocompatible resin). In some aspects, the material used to form the back substrate is or includes the same polymerizable / curable biocompatible polymer material present in the flowable material used to form the microneedle(s) on which the back substrate is provided. In some aspects, the material used to form the back substrate is or includes the same material as the flowable material used to form the microneedle(s) on which the back substrate is provided (e.g., including the surfactant, optional cosurfactant, and drug). Thus, in some embodiments the back substrate can be a continuation of the same composite material comprising the microneedles (e.g., as shown in FIG. 8). In some aspects, the material used to form the back substrate is or includes the same polymerizable / curable biocompatible polymer material present in the flowable material used to form the microneedle(s) on which the back substrate is provided, and optionally includes one or more other components present in the flowable material, e.g., one or more of the surfactant(s), optional cosurfactant(s), and drug(s). In some aspects, the material used toform the back substrate is or includes the same polymerizable / curable biocompatible polymer material present in the flowable material used to form the microneedle(s) on which the back substrate is provided, and includes one or more or all non-drug components present in the flowable material, e.g., one or more or all of the surfactant(s), optional cosurfactant(s), and any other non-drug excipients. In some embodiments the back substrate can be a secondary, drug-loaded material, including a drug-loaded composite material as described herein. In some embodiments, the back substrate comprises a detectable marker, such as a fluorescent dye, to facilitate quality control (QC).

[0122] In some embodiments, the content and / or relative amounts of components varies across the structure of the microneedle, e.g., from back substrate to base to tip, or any subregion thereof. For example, the tip of the microneedle may contain a relatively high amount of drug particles per unit area while the base and / or back substrate may contain little or no drug particles. Additionally or alternatively the tip may contain a relatively high amount of surfactant(s) and optional cosurfactant(s), while the base and / or backing substrate may contain lower amounts, or none. In some embodiments, the amount of one or more or all of the surfactant(s), optional cosurfactant(s), and drug(s) varies across the length of the microneedle from base to tip, with greater amount(s) near the tip and lower amounts near the base. In some embodiments, the microneedle may have defined regions wherein a first region includes a first amount of surfactant(s), optional cosurfactant(s), and drug(s); a second region includes a second amount of surfactant(s), optional cosurfactant(s), and drug(s); a third region includes a third amount of surfactant(s), optional cosurfactant(s), and drug(s); and so forth.

[0123] A microneedle or array of microneedles carried on a back substrate may be referred to herein as a “microneedle patch.”

[0124] A microneedle patch or other array of microneedles may include any suitable number of microneedles, such as from about 10 microneedles to about 1100 microneedles, or from about 100 to about 1100 microneedles. The microneedles may be arranged at any suitable density, such as from about 10 microneedles per cm2to about 150 per cm2, or any value therebetween. Typically, the microneedles of a patch or other array will be spaced about0.5 mm apart, about 1 mm apart, or about 2 mm apart, as measured tip to tip. The microneedles may be spaced about 0.5 mm apart, about 1 mm apart, about 1.1 mm apart, about 1.2 mm apart, about 1.3 mm apart, about 1.4 mm apart, about 1.5 mm apart, about 1.6 mm apart, about 1.7 mm apart, about 1.8 mm apart, about 1.9 mm apart, about 2.0 mm apart, or any value including and / or in-between any two of these values. Additionally or alternatively, spacing between microneedles may be proportional to microneedle height. For example, the ratio of microneedle height to microneedle spacing may be from about 0.5 : 1 to about 1 : 1, including about 0.7 : 1.

[0125] Typically, a microneedle patch or other array of microneedles may include about 100 microneedles per cm2. It should be understood, however, that the number of microneedles per patch (or other array) may be selected based on the drug being formulated and dose to be delivered. Thus, drugs requiring a smaller dose may be formulated in patches with a relatively low number of microneedles, while drugs requiring a larger dose may be formulated in patches with a relatively high number of microneedles.

[0126] The microneedles disclosed herein permit high drug loading capacity, due in part to the ability to formulate the drug without solvent. For example, as discussed in more detail below, the microneedles may be formed from a flowable material that comprises from about 1 wt.% to about 70 wt.% drug particles, including from about 5 wt.% to about 40 wt.%, drug particles, which will result in a microneedle having a solid composite structure that is comprised of from about 1 wt.% to about 70 wt.% drug particles, or from about 5 wt.% to about 40 wt.% drug particles, respectively. In some aspects, the drug loading capacity may be picograms to milligrams per microneedle (for example 20 micrograms or more of drug substance per 70 nanoliter, which may be a typical approximate volume of one microneedle) or picograms to grams per patch. The microneedles also provide reliable skin penetration.

[0127] A polymer that makes a strong bond with the microneedles may be used as a material to form the back substrate. The material used to form the back substrate may be rigid or flexible depending on the intended application. Suitable flexible materials include, but are not limited to, paper, textile, polyether ether ketone (PEEK), polyethylene terephthalate(PET), polyethylene naphthalate (PEN), polytetrafluoroethylene (PTFE), parylene, and polyimide. Elastic and flexible resins may also be used (e.g., Elastic 50A Resin (Part Number: FLELCL01), Flexible 80A Resin (Part Number: FLFL8001)). UV curable resins may also be used, such as when there is a need for conformality, flexibility, and elasticity in a microneedle patch. As noted above, in some aspects, the material used to form the back substrate is or includes the same polymerizable / curable biocompatible polymer material present in the flowable material used to form the microneedle(s) on which the back substrate is provided. Hard resins may be used for applications having a need for rigid back substrates. A suitable example of a hard resin includes, but is not limited to, Surgical Guide Resin (Part Number: FLSGAM01).

[0128] In some embodiments, wherein the back substrate is planar or substantially planar, the “planar area” of the microneedle patch can be calculated as the area of the patch in the plane defined by the back substrate. In some such embodiments, the “microneedle planar area” of the patch can be calculated as the area of a regular or irregular polygon, wherein the polygon is defined as that having the largest area circumscribed by the locus of all lines: (1) in the plane of the back substrate and (2) that connect all microneedles in pairs. Stated more plainly, but without wishing to modify the foregoing geometric definition, the microneedle planar area 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 cm2. In some embodiments, the planar microneedles area 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, or 225 cm2. In some embodiments, the planar area of the patch is between about 0.1 and 1, 1 and 5, 1 and 10, 5 and 10, 10 and 20, 10 and 100, 20 and 50, 50 and 100, 100 and 150, 150 and 200, or 200 and 250 cm2. In some embodiments, the planar microneedle area of the patch is between about 0.1 and 1, 0.5 and 100, 1 and 5, 1 and 10, 5 and 10, 10 and 20, 10 and 100, 20 and 50, 50 and 100, 100 and 150, 150 and 200, or 200 and 250 cm2.Microneedle Fabrication

[0129] The microneedles disclosed herein can be made by methodologies known in the art, adapted in view of the present disclosure. One non-limiting example of a process to make microneedles as disclosed herein is set forth in FIGs. 4 through 8. FIG. 4 shows a flowable material 10, including an unpolymerized polymerizable / curable biocompatible polymeric material (e.g., unpolymerized resin), surfactant (and, optionally, cosurfactant), in which is dispersed a drug in particulate form 12 (better seen diagramatically in the enlarged area of FIG. 4). The flowable material 10 may be prepared by mixing unpolymerized polymerizable / curable biocompatible polymer material (e.g., unpolymerized resin), surfactant, and, optionally, cosurfactant, with the drug in particulate form 12. In some embodiments, the flowable material may be prepared by first preparing a mixture of the non-drug components of the flowable material, and then adding the drug in particulate form. In some embodiments, the flowable material may be prepared by first mixing the surfactant, cosurfactant (if present), and drug in particulate form, and then combining with the unpolymerized polymerizable / curable biocompatible polymeric material (e.g., unpolymerized resin). In the discussion that follows, the flowable material containing drug in particulate form is referred to as a “casting paste.”

[0130] Mixing may be accomplished by any suitable method. The mixing process may be performed under ambient conditions. Optionally, the drug in particulate form may be added and mixed gradually or step-wise in small additions with mixing in between to evenly disperse the drug.

