Microneedle assembly

Abstract

Micro-needle assemblies capable of transdermally delivering a pharmaceutical compound, such as a vaccine (e.g., a vaccine), across the skin barrier of a subject (e.g., a human) and / or detecting the presence of an analyte in a subject are provided. The micro-needle assemblies include a plurality of micro-needles arranged on a support, each micro-needle comprising a tip and a base, one or both of which are formed from a polymer composition comprising a liquid crystal polymer. By selectively controlling the particular components of the polymer composition, as well as their relative concentrations, the resulting micro-needles can exhibit a high degree of physical alignment, which can help ensure better performance of the micro-needle assemblies during use.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS BACKGROUND SUMMARY DETAILED DESCRIPTION

[0001] Cross Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 016,560, filed April 28, 2020, U.S. Provisional Patent Application Serial No. 63 / 034,429, filed June 4, 2020, and U.S. Provisional Patent Application Serial No. 63 / 069,891, filed August 25, 2020, the entire contents of which are incorporated herein by reference. BACKGROUND

[0003] Due to the relatively high molecular weight and viscosity of most vaccines, the most vaccines need to be delivered to a subject via oral delivery, injection, or infusion. Unfortunately, these methods present problems for various reasons. For example, injections typically use small gauge needles, which cause pain and can require long times to deliver the vaccine at very high pressures. Oral delivery also requires successful absorption of the vaccine through the epithelial layer of the digestive tract and avoidance of breakdown by digestive substances. Both injection and oral delivery also tend to provide a bolus of vaccine and widely fluctuating systemic concentrations, rather than the preferred steady state delivery. Infusion therapy can also be used to deliver vaccines directly to blood vessels, muscle, or subcutaneous connective tissue. However, infusion therapy is invasive, which increases the risk of infection at the infusion site, and necessitates the use of pumps, transdermal tubes, and the like. Due to these problems, attempts have also been made to deliver vaccines through transdermal delivery devices. Unfortunately, due to the relatively small size of microneedles, it is often complex to manufacture microneedles of uniform size and shape. Furthermore, microneedles often do not properly align with each other, which can result in inconsistent delivery of vaccine doses.

[0004] Accordingly, there is a current need for improved transdermal delivery devices. SUMMARY

[0005] According to one embodiment of the present application, a microneedle assembly is disclosed, the microneedle assembly comprising an array of microneedles arranged in at least one predetermined geometric pattern on a support. Each microneedle comprises a base including a lower portion located proximate the support and an opposing upper portion extending from the lower portion in a longitudinal direction. A tip extends from the upper portion of the base in the longitudinal direction and terminates at an edge. The tip, the base, or a combination thereof comprises a polymer composition comprising a liquid crystal polymer. Furthermore, a centerline extends through the base in the longitudinal direction, and the microneedle exhibits an offset factor k of about 20 or less determined according to the following equation:

[0006] k = 0 / ((L1 + L2) / D)

[0007] wherein,

[0008] O is a distance that the edge of the tip deviates from the centerline in a transverse direction perpendicular to the longitudinal direction;

[0009] L1 is the length of the tip; and

[0010] L2 is the length of the base; and

[0011] D is the width of the base.

[0012] Other features and aspects of the present application will be in part apparent from and in part elab orated with reference to the detailed description and drawings that follow. BRIEF DESCRIPTION OF DRAWINGS

[0013] The complete and enabling disclosure of this application, including the best mode thereof, will be more fully elab orated in the remainder of the specification, including the references to the accompanying drawings, in which:

[0014] Figure 1 is a schematic front view of a microneedle assembly that can be formed in accordance with the present application;

[0015] Figure 2 is a schematic plan view of the microneedle assembly of Figure 1

[0016] Figure 3 is a schematic view of one embodiment of a microneedle that can be used in the microneedle assembly of the present application;

[0017] Figure 4 is a schematic front view of another embodiment of a microneedle assembly that can be formed in accordance with the present application; and

[0018] Figure 5 is a schematic view of the microneedle of Figure 3 DETAILED DESCRIPTION

[0019] It should be understood by those of ordinary skill in the art that the discussion is merely an elab oration of exemplary embodiments and is not intended to limit the broader aspects of the application.

[0020] In general, the present application relates to a microneedle assembly that is capable of transdermally delivering a pharmaceutical compound, such as a vaccine (e.g., a vaccine), across the skin barrier of a subject (e.g., a human), and / or detecting the presence of an analyte in a subject. The microneedle assembly includes a plurality of microneedles arranged on a support, each microneedle comprising a tip and a base, one or both of which is formed from a polymer composition comprising a liquid crystal polymer. The present inventors have discovered that by selectively controlling the particular components of the polymer composition, as well as their relative concentrations, the resulting microneedle can exhibit a high degree of physical alignment, which can help to ensure better performance of the microneedle assembly during use.

[0021] Various embodiments of the present application will now be described in greater detail.​​

[0022] I. Polymer components

[0023] A. Liquid crystal polymer

[0024] Liquid crystalline polymers are generally classified as "thermotropic" in the sense that they can have a rod-like structure and exhibit crystalline behavior in their molten state (e.g., a thermotropic nematic state). The melting temperature of such polymers is typically about 280 °C or higher, in some embodiments about 300 °C or higher, in some embodiments about 320 °C or higher, and in some embodiments about 330 °C to about 450 °C. The polymers can be formed from one or more types of repeating units known in the art. The liquid crystalline polymers can for example include one or more aromatic ester repeating units generally represented by the following formula (I):

[0025]

[0026] wherein,

[0027] Ring B is a substituted or unsubstituted 6-membered aryl (e.g., 1,4-phenylene or 1,3- phenylene), a substituted or unsubstituted 6-membered aryl fused to a substituted or unsubstituted 5- or 6-membered aryl (e.g., 2,6-naphthalene), or a substituted or unsubstituted 6-membered aryl bonded to a substituted or unsubstituted 5- or 6-membered aryl (e.g., 4,4-biphenylene); and

[0028] Y1and Y2are independently O, C(O), NH, C(O)HN, or NHC(O).

[0029] Typically, at least one of Y1and Y2is C(O). Examples of such aromatic ester repeating units can include, for example, aromatic dicarboxylic acid repeating units (Y1and Y2are C(O) in formula I), aromatic hydroxycarboxylic acid repeating units (Y1is O and Y2is C(O) in formula I), and various combinations thereof.

[0030] For example, aromatic hydroxycarboxylic acid repeat units derived from aromatic hydroxycarboxylic acids (e.g., 4-hydroxybenzoic acid; 4-hydroxy-4'-biphenylcarboxylic acid; 2-hydroxy-6-naphthoic acid; 2-hydroxy-5-naphthoic acid; 3-hydroxy-2-naphthoic acid; 2-hydroxy-3-naphthoic acid; 4'-hydroxyphenyl-4-benzoic acid; 3'-hydroxyphenyl-4-benzoic acid; 4'-hydroxyphenyl-3-benzoic acid; and the like), as well as alkyl, alkoxy, aryl, and halogen substituted versions thereof, and combinations thereof, can be used. Particularly suitable aromatic hydroxycarboxylic acids are 4-hydroxybenzoic acid ("HBA") and 6-hydroxy-2-naphthoic acid ("HNA"). When used, repeat units derived from hydroxycarboxylic acids (e.g., HBA and / or HNA) typically comprise about 20 mole percent or more of the polymer, in some embodiments about 25 mole percent or more, in some embodiments about 30 mole percent or more, in some embodiments about 40 mole percent or more, in some embodiments about 50 mole percent or more, in some embodiments about 55 mole percent to 100 mole percent, and in some embodiments about 60 mole percent to about 95 mole percent.

[0031] Aromatic dicarboxylic acid repeat units derived from aromatic dicarboxylic acids (e.g., terephthalic acid, isophthalic acid, 2,6-naphthalene dicarboxylic acid, diphenyl ether-4,4'-dicarboxylic acid, 1,6-naphthalene dicarboxylic acid, 2,7-naphthalene dicarboxylic acid, 4,4'-dicarboxybiphenyl, bis(4-carboxyphenyl)ether, bis(4-carboxyphenyl)butane, bis(4-carboxyphenyl)ethane, bis(3-carboxyphenyl)ether, bis(3-carboxyphenyl)ethane, and the like), as well as alkyl, alkoxy, aryl, and halogen substituted versions thereof, and combinations thereof, can also be used. Particularly suitable aromatic dicarboxylic acids can include, for example, terephthalic acid ("TA"), isophthalic acid ("IA"), and 2,6-naphthalene dicarboxylic acid ("NDA"). When used, repeat units derived from aromatic dicarboxylic acids (e.g., IA, TA, and / or NDA) typically each comprise about 1 mole percent to about 40 mole percent of the polymer, in some embodiments about 2 mole percent to about 30 mole percent, and in some embodiments about 5 mole percent to about 25 percent.

[0032] Other repeat units can also be used in the polymer. In certain embodiments, for example, repeat units derived from aromatic diols (e.g., p-phenylenediamine, m-phenylenediamine, 2,6-dihydroxynaphthalene, 2,7-dihydroxynaphthalene, 1,6-dihydroxynaphthalene, 4,4'-dihydroxybiphenyl (or 4,4'-biphenol), 3,3'-dihydroxybiphenyl, 3,4'-dihydroxybiphenyl, 4,4'-dihydroxydiphenyl ether, bis(4-hydroxyphenyl)ethane, etc.), as well as alkyl, alkoxy, aryl, and halogen substituted versions thereof, and combinations thereof, can be used. Particularly suitable aromatic diols can include, for example, p-phenylenediamine (“HQ”) and 4,4’-biphenol (“BP”). When used, repeat units derived from aromatic diols (e.g., HQ and / or BP) typically comprise about 1 mole % to about 50 mole % of the polymer, in some embodiments about 1 mole % to about 40 mole %, in some embodiments about 2 mole % to about 40 mole %, in some embodiments about 5 mole % to about 35 mole %, and in some embodiments about 5 mole % to about 25 %.