[0131] As noted above, the drug in particulate form (e.g., dry drug powder) is nonnally not soluble in the polymeric component(s) of the flowable material (e.g., unpolymerized resin). Thus, combining the drug in particulate form with the other components of the flowable material may obtain a paste-like dispersion (the casting paste), which can be cast into a mold. Casting and curing of such a paste creates a generally solid composite material that includes, for example, hard-cured polymerized resin matrix and drug particles forming an interconnected drug network facilitated by the surfactant and optional cosurfactant throughout the polymer matrix and extending to surfaces of the microneedles.

[0132] As illustrated in FIG. 5, once prepared, the casting paste is cast onto a mold 14 comprising cavities 16 having the inverse shape of a microneedle array. As shown in FIG. 6, the casting paste comprising flowable material 10, for example, including unpolymerized resin, surfactant (and, optionally, cosurfactant), in which is dispersed drug in particulate form 12 fills the cavities.

[0133] FIG. 7 illustrates curing of the casting paste comprising flowable material 10, including, for example, unpolymerized resin, surfactant (and, optionally, cosurfactant), in which is dispersed a drug in particulate form 12 in the mold 14, for example, by photocuring. FIG. 8 illustrates cured polymeric material (e.g., polymerized resin) 20 that still includes the drug particles 12 removed from the mold, retaining needle-like shapes 22 (e.g., microneedle structures) from the mold cavities. FIG. 9 illustrates diagrammatically that the cured polymeric material (e.g., polymerized resin) 20 of each needle 22 includes undissolved drug particles 12 within the cured polymeric material 20. As discussed above, the cured polymeric material (e.g., polymerized resin) may have a hardness of at least about 40 Shore A, or any value discussed above.

[0134] The molds used to make the microneedles may be prepared by any suitable methodology. For example, molds may be formed using cross-over lines (COL) laser lithography to make microneedles that combine the benefits of both hard and soft microneedles, as disclosed in WO 2019 / 203888. As another example, molds may be 3D printed using any suitable material as the 3D printing “ink.”

[0135] FIG. 10 shows an array of microneedles 22 carried on a bandage 30 that includes adhesive areas 32.

[0136] Turning to FIG. 11, some methods of fabricating a microneedle mold 100, microneedles 102, and a microneedle patch 104 in accordance with the present disclosure are shown. Fabrication of the microneedle mold 100 may begin with laser cutting one or more microneedle-shaped depressions 106 into a first material in a crossover line pattern using the cross-over-lines (COL) fabrication procedure (see WO 2019 / 203888) to provide a first mold 108. A second material may be cast onto the first mold 108 to fill the microneedle-shaped depressions 106 with the second material. Subsequent curing of thesecond material may provide a second mold 110 having one or more microneedles 112 formed within the microneedle-shaped depressions 106. The cured second mold 110 may be removed from the first mold 108, and a surface of the cured second mold 110 may undergo plasma treatment to activate the surface 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(lH, lH,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 the microneedle mold 100 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 an ultra-elastic silicone rubber such as EcoFlex™.

[0137] With continued reference to FIG. 11, fabrication of the microneedles 102 and the microneedle patch 104 will now be described. The use of an ultra-elastic microneedle mold 100 enables the microneedle mold 100 to be stretched to facilitate embedding a highly viscous casting paste into the mold 100. Additionally, utilizing an ultra-elastic mold may decrease the microneedle fabrication time drastically by avoiding a vacuuming procedure to embed the casting paste into the tiny microneedle needle-forming cavities of the mold. As shown in FIG. 11, the microneedle mold 100 may be stretched beyond its original size to expand the size of the microneedle-forming cavities 114. A casting paste mixture 116 (e.g., comprising drug particles, a biocompatible unpolymerized resin, a surfactant, and, optionally, a cosurfactant), may be cast on the microneedle mold 100 such that the mixture 116 fills the expanded microneedle-forming cavities 114.

[0138] The microneedle mold 100 may be allowed to relax / contract to its original size (e.g., unstretched state), and the biocompatible polymeric material (e.g., unpolymerized resin may be cured to provide the microneedles 102. In some embodiments, the unpolymerized resin may be photocured, such as by exposure to ultraviolet light. In one embodiment, the unpolymerized resin is photocured by exposure to 405 nanometer (nm) light. In any embodiments, the resulting microneedles 102 may be a generally solidcomposite material with drug particles and surfactant (and optional cosurfactant) distributed throughout the microneedles 102, forming an interconnected drug network. See, e.g., FIG. 2.

[0139] A polymerizable / curable biocompatible polymer material 118 may be cast on the microneedle mold 100 over the microneedles 102 to provide back substrate 120, as shown in FIG. 11. Curing the polymerizable / curable biocompatible polymer material 118 may provide microneedle patch 104 having back substrate 120 bonded to microneedles 102. In some embodiments, the polymerizable / curable biocompatible polymer material may be photocured, such as by exposure to ultraviolet light. The microneedle patch 104 may then be removed from the microneedle mold 100. A back substrate 120 may be configured to conformably adapt to curvature of skin of any body part for application of the microneedle patch 104 to any body part.

[0140] In one aspect, the present disclosure provides a method of fabricating a microneedle for transdermal drug delivery. The method can include one or more or all of the following steps: stretching a microneedle mold having at least one microneedleforming cavity to expand a size of the at least one microneedle-forming cavity; and casting a flowable mixture as described herein (e.g., comprising drug particles and a polymerizable / curable biocompatible polymer material (e.g., biocompatible resin material), surfactant, and, optionally, cosurfactant), on the microneedle mold such that the mixture fills (or partially fills) the expanded microneedle-forming cavity (wherein the drug particles optionally may have a D(50) particle size of 100 nm to 100 pm, or from 500 nm to 100 pm, or having a particle size distribution as discussed above); allowing the microneedle mold to contract to an original size of the microneedle mold; curing the mixture in the microneedle-forming cavity to provide the microneedle, the microneedle having a generally solid structure with drug particles and surfactant (and optionally, cosurfactant) dispersed throughout an insoluble (e.g. rigid) polymerize / cured polymer matrix (e.g., polymerized resin), forming an interconnected drug network facilitated by the surfactant and optional cosurfactant and extending to the surface of the microneedles; and removing the microneedle from the microneedle mold.

[0141] In another aspect, the present disclosure provides a method of fabricating a microneedle patch for transdermal drug delivery. The method can include forming a microneedle as described above, but prior to removing the microneedle from the microneedle mold, and, optionally, prior to curing, casting a second polymerizable / curable biocompatible polymer material on the microneedle mold (which may be the same as or different from the polymerizable / curable biocompatible polymer material of the flowable mixture, or may be the same material as the flowable material), and the method further comprises curing the second polymerizable / curable biocompatible polymer material to bond it to the microneedle (or curing the microneedle material and the second polymerizable / curable biocompatible polymer material at the same time) to thereby provide a microneedle patch; and removing the microneedle patch from the mold.

[0142] In some embodiments, the microneedles may be prepared using drugcontaining flowable material to prepare the entire microneedle structure. In other embodiments, the microneedles may be prepared using drug-containing flowable material to prepare only a portion of the microneedle structure, for example, only a portion including the tip, or a portion from below the tip to the base, or any region thereof. Such embodiments may be advantageous when it is desired to minimize the amount of drug needed to prepare the microneedles, or to control the dose delivered by the microneedles, or to control the drug delivery rate, etc. In such embodiments, the microneedles may be prepared as described above, but only partially filling the mold with drug-containing flowable material and filling a remaining region of the mold with flowable material that does not include drug (and optionally does not include surfactant or cosurfactant). Additionally or alternatively, in some embodiments, the microneedles may be prepared as described above, only partially filling the mold with flowable material containing surfactant(s) and optional cosurfactant(s) and drug(s), filling another portion of the mold with flowable material containing surfactant(s) and optional cosurfactant(s) (but not drug), and, optionally, filling another portion of the mold with flowable material that does not include surfactant(s), cosurfactant(s), or drug. Thus, encompassed by the present disclosure are embodiments that include microneedles formed from alternating layers of flowable material in any desired configuration, e.g., drug / no-drug, drug / no-drug / drug / no-drug, or no-drug / drug / no-drug, drug with excipient / no-drug with excipient / drug without excipient / no-drug no-excipient, drug with excipient / drug without excipient / no-drug with excipient / no-drug no excipient, etc. (where “excipient” refers to one or more surfactant(s), optional cosurfactant(s), and other non-drug components). Such embodiments could be prepared by sequentially filling and curing each layer, or by filling all layers and then curing them. Likewise, microneedles can be prepared with a drugcontaining layers or regions having varying amounts of drug, such as microneedles having a gradient of drug loading from tip to base, such as having greater drug-loading near the tip, moderate drug loading in the middle, and less or no drug-loading near the base, etc. Such microneedles could be prepared from flowable materials having different concentrations of drug. Such embodiments could be prepared by sequentially filling and curing each layer, or by filling all layers and then curing them. Other permutations, combinations, and variations along these lines will be apparent to those skilled in the field based on this disclosure and are contemplated and encompassed herein.

[0143] As noted above, in embodiments comprising more than one drug, two or more drugs may be formulated together in the same microneedle formulation (such that one microneedle contains the two or more drugs) or different drugs may be formulated in different microneedle formulations used to prepare a single microneedle patch (such that one set of microneedles contains Drug(s) A and another set of microneedles contains Drug(s) B, etc ). Additionally, different microneedles within the same microneedle patch may vary in their design and characteristics. As a non-limiting example, microneedles containing Drug(s) A may have drug particles with a particle size distribution with a first D(10), D(50), and D(90), and microneedles containing Drug(s) B may have drug particles with a particle size distribution with a second D(10), D(50), and D(90), that reflects larger or smaller particles than the first. As another non-limiting example, microneedles containing drug(s) A may be formed using a flowable material having a first ratio of resin : drug : surfactant : optional cosurfactant, and microneedles containing drug(s) B may be formed using a flowable material having a second ratio of resin : drug : surfactant : optional cosurfactant, wherein one or the other or both may include a cosurfactant. As another non-limiting example, microneedles containing drug(s) A may be formed usingalternating layers in a configuration of drug / no-drug / drug / no-drug, and microneedles containing drug(s) B may be formed with a gradient of drug loading and excipients from tip to base with greater drug loading near the tip and higher concentration of excipients near the base, or one or the other may be prepared with uniform drug loading from tip to base. Other permutations, combinations, and variations along these lines will be apparent to those skilled in the field based on this disclosure and are contemplated and encompassed herein. This design flexibility offers many advantages, including permitting co-deliveiy of drugs that could be difficult to formulate in the same casting paste, and permitting independent dosing of different drugs via the same patch, which can be selected and controlled via the number and relative number of microneedles containing a given drug.

[0144] The methods described herein can also include additional steps relating to fabrication of the microneedle mold. Such additional steps can include: laser cutting one or more microneedle-shaped depressions into a first material to provide a first mold; casting a second material onto the first mold to fill the one or more microneedle-shaped depressions 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 microneedleshaped depressions; removing the cured second mold from the first mold; plasma treating a surface of the cured second mold having the one or more microneedles; applying a release layer to the surface of the cured second mold; casting a third material onto the surface of the cured second mold; curing the third material to provide the microneedle mold having the microneedle-forming cavity; and removing the microneedle mold from the cured second mold. The laser-cutting can include use of a crossover line pattern. The first material can be an acrylic sheet, the second material can be a silicone elastomer, and the third material can be an ultra-elastic silicone rubber. Applying the release layer can involve silanizing the surface of the cured silicone elastomer. The silanizing can be performed with trichloro(lH, lH,2H,2H-perfluorooctyl) silane.

[0145] The methods described herein can also include additional method steps relating to making the flowable mixture (casting paste). Such additional steps can include preparing the drug particles, including optionally grinding drug particles into fineparticles having a desired particle size / particle size distribution, e.g., around a D(50) of from 10 nm to 100 pm, or 100 nm to 100 pm, or 500 nm to 100 pm, or the more specific values discussed above. Such additional steps also can include preparing the flowable mixture by mixing the components as described above, in any suitable ratios / amounts as described above.

[0146] The curing steps of the methods described herein can be achieved by curing methods understood to those having ordinary skill in the polymeric arts, including but not limited to, photocuring via exposure to curing radiation, such as ultraviolet light and / or light having a wavelength of 405 nm.

[0147] As noted above, as an alternative to molding, flowable material (e.g., casting paste) as described herein can be used as the “ink” of 3D printing to form any desired structure (including microneedles).Use and Performance of Microneedles

[0148] FIGS. 12A and 12B show a microneedle 22 with drug in particulate form 12 in a rigid polymerized / cured polymer matrix 20 formed from polymerization / curing of the polymerizable / curable biocompatible polymer material, with the microneedle 22 applied to the skin and extending through the epidermis layer 34, into the dermis layer 36 and optionally into the subcutaneous layer 38. In accordance with various aspects, the drug may be located throughout the entire microneedle, or the drug may be provided in only select locations as described above. As shown with reference to FIG. 12B, over time, more drug is diffused into the dermal environment.

[0149] As discussed above, when first contacted with interstitial fluid (or other release media), drug particles on the surface of the microneedle will be released (e.g., dissolve and / or disperse) into the surrounding fluid. As these particles release, voids appear in their locations, creating pores and channels through which fluid penetrates further into the microneedle structure. Release of additional drug particles leads to the formation of additional pores and channels throughout the microneedle structure, and release and diffusion out of additional drug particles.

[0150] Over time, the microneedles release the drug into the dermal environment. As discussed above, with time (e.g., from about 1 hour to about 24 hours), complete or nearcomplete release and delivery of all drug may occur. Eventually, the spent microneedles have an open, porous structure devoid (or nearly devoid) of drug, as all or nearly all the drug has released from the microneedles and been delivered into the skin. Thus, the interconnected network of drug particles, which is facilitated by the surfactant (and optional cosurfactant), enables a more complete drug delivery process. In some embodiments, the microneedles disclosed herein are able to release 80% or more of the drug loaded therein, including 80%, 85%, 90%, 95%, 97%, or more. Advantageously for complete drug release, the drug particles and polymerizable / curable biocompatible polymer material (e.g., unpolymerized resin) are immiscible. Thus, as discussed above, a hydrophobic unpolymerized resin material may work most efficiently with water-soluble drugs, such as peptides, proteins, and monoclonal antibodies.

[0151] A drug-loaded microneedle array / patch as disclosed herein may be applied to the skin for any amount of time suitable or effective to achieve the desired drug delivery. For example, from less than 1 minute to between about 1 minute and about 5 minutes, to between about 5 and 30 minute, to between about 30 and 60 minutes, or longer. In some embodiments a drug-loaded microneedle array / patch may be applied to the skin for between about 1 and 24 hours, or any value therebetween. In some embodiments a drug-loaded microneedle array / patch may be applied to the skin for between about 1 and 10 hours, or any value therebetween, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours. In some embodiments a drug-loaded microneedle array patch may be applied to the skin for between about 8 and 12 hours. In some embodiments a drug-loaded microneedle array patch may be applied to the skin for 12 to 24 hours, or longer. In some embodiments the drug-loaded microneedle array patch may be applied to the skin for between about 6 and 10 hours. In some embodiments a drug-loaded microneedle array patch may be applied at night and removed the following morning. In some embodiments the microneedles may be in place for a longer period of time.

[0152] Microneedles as disclosed herein and patches containing them may be designed and constructed to provide desirable in vivo pharmacokinetic profiles. As discussed herein, “fine-tuning” of the pharmacokinetic profile can be achieved by modifying one or both of themicroneedle formulation (e.g., to adjust the rate of drug release) and the number of microneedles per patch (e.g., to adjust the magnitude of drug release). For example, a microneedle patch comprising an array of microneedles as described herein may be formulated and designed to achieve plasma levels of the drug(s) within a target therapeutic window, as illustrated in FIGS. 17 and 20. In some embodiments, a microneedle patch comprising an array of microneedles as described herein may avoid an initial plasma concentration spike that may occur with subcutaneous injection, as illustrated in FIG. 17. In some embodiments, a microneedle patch comprising an array of microneedles as described herein may result in a pharmacokinetic profile with a relatively small difference between the maximum (Cmax) and target (Ceff) plasma concentrations, as illustrated in FIG. 17. In some embodiments, a microneedle patch comprising an array of microneedles as described herein may achieve therapeutic plasma concentration(s) of the drug(s) over the treatment period with less overall plasma exposure to the drug(s) (e g., by avoiding or minimizing an initial plasma concentration spike and / or achieving a relatively flat plasma concentration profile during the treatment period), thereby potentially improving the safety of the treatment protocol.