[0033] Repeat units derived from aromatic amides (e.g., p-acetaminophenol (“APAP”)) and / or aromatic amines (e.g., 4-aminophenol (“AP”), 3-aminophenol, 1,4-phenylenediamine, 1,3-phenylenediamine, etc.) can also be used. When used, repeat units derived from aromatic amides (e.g., APAP) and / or aromatic amines (e.g., AP) typically comprise about 0.1 mole % to about 20 mole % of the polymer, in some embodiments about 0.5 mole % to about 15 mole %, and in some embodiments about 1 mole % to about 10 %. It will also be appreciated that various other monomer repeat units can be incorporated into the polymer. For example, in certain embodiments, the polymer can contain one or more repeat units derived from non-aromatic monomers, such as aliphatic or cycloaliphatic hydroxycarboxylic acids, dicarboxylic acids, diols, amides, amines, etc. Of course, in other embodiments, the polymer can be “wholly aromatic” in that it lacks repeat units derived from non-aromatic (e.g., aliphatic or cycloaliphatic) monomers.

[0034] In certain embodiments, the liquid crystalline polymer can be a "high cycloalkane" polymer in the sense that it contains a relatively high content of repeating units derived from cycloalkane hydroxycarboxylic acids and cycloalkane dicarboxylic acids (e.g., NDA, HNA, or combinations thereof). That is, the total amount of repeating units derived from cycloalkane hydroxycarboxylic acids and / or cycloalkane dicarboxylic acids (e.g., NDA, HNA, or combinations of HNA and NDA) is typically about 10 mol% or more of the polymer, in some embodiments about 12 mol% or more, in some embodiments about 15 mol% or more, in some embodiments about 18 mol% or more, in some embodiments about 30 mol% or more, in some embodiments about 40 mol% or more, in some embodiments about 45 mol% or more, in some embodiments about 50 mol% or more, in some embodiments about 55 mol% or more, and in some embodiments from about 55 mol% to about 95 mol%. Without being limited by theory, it is believed that such "high cycloalkane" polymers are capable of reducing the tendency of the polymer composition to absorb water, which aids in the processability and proper alignment of the microneedles. That is, the water absorption of such high cycloalkane polymers is typically about 0.015% or less, in some embodiments about 0.01% or less, and in some embodiments from about 0.0001% to about 0.008% according to ISO 62-1 :2008 after immersion in water for 24 hours. The moisture adsorption of such high cycloalkane polymers can also be about 0.01% or less, in some embodiments about 0.008% or less, and in some embodiments from about 0.0001% to about 0.006% according to ISO 62-4:2008 after exposure to a humid environment (50% relative humidity) at a temperature of 23 °C.

[0035] For example, in one embodiment, repeating units derived from HNA can comprise 30 mole percent or more of the polymer, in some embodiments about 40 mole percent or more, in some embodiments about 45 mole percent or more, in some embodiments 50 mole percent or more, in some embodiments about 55 mole percent or more, and in some embodiments about 55 mole percent to about 95 mole percent. In such embodiments, the liquid crystalline polymer can comprise various other monomers, for example, aromatic hydroxycarboxylic acid (e.g., HBA) in an amount of about 1 mole percent to about 50 mole percent, and in some embodiments about 1 mole percent to about 20 mole percent, and in some embodiments about 2 mole percent to about 10 mole percent; aromatic dicarboxylic acid (e.g., IA and / or TA) in an amount of about 1 mole percent to about 40 mole percent, and in some embodiments about 5 mole percent to about 25 mole percent; and / or aromatic diol (e.g., BP and / or HQ) in an amount of about 1 mole percent to about 40 mole percent, and in some embodiments about 5 mole percent to about 25 mole percent. In another embodiment, repeating units derived from NDA can comprise 10 mole percent or more of the polymer, in some embodiments about 12 mole percent or more, in some embodiments about 15 mole percent or more, and in some embodiments about 18 mole percent to about 95 mole percent. In such embodiments, the liquid crystalline polymer can further comprise various other monomers, for example, aromatic hydroxycarboxylic acid (e.g., HBA) in an amount of about 20 mole percent to about 60 mole percent, and in some embodiments about 30 mole percent to about 50 mole percent; aromatic dicarboxylic acid (e.g., IA and / or TA) in an amount of about 2 mole percent to about 30 mole percent, and in some embodiments about 5 mole percent to about 25 mole percent; and / or aromatic diol