[0153] Due to the customizable nature of the fabrication process previously described herein (and additionally described in (WO 2019 / 203888)), the geometry of the array consisting of at least one microneedle can take many shapes and sizes. This is significant for use cases, as the microneedle array patch can be designed to conform to specific locations on a patient’s body, depending on the indication and desired location for delivery. In some embodiments the array can be a thin long strip (e.g. 1 by 100 or 2 by 200 microneedles) to deliver a drug along a patient’s limb, for example. In some embodiments the array can be arranged in a circle with a central region void of any microneedles to deliver a drug around a patient’s joint, for example. In some embodiments, the microneedle array can be in the form of a recognizable shape, e.g., a smiley face or company logo to meet the needs of commercial marketing.

[0154] The fabrication processes described above can be used to optimize the microneedle patch mechanics, including the back substrate mechanical and geometrical properties, and microneedle shape to achieve maximum penetration efficiency. In some embodiments the microneedles are securely assembled on a thin transparent elastic back-substrate by using anelastic resin compatible with the polymer forming the microneedles, or by using the same polymer(s) (as discussed above). In some embodiments the back substrate is further attached to a layer of adhesive. In some embodiments the combination of the back substrate and the thin adhesive are about 100 pm in thickness. As a result of having a thin, flexible adhesive back substrate, the patch firmly adheres to the skin surface and is very conformal. A thin substrate also generally exhibits better microneedle penetration as compared to a thick substrate (e.g., having a thickness greater than about 1 millimeter). With a thin substrate, force directly transfers to the microneedles (rather than diffusing into back substrate), and individual microneedles can be subjected to force to achieve effective penetration.Other Uses

[0155] The microneedles and microneedle patches described herein can be useful for application to, and drug delivery across, anatomic structures and membranes other than skin, e.g., mucosa (oral, buccal, sublingual, nasal), gingiva, conjunctiva, sclera, retina, ear canal, tympanic membrane, epithelium (e.g., gastrointestinal, respiratory, vaginal, uterine, vesicular, urethral), serosa, and arterial or venous intima.

[0156] Microneedles disclosed herein can also find use in veterinary medicine, e.g., pets and livestock, and particularly in mammals.

[0157] As noted above, although the present disclosure has focused on microneedle structures, the composite materials described herein having a generally solid structure with drug particles and surfactant (and optionally, cosurfactant) dispersed throughout an insoluble (e.g., rigid) polymerize / cured polymer matrix (e.g., polymerized biocompatible resin), also may be suitably used as implantable devices.

[0158] The present technology, thus generally described, may be further understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present technology.EXAMPLESMicroneedle Fabrication Procedure

[0159] A cross-over-lines (COL) fabrication procedure was used to make microneedle patches, as shown in FIG. 1 1. A CO2 laser (Boss LS- 1416 from Boss Laser, LLC; Sanford, FL, USA) was used to create negative volume on Clear Scratch- and UV-Resistant Cast Acrylic Sheets (part number 8560K359. McMaster-Carr; Princeton, NJ, USA). The engraved acrylic mold was washed with isopropanol and distilled water to remove any dust or other foreign matter from the surface and engraved areas. A nitrogen gun was used to remove the excess water on the surface. The mold was then dried in an atmospheric oven at 80°C for 30 minutes. Then, polydimethylsiloxane (PDMS, Dow Sylgard1M184 Silicone Elastomer; Dow Silicones Corporation in Midland, MI, USA) was cast on the acrylic sheet. The PDMS-casted sheet was degassed and subsequently cured in the oven at 80°C for 2 hours. After complete curing of the PDMS, the PDMS microneedles were peeled off of the acrylic sheet and were treated with oxygen plasma to activate the surface of the PDMS microneedles. The PDMS microneedles were then silanized with trichloro(lH, lH,2H,2H-perfluorooctyl)silane (SKU: 448931-10G, from MilliporeSigma; Burlington, MA, USA) under vacuum in a desiccator overnight. Ecoflex™ 00-50 (Smooth-On, Incorporated, Macungie, PA, USA) with the ratio of 1 : 1 was cast on the silanized PDMS microneedles followed by curing at room temperature. The silane layer creates a barrier between the PDMS microneedles and the Ecoflex mold and prevents them from bonding together, facilitating their detachment. The achieved Ecoflex mold is extremely flexible and stretchable, and can be stretched to about three times its original size. Having a stretchable mold allows the microneedle patches to be made in a much shorter time. The final Ecoflex mold can be used to create microneedles made from different polymers. The flowable material can be cast on the stretched mold. Here, the flowable material is a paste including biocompatible unpolymerized resin, surfactant, optional cosurfactant, and drug particles. The Ecoflex mold was stretched, and the flowable material was cast on the stretched Ecoflex mold. Then, the mold was put under rest mode and the excessive flowable material was removed from the surface of the mold. Following removal of excess flowable material, a thin layer of biocompatibleunpolymerized resin that was used for the flowable material was cast on the surface of the mold as a back substrate to the microneedles and cured under UV light to harden the flowable material and the back substrate. Finally, the microneedles with the back substrate were peeled off of the mold with the needles bonded to the back substrate. Referring to FIG. 11, a 6 centimeter by 20 centimeter microneedle patch having conformability and flexibility was prepared. Microneedle patches may be fabricated in any form and shape according to this procedure. The method provides a high drug loading capacity, and the drugs can be distributed without the need for cold refrigeration.Drug-Loaded Microneedle Patches (Vitamin Bl 2)

[0160] Microneedles were prepared as described above using a casting paste comprising a biocompatible unpolymerized resin (Dental SG) from NextDent and vitamin B 12 (cyanocobalamin, EMPROVE® ESSENTIAL Millipore Sigma) as a model drug, formulated (i) without surfactant and cosurfactant, (ii) with surfactant alone, and (iii) with surfactant and cosurfactant, to assess drug loading and release in the different formulations. The commercially sourced vitamin B 12 particles were ground into finer particles with an average particle size of about 38 pm. The surfactant used was TWEEN 80 (polyoxyethylene sorbitan monooleate); the cosurfactant used was TRANSCUTOL® HP (diethylene glycol monoethyl ether).

[0161] The microneedle formulation (casting paste) without surfactant and cosurfactant was prepared in a weight ratio of resin : drug of about 6:3. The microneedle formulation with surfactant and without cosurfactant was prepared in a weight ratio of resin : drug : surfactant of about 6:3:0.5. The microneedle formulation with surfactant and cosurfactant was prepared in a weight ratio of resin : drug : surfactant : cosurfactant of about 3: 1 :0.25:2.

[0162] The microneedles prepared without surfactant and cosurfactant were difficult to cast and exhibited breakage, and so were not subject to quantitative in vitro drug release testing.

[0163] In vitro drug release of the other types of microneedles was assessed by immersing the microneedles in 20 mL of release media (phosphate buffer saline, pH 7.1 (PBS)). After gentle swirling to ensure uniform immersion, patches were immersed for 24 hours. Results are reported below.

[0164] The microneedles prepared with surfactant (only) were prepared in arrays of 106 microneedles. They exhibited greater mechanical strength than the microneedles prepared without surfactant, but exhibited poor drug release (<15% of loaded drug was released within 24 hours).Table 1 : Vitamin B12 release from microneedles with surfactant (only)

[0165] The microneedles prepared with surfactant and cosurfactant were prepared in arrays of 243 microneedles. They exhibited good mechanical strength and surprisingly excellent drug release (>95% of loaded drug was released within 24 hours). After 24 hours in the release media, the microneedles appeared substantially clear by visualization, consistent with the near complete release of the drug (vitamin B 12). Results from multiple batches are reported below.Table 2: Vitamin B12 release from microneedles with surfactant and cosurfactant

[0166] In Table 2, samples 1-5 were prepared from one batch of casting paste while samples 6-14 were prepared from a second batch of casting paste. The mean % drug release from samples 1-5 was 98.7% with a standard deviation of 1.244 and a %RSD of 1.258 and the mean % drug release from samples 6-14 was 97.3% with a standard deviation of 2.813 and %RSD of 2.892.

[0167] These results in Table 2 demonstrate the synergistic effect with regard to drug release of formulating microneedles as described herein with both a surfactant and cosurfactant. While use of a surfactant improved mechanical properties of the microneedles, drug release of vitamin B12 was still low. In contrast, formulating the microneedles with both a surfactant and cosurfactant resulted in not only good mechanical properties, but unexpectedly high drug release (>95%).

[0168] To increase vitamin B12 loading, a microneedle formulation as described above (with surfactant and cosurfactant) was cast in an array of 745 microneedles. The resulting microneedle patch had a theoretical loading of about 5.00 mg vitamin B 12. After immersing the 745 microneedle patch in release media for 24 hours, the microneedles appeared substantially transparent, suggesting complete or near-complete release of the vitamin B12. Results are reported in Table 3.Table 3: Vitamin B12 release from 745 microneedle array (surfactant and cosurfactant)As shown in Table 3, the mean percentage of drug released within 24 hours was 97.82% with a standard deviation of 1.241 and a %RSD of 1.268, and total drug release (4.96 ± 0.07 mg) consistent with a theoretical loading of about 5.00 mg.

[0169] Scanning electron microscopy (SEM) images of vitamin B 12-containing microneedles as described herein (formulated with surfactant and cosurfactant) before and after drug release are presented in FIGS. 13A- 13C (outer surfaces before release), 14A-14C (cross-section / internal structure before release), 15A-15C (outer surfaces after release), and 16A-16C (cross-section / internal structure after release). Prior to release, the microneedle had a relatively solid, non-porous surface and internal structure, smoother than that of the comparison ibuprofen microneedles discussed below (see FIGS. 21A- 2 IB). After release (after immersion in phosphate buffered saline for one hour) the microneedle had a porous structure with deep pores substantially evenly dispersed across the surface and throughout the remaining internal structure. The resulting pores indicate both good dispersion of the drug particles throughout the microneedle structure, and good dissolution and release of the drug particles from the microneedle. The dispersion of the pores throughout the microneedle structure indicate that channels were formed throughout the internal microneedle structure that permitted drug to be released from throughout the microneedle structure, not just at or near the surface, consistent with the high drug release (>95%) reported above, and as illustrated schematically in FIG. 2.In Vivo Assessment of Drug-Loaded Microneedle Patches (Vitamin Bl 2)

[0170] In vivo pharmacokinetics of vitamin B 12 release from a microneedle patch prepared as described above were evaluated in 6 human subjects and compared to subcutaneous injection of vitamin Bl 2.

[0171] Vitamin B12 microneedle patches, each having an array of 745 microneedles, were fabricated as described above using a casting paste comprising a biocompatible unpolymerized resin (Dental SG) and vitamin B12 (cyanocobalamin, EMPROVE® ESSENTIAL Millipore Sigma), formulated with TWEEN 80 (polyoxyethylene sorbitan monooleate) surfactant and TRANSCUTOL® HP (diethylene glycol monoethyl ether) cosurfactant. Mean drug loading per patch was 5.4 mg.

[0172] One microneedle patch was administered to each of six human subjects, and blood samples were drawn periodically over 96 hours to measure vitamin B12 levels. In particular, a microneedle patch was applied on the forearm of each subject using a spring loaded applicator and self-adherent wrap was used to secure the patch. The patch was worn for 24 hours, after which the patch was removed. As a control arm, commercial injections containing 1 mg / mL vitamin B 12 were administered to six control human subjects via subcutaneous (SQ) injection. Throughout the study, subjects were monitored for potential adverse events and blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-application.

[0173] Results are reported in FIG. 17, which shows the serum concentration (pg / ml) vs. time curve for vitamin B 12 delivered by a microneedle array (■) as compared to subcutaneous injection (•), where the dashed lines show the target plasma concentration. The mean maximum concentration (Cmax) achieved in microneedle subjects was 1787 pg / mL, which was 4% of the Cmax achieved in the control SQ subjects. The time to achieve Cmax (Tmax) was 24 hours post patch application (e.g., at the time of patch removal). The mean area under the plasma concentration vs. time curve over the 24 hour application period (AUCo-24h) and the 96 hour measurement period (AUCo-96h) were 27155 pg-h / mL and 74877 pg-h / mL, respectively. These AUC values are 14% and 32% of those achieved in control SQ subjects. Thus, the serum exposure of vitamin B12 for the microneedle patch was 13-30% that of SQ injection, while still achieving and maintaining plasma concentration within the target therapeutic window for the same amount of time (approximately 72 hours).

[0174] Post study, the six microneedle-treated subjects were subjected to physical examination. Vital signs for all six microneedle-treated subjects were normal with no systemic adverse events. The patch application was well tolerated at 24 hours of wear. Throughout the patch application and removal processes, the microneedles remained intact, and no major complaints were reported.Drug-Loaded Microneedle Patches (Liraglutide)

[0175] Microneedles were prepared as described above using a casting paste comprising a biocompatible unpolymerized resin (Dental SG) from NextDent and liraglutide (Bachem Americas, Inc.) as a model drug, formulated with surfactant and cosurfactant in different relative amounts, to assess drug loading and release in the different formulations. The liraglutide particles were ground into finer particles with an average particle size of less than 38 pm. The surfactant used was TWEEN 80 (polyoxyethylene sorbitan monooleate); the cosurfactant used was TRANSCUTOL® HP (diethylene glycol monoethyl ether).

[0176] Three microneedle formulations with surfactant and cosurfactant were prepared in a weight ratio of resin : drug : surfactant : cosurfactant of (i) about 10:6:2:2, (ii) about 9:7:2:2, and (iii) about 8:7:2.5:2.5. In vitro drug release was assessed as described above.

[0177] The microneedles of formulation (i) were prepared in arrays of 106 microneedles. These microneedles exhibited relatively poor drug loading and lower drug release (<20% of loaded drug was released in 24 hours). This result indicated that the relatively large amount of resin (being hydrophobic) negatively affected drug loading and release for this specific drug. As reported in Table 4 below, the mean % drug release, standard deviation and %RSD were 15.91, 0.573 and 3.6, respectively.Table 4: Liraglutide release from 10:6:2:2 resin: drug: surfactant: cosurfactant formulation

[0178] The microneedles of formulation (ii) were prepared in arrays of 106 microneedles. These microneedles exhibited somewhat improved drug loading and drug release. This result indicated that the relatively lower amount of resin than formulation (i) provided greater drug loading and drug release. However, total drug release at the end of 24 hours was less than 50% of loaded drug. As reported in Table 5, the mean % drug release, standard deviation and %RSD were 40.14, 3.269 and 8.144, respectively.Table 5: Liraglutide release from 9:7:2:2 resin:drug:surfactant:cosurfactant formulation

[0179] Microneedles of formulation (iii) were prepared in arrays of 106 microneedles. These microneedles exhibited a higher drug loading and drug release compared to the formulations (i) and (ii), releasing almost 80% of loaded drug at the end of 24 hours. As reported in Table 6, the mean % drug release, standard deviation and %RSD were 82.42, 3.037 and 3.685, respectively.Table 6: Liraglutide release from 8:7:2.5:2.5 formulation

[0180] Formulation (iii) has relatively less resin that formulations (i) and (ii) and more surfactant and cosurfactant. These results indicate that the combined effect of the relatively lower amount of resin and higher amount of surfactant / cosurfactant may work together synergistically to improve drug release.

[0181] Collectively, these results indicate that by varying the relative amounts of resin, drug particles, surfactant and optional cosurfactant, the drug loading and drug release properties of a microneedle device as described herein can be adjusted. For example, depending on the physicochemical properties of the drug being formulated (e.g., solubility, hydrophilicity, etc.), relatively more or less amounts of resin and drug, relatively more or less amounts of surfactant, and the optional use and amount of cosurfactant may be used to achieved the desired drug loading and drug release properties.Drug-Loaded Microneedle Patches (Semaglutide)

[0182] Microneedles were prepared as generally described above using a casting paste comprising a biocompatible unpolymerized resin (Dental SG) from NextDent and semaglutide drug powder (Hubei JXBio Pharmaceuticals Co, Ltd.) as a model drug, formulated with surfactant (TWEEN 80 (polyoxyethylene sorbitan monooleate)) and cosurfactant (TRANSCUTOL® HP (diethylene glycol monoethyl ether)), prepared in a weight ratio of resin : drug : surfactant : cosurfactant of about 6:6: 1 : 1. Microneedle patches were fabricated with an array of 313 microneedles, and a drug loading of about 7.2 mg per patch.

[0183] In vitro drug release was assessed as generally described above, after immersion in phosphate buffered saline for one hour. Almost 90% of the semaglutide was released within 1 hour, and 100% drug release was achieved within 2 hours, suggesting rapid drug release from the microneedles. Results are reported in Table 7 below, where it can be seen that the mean % drug release, standard deviation, and %RSD were 99.4, 1.192 and 1.198, respectively.Table 7: Semaglutide release from 313 microneedle array (surfactant and cosurfactant)

[0184] Scanning electron microscopy (SEM) images of the semaglutide-containing microneedles before and after drug release are presented in FIGS. 18A (outer surfaces before release), 18B-18C (cross-section / intemal structure before release), 19A (outer surfaces after release), and 19B-19C (cross-section / intemal structure after release). Prior to release, the microneedle had a relatively solid, non-porous surface and internal structure. After release (after immersion in phosphate buffered saline for one hour) the microneedle had a porous structure with deep pores substantially evenly dispersed across the surface and throughout the remaining internal structure. The resulting pores indicate both good dispersion of the drug particles throughout the microneedle structure, and good dissolution and release of the drug particles from the microneedle. The dispersion of the pores throughout the microneedle structure indicate that channels were formed throughout the internal microneedle structure that permitted drug to be released from throughout the microneedle structure, not just at or near the surface, consistent with the high drug release (-100%) reported above, and as illustrated schematically in FIG. 2.In Vivo Assessment of Drug-Loaded Microneedle Patches (Semaglutide)

[0185] In vivo pharmacokinetics of semaglutide release from a microneedle patch prepared as described above were evaluated in a swine model and compared to subcutaneous injection of semaglutide. As above, the mean semaglutide loading per microneedle patch was 7.2 mg.

[0186] Semaglutide microneedle patches were fabricated from the casting paste described above with each patch having an array of 313 microneedles. The microneedle patches were administered to three pigs to assess patch application, penetration, and drug delivery. The microneedle patches were applied to anesthetized pigs near the upper right side of the flank region of the pig using a spring-loaded applicator, and patches weresecured using a self-adherent cartridge. The pigs wore the patch for 4 hours while anesthetized. Blood samples were collected at different time points up to 72 hours after administration to determine semaglutide plasma concentration. The patches remained completely adhered throughout the wear time. Upon visual examination, there was no sign of skin inflammation, blistering or severe redness, suggesting tolerance of the patch. Throughout the patch application and removal process, the microneedles remained intact.

[0187] As a control arm, three pigs were administered semaglutide by subcutaneous injection of 1 mg / 0.75 mL and blood samples were collected at different time points up to 72 hours after injection to determine semaglutide plasma concentration.

[0188] Semaglutide levels were quantified using ELISA kits and the pharmacokinetic profiles were derived. Results are reported in FIG. 20, which shows the serum concentration (pM) vs. time curve for semaglutide delivered microneedle (•) as compared to subcutaneous injection (■). Over the 72 hour period, the Cmax of semaglutide released from the microneedle patch was 748.5 ng / mL, and was 4.3-fold higher than the Cmax achieved with SQ injection. The Tmax was 10 hours post patch application. The data indicate about 90% of semaglutide was released within 1 hour of application, providing improved in vivo distribution of semaglutide as compared to subcutaneous injection. Results demonstrated significantly higher systemic exposure on average across the microneedle patch group compared to the SQ injection (9,590,976 pM-h vs. 2,088,386 pM-h, respectively). After normalization for dose and weight, the average bioavailability of the patch-delivered semaglutide was 59% relative to injection, based on nominal patch load (7.2 mg per patch), and 86% based on actual amount of drug delivered from the patch (i.e., accounting for residual drug remaining in the microneedles).

[0189] Optical coherence tomography confirmed uniform microneedle insertion depths into the skin of the study animals.This analysis confirms that a substantial portion of semaglutide loaded into the microneedles was both successfully delivered and systemically absorbed, and support that the microneedle patches as described herein are a viable platform for non-invasive drug delivery.Drug-Loaded Microneedle Patches (Apelin)

[0190] Microneedles were prepared as generally described above using a casting paste comprising a biocompatible unpolymerized resin (Dental SG) from NextDent and [Pyrl]apelin-13 (SAGECHEM LIMITED), a highly potent pyroglutamyl form of apelin- 13, as a model drug, used in dry / powder form and formulated with surfactant but not cosurfactant, to assess drug loading and release. The surfactant used was TWEEN 80 (polyoxyethylene sorbitan monooleate). The microneedle formulation has a weight ratio of resin : drug : surfactant of about 6:4: 1. Microneedle patches were prepared with arrays of 313 microneedles and a drug loading of about 5.5 mg per patch.

[0191] In vitro drug release was assessed by immersion in phosphate-buffered saline over 24 hours. After 24 hours in release media, about 90-100% of the apelin was released. Results are reported in Table 8 below. As seen in the table, the mean % drug release, standard deviation, and %RSD were 97.83, 3.16, and 3.236, respectively.Table 8: Apelin release from 313 microneedle array (surfactant (only))Comparison Microneedles (Ibuprofen)

[0192] Microneedles were prepared as described above except without using surfactant and without using cosurfactant, using ibuprofen as a model drug. The flowable material (casting paste) comprised a biocompatible resin (Dental SG) from Formlabs (Somerville, MA, USA) and ibuprofen in a weight ratio of resin : drug of 1 :1. The commercially sourced ibuprofen drug particles were ground into finer particles with an average particle size of less than 125 pm. After fabrication, the ibuprofen microneedles were immersed in release media as described above.

[0193] As seen in FIGS. 21 A, 21C, and 2 ID, scanning electron microscopy (SEM) images of the microneedles prepared without surfactant / cosurfactant show a somewhat rough surface, especially as compared to microneedles of the present disclosure prepared with surfactant / cosurfactant. As seen in FIGS. 2 IE and 2 IF, SEM images of the microneedles prepared without surfactant / cosurfactant after drug release reveal large pores at the surface formed from release of drug particles at the surface. However, the microneedles prepared without surfactant / cosurfactant are not expected to have pores dispersed as extensively throughout the microneedle structure as a microneedle prepared with surfactant / cosurfactant, because without the interconnected network of drug particles throughout the microneedle structure facilitated by the surfactant / cosurfactant, pores and channels will not able to form as extensively throughout the microneedle structure, leading to incomplete drug release.Microneedle Patches Formulated With Two or More Drugs

[0194] Microneedle patches including two or more drugs may be prepared generally as described above, formulating the drugs in separate casting pastes or in the same casting paste, as described in more detail below.

[0195] Combination patches including pyr-Apelin-13 microneedles and semaglutide microneedles were prepared as follows. Microneedles were prepared using a casting paste comprising a biocompatible unpolymerized resin (Dental SG) from NextDent, and either pyr-Apelin-13 (Sagechem Ltd.) or semaglutide (Hubei JXBio Pharmaceuticals Co, Ltd.) as model drugs. Pyr-Apelin-13 drug powder was formulated with the resin, surfactant (TWEEN 80 (polyoxyethylene sorbitan monooleate)) and buffering / hydrophilic agent (sodium phosphate dibasic dihydrate), prepared in a weight ratio of resin : drug : surfactant : buffering agent of about 6:6: 1 : 1. Semaglutide drug powder was formulated with the resin, surfactant (TWEEN 80 (polyoxyethylene sorbitan monooleate)) and cosurfactant (TRANSCUTOL® HP (diethylene glycol monoethyl ether)), prepared in a weight ratio of resin : drug : surfactant : cosurfactant of about 6:6: 1 : 1. Microneedle patches were fabricated with an array of 108 microneedles, with 54 microneedles formed from apelin-containing casting paste and 54 formed fromsemaglutide-containing casting paste, for a total drug loading of about 1.2 mg of pyr- Apelin-13 and 1.1 mg of semaglutide per patch.

[0196] Combination patches including a long-acting insulin (insulin degludec) and liraglutide in the same microneedles were prepared as follows. Microneedles were prepared using a casting paste comprising a biocompatible unpolymerized resin (Dental SG) from NextDent, and insulin degludec drug powder (Zuhai Gene Biocon Biological Technology Co., Ltd.) and liraglutide as model drugs. The casting paste was prepared using surfactant (TWEEN 80 (polyoxyethylene sorbitan monooleate)) and cosurfactant (TRANSCUTOL® HP (diethylene glycol monoethyl ether)), and a weight ratio of resin : drug A: drug B: surfactant : cosurfactant of about 8: 3.5: 3.5: 3.5: 1.5. Microneedle patches were fabricated with an array of 588 microneedles, and a drug loading of about 3.3 mg of insulin deglutec and 3.3 mg of liraglutide per patch.In vitro drug release

[0197] In vitro drug release was assessed after immersion in phosphate buffered saline for 24 hours. Samples of 1 ml were analyzed by HPLC at specific timepoints (30min, Ih, 2h, 3h, 4h, 24h).

[0198] As shown in FIG. 22 for the Apelin + semaglutide patch, approximately 60% of pyr-Apelin-13 was rapidly released within 1 hour, and 91% drug release was achieved within 4 hours reaching 95% between 4-24 hours. Rapid semaglutide release of 68% was achieved within 30 minutes, reaching a peak at 77% at 4 hours. Results are reported in Table 9 below. The mean % drug release for pyr-Apelin-13, drug (mg) released, and standard deviation (mg) were 95%, 1.126 mg and 0.08, respectively. The mean % drug release for semaglutide, drug (mg) released, and standard deviation (mg) were 77%, 0.832 mg and 0.03, respectively.Table 9: Release from 108 microneedle patch (54 each pyr-Apelin-13 and semaglutide)

[0199] Results for the combination patch with insulin degludec and liraglutide in the same microneedles are shown in FIG. 23. As shown in the figure, almost 50% of both drugs was released within the first 30 minutes, and total drug release for both drugs occurred within 3 hours, with 90% release for insulin degludec and 75% drug release for liraglutide. Results are reported in Tale 10 below. The mean % drug release for insulin degludec, drug (mg) released, and standard deviation (mg) were 90%, 2.940 mg and 0.22, respectively. The mean % drug release for liraglutide, drug (mg) released, and standard deviation (mg) were 76%, 2.475 mg and 0.23, respectively.Table 10: Insulin degludec and liraglutide release from 588 microneedle patchThese results show that two or more drugs can be formulated in a single microneedle patch as described herein, with each drug having an independent drug release profile, wherein the drugs are formulated in the same microneedles or different microneedles.

Claims

CLAIMS1. A microneedle for delivering a drug, comprising: a solid composite material comprising a polymerized / cured biocompatible polymer matrix, drug particles, and a surfactant, wherein drug particles and surfactant are dispersed throughout the polymer matrix forming an interconnected drug network extending to a surface of the microneedle.

2. The microneedle of claim 1, wherein the polymerized / cured biocompatible polymer matrix comprises a photocured biocompatible resin.

3. The microneedle of claim 2, wherein the biocompatible resin is a dental resin.

4. The microneedle of any one of the preceding claims, wherein the drug particles have a particle size distribution having a D(10) greater than or equal to about 500 nm, a D(50) of from about 1 gm to about 50 gm, and a D(90) less than or equal to about 100 gm, including a particle size distribution having a D(10) greater than or equal to 500 nm, a D(50) of 1 gm to 50 gm, and a D(90) less than or equal to 100 gm.

5. The microneedle of any one of the preceding claims, wherein the drug particles have a particle size distribution having a D(10) greater than or equal to about 2 gm, a D(50) of from about 2 gm to about 25 gm, and a D(90) less than or equal to about 50 gm, including a particle size distribution having a D(10) greater than or equal to 2 gm, a D(50) of 2 gm to 25 gm, and a D(90) less than or equal to 50 gm.

6. The microneedle of any one of the preceding claims, wherein the surfactant has an average HLB value >10, optionally wherein the surfactant has an average HLB value of about 12 to about 15.

7. The microneedle of any one of the preceding claims, wherein the surfactant comprises one or more surfactants selected from sorbitan esters, polysorbates, cremophor, D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS), fatty acid esters, alkyl polyglycosides, and aliphatic alcohol-based non-ionic surfactants.

8. The microneedle of any one of the preceding claims, further comprising a cosurfactant dispersed throughout the polymer matrix, optionally wherein the cosurfactant has an average HLB value <10, further optionally wherein the cosurfactant has an average HLB value of about 2 to about 6.

9. The microneedle of claim 8, wherein the cosurfactant comprises one or more selected from propylene glycol, polyethylene glycol 12-hydroxy stearate, glycerin, isopropyl alcohol, diethylene glycol monoethyl ether, a polyethylene glycol, a castor oil derivative, an ethoxylated vegetable oil derivative, propylene glycol monocaprylate, glyceryl monooleate, oleyl alcohol, isopropyl myristate, diisopropyl adipate, ethyl oleate, and lauryl lactate.

10. The microneedle of claim 8 or claim 9, wherein the surfactant comprises polyoxyethylene sorbitan monooleate and the cosurfactant comprises diethylene glycol monoethyl ether.

11. The microneedle of any one of the preceding claims, wherein the drug is water- soluble, optionally wherein the drug comprises one or more selected from a therapeutic agent, a prophylactic agent, a diagnostic agent, and a cosmetic agent, optionally wherein the drug is an antibody (e.g., a monoclonal antibody), a therapeutic peptide or protein (e.g., vitamin B12, liraglutide, semaglutide, tirzepatide, apelin, amylin, ibuprofen, insulin, insulin degludec), a nucleotide (e.g., DNA, RNA, including mRNA), a low- molecular weight drug (e.g., having a molecular weight less than 500 Daltons), or any combination of two or more thereof.

12. The microneedle of any one of the preceding claims, wherein the drug has a molecular weight greater than 500 Daltons.

13. The microneedle of any one of the preceding claims, where the drug particles consist of the drug.

14. The microneedle of any one of the preceding claims, where the drug particles comprise a composition comprising drug and a pharmaceutically acceptable excipient.

15. The microneedle of any one of the preceding claims, where the drug particles comprise spray-dried drug particles.

16. The microneedle of any one of the preceding claims, where the drug particles have a heterogenous structure, optionally wherein the drug particles have a structure selected from a core-shell structure, a liposome, a polymeric microparticle, and a lipid nanoparticle.

17. The microneedle of any one of the preceding claims, wherein the drug particles are substantially solvent-free, optionally wherein the drug particles are substantially water-free.

18. The microneedle of any one of the preceding claims, wherein microneedle has an axial length of from about 0.5 mm to about 1.5 mm.

19. The microneedle of any one of the preceding claims, wherein the microneedle has a hardness of from about 40 Shore A to about 90 Shore D, optionally wherein a tip of the microneedle breaks at an applied force of greater than about 0.26 newtons.

20. The microneedle of any one of the preceding claims, comprising a tip region, a base region, and, optionally, an intermediate region between the tip region and the base region, wherein the tip region comprises the solid composite material comprising polymerized / cured biocompatible polymer matrix, drug particles, and surfactant and optional cosurfactant (if present).

21. The microneedle of claim 20, wherein the optional intermediate region is present and comprises a solid composite material comprising the polymerized / cured biocompatible polymer matrix, optionally comprises the surfactant and optional cosurfactant (if present), and further optionally comprises drug particles, optionally wherein a percent by weight of drug particles in the solid composite material of the intermediate region is less than a percent by weight of drug particles in the solid composite material of the tip region.

22. The microneedle of claim 20 or claim 21, wherein the base region comprises a solid composite material comprising the polymerized / cured biocompatible polymer matrix, optionally comprises the surfactant and optional cosurfactant (if present), and further optionally comprises drug particles, optionally wherein a percent by weight of drug particles in the solid composite material of the base region is less than a percent by weight of drug particles in the solid composite material of one or both of the tip region and the intermediate region.

23. The microneedle of any one of the preceding claims, wherein, after 24 hours in aqueous release media, the microneedle releases 80% or more of drug loaded therein, optionally wherein the microneedle releases 80%, 85%, 90%, 95%, 97%, or more, of drug loaded therein.

24. The microneedle of any one of the preceding claims, prepared from a flowable material comprising a polymerizable / curable biocompatible polymer material, drug particles, and a liquid surfactant, wherein the drug particles are dispersed in the flowable material.

25. The microneedle of claim 24, wherein the flowable material comprises from about 30 wt.% to about 70 wt.%, or from about 40 wt.% to about 60 wt.%, of the polymer material.

26. The microneedle of claim 24 or claim 25, wherein the flowable material comprises from about 1 wt.% to about 70 wt.%, or from about 5 wt.% to about 40 wt.%, of the drug particles.

27. The microneedle of any one of claims 24-26, wherein the flowable material comprises from about 1 wt.% to about 35 wt.% of the liquid surfactant.

28. The microneedle of any one of claims 24-26, wherein the flowable material further comprises liquid cosurfactant in an amount of about 1 wt.% to about 35 wt.%.

29. The microneedle of claim 28, wherein the flowable material comprises from about 1 wt.% to about 55 wt.% of surfactant and optional cosurfactant combined.

30. The microneedle of any one of the preceding claims, prepared by a process comprising: forming a flowable mixture comprising a polymerizable / curable biocompatible polymer material, drug particles, and a liquid surfactant, wherein the drug particles are dispersed in the flowable material; forming the flowable mixture into a microneedle shape; and one or both of polymerizing and curing the flowable mixture to form the microneedle.

31. The microneedle of claim 30, wherein forming the flowable mixture into a microneedle shape comprises casting the flowable mixture into a microneedle-forming mold.

32. The microneedle of claim30, wherein forming the flowable mixture into a microneedle shape comprises 3D printing the flowable mixture into a microneedle shape.

33. A microneedle patch comprising a plurality of microneedles of any one of claims 1-32 on a back substrate, optionally wherein the plurality is 50 or more, further optionally wherein the plurality is 100 or more.

34. A microneedle patch comprising: a first plurality of microneedles of any one of claims 1-33 comprising a first solid composite material comprising a first polymerized / cured biocompatible polymer matrix, first drug particles, a first surfactant, and, optionally, a first cosurfactant; and a second plurality of microneedles of any one of claims 1-33 comprising a second solid composite material comprising a second polymerized / cured biocompatible polymer matrix, second drug particles, a second surfactant, and, optionally, a second cosurfactant, wherein one or more or all of: the first drug particles comprise a first drug and the second drug particles comprise a second drug the same as or different from the first drug;the first drug particles have particle size distribution having a D(10), D(50), and D(90) the same as or different from those of a particle size distribution of the second drug particles; the first biocompatible polymer matrix comprises a first resin and the second biocompatible polymer matrix comprises a second resin the same as or different from the first resin; the first surfactant is the same as or different from the second surfactant; the first solid composite material comprises a cosurfactant and the second solid composite material does not comprise a cosurfactant; the first solid composite material comprises a first cosurfactant and the second solid composite material comprises a second cosurfactant the same as or different from the first co surfactant; a ratio by weight in the first solid composite material of the first polymerized / cured biocompatible polymer matrix, first drug particles, first surfactant and optional first cosurfactant (if present) is the same as or different from a ratio by weight in the second solid composite material of the second polymerized / cured biocompatible polymer matrix, second drug particles, second surfactant and optional second cosurfactant (if present).

35. A microneedle patch comprising a plurality of microneedles of any one of claims 1-34 spaced about 0.5 mm apart, about 1 mm apart, about 2 mm apart, or any value therebetween, optionally wherein the patch has a planar microneedle area of from about 0.5 cm2to about 100 cm2.

36. A flowable material comprising a polymerizable / curable biocompatible polymer material, drug particles, and a liquid surfactant, wherein the drug particles are dispersed in the flowable material.

37. The flowable material of claim 36, wherein the flowable material comprises from about 30 wt.% to about 70 wt.% or from about 40 wt.% to about 60 wt.% of the polymer material.

38. The flowable material of claim 36 or claim 37, wherein the flowable material comprises from about 1 wt.% to about 70 wt.% or from about 5 wt.% to about 40 wt.% of the drug particles.

39. The flowable material of any one of claims 36-38, wherein the flowable material comprises from about 1 wt.% to about 35 wt.% of the liquid surfactant.

40. The flowable material of any one of claims 36-39, wherein the flowable material further comprises liquid cosurfactant in an amount about 1 wt.% to about 35 wt.%.

41. The flowable material of claim 40, wherein the flowable material comprises from about 1 wt.% to about 55 wt.% of surfactant and optional cosurfactant combined.

42. A process for preparing a microneedle according to any one of claims 1-32, comprising: forming a flowable mixture comprising the polymerizable / curable biocompatible polymer material, drug particles, and liquid surfactant, wherein the drug particles are dispersed in the flowable material; forming the flowable mixture into a microneedle shape; and one or both of polymerizing and curing the flowable mixture to form the microneedle.

43. The process of claim 42, wherein forming the flowable mixture into a microneedle shape comprises 3D printing the flowable mixture into a microneedle shape.

44. The process of claim 42, wherein forming the flowable mixture into a microneedle shape comprises casting the flowable mixture onto a microneedle-forming mold having a microneedle-forming cavity, and wherein one or both of polymerizing and curing the flowable mixture comprises curing the flowable mixture in the microneedle-forming cavity to obtain a solid microneedle.

45. A process for preparing a microneedle according to any one of claims 1-32, comprising:forming a flowable mixture comprising the polymerizable / curable biocompatible polymer material, drug particles, and liquid surfactant, wherein the drug particles are dispersed in the flowable material; stretching a microneedle-forming mold having a microneedle-forming cavity beyond an original size of the mold; casting the flowable mixture onto the stretched microneedle-forming mold; permitting the stretched microneedle-forming mold to relax into an unstretched state; curing the flowable mixture in the microneedle-forming cavity to obtain a solid microneedle; and removing the solid microneedle from the mold.

46. A process for preparing a microneedle according to any one of claims 1-32, comprising: casting a first flowable mixture onto a microneedle-forming mold having a microneedle-forming cavity comprises a tip region, a base region, and, optionally, an intermediate region between the tip region and the base region, wherein the casting fills a region of the microneedle-forming cavity that comprises at least the tip region, and curing the first flowable mixture in the mold, wherein the first flowable mixture comprises the polymerizable / curable biocompatible polymer material, drug particles, and liquid surfactant and optional cosurfactant (if present), wherein the drug particles are dispersed in the flowable material; optionally casting a second flowable mixture into an unfilled region of the microneedle-forming cavity that comprises the intermediate region, and curing the second flowable mixture in the mold, wherein the second flowable mixture comprises the polymerizable / curable biocompatible polymer material, optionally comprises the liquid surfactant, optionally comprises the cosurfactant (if present), and further optionally comprises drug particles dispersed in the flowable material; and casting a third flowable mixture into an unfilled region of the microneedleforming cavity that comprises at least the base region, and curing the third flowable mixture in the mold, wherein the third flowable mixture comprises thepolymerizable / curable biocompatible polymer material, optionally comprises the liquid surfactant, optionally comprises the cosurfactant (if present), and further optionally comprises drug particles dispersed in the flowable material; and removing the solid microneedle from the mold.

47. The process of claim 45 or claim 46, further comprising:(i) before removing the solid microneedle from the mold, casting a second polymerizable / curable biocompatible polymer material on the microneedle mold, and curing the second polymerizable / curable biocompatible polymer material to bond it to the microneedle, to obtain a back substrate on the microneedle; or(ii) before curing the flowable mixture in the microneedle-forming cavity, casting a second polymerizable / curable biocompatible polymer material on the microneedle mold, and curing the flowable mixture and second polymerizable / curable biocompatible polymer material, to obtain a microneedle on a back substrate.

48. The process of any one of claims 42-47, comprising curing the flowable mixture by photocuring, optionally by UV light, further optionally by light at a wavelength of 405 nm.

49. The process of any one of claims 44-48, wherein the mold comprises a plurality of microneedle-forming cavities arranged in an array, and the process obtains a plurality of microneedles arranged in an array.

50. A process for preparing a microneedle according to any one of claims 1-32, comprising forming a microneedle comprising a tip region, a base region, and, optionally, an intermediate region between the tip region and the base region, by a process comprising: forming the tip region by 3D printing from a flowable mixture comprising polymerizable / curable biocompatible polymer material, drug particles, and surfactant and optional cosurfactant (if present), wherein the drug particles are dispersed in the flowable material; optionally, forming the intermediate region by 3D printing from a second flowable mixture comprising the polymerizable / curable biocompatible polymermaterial, optionally comprising the liquid surfactant, optionally comprising the cosurfactant (if present), and further optionally comprising drug particles dispersed in the flowable material; and forming the base region by 3D printing from a third flowable mixture comprising the polymerizable / curable biocompatible polymer material, optionally comprising the liquid surfactant, optionally comprising the cosurfactant (if present), and further optionally comprising drug particles dispersed in the flowable material.

51. The process of any one of claims 42-50, wherein the drug particles are formulated in the flowable mixture in powder form.

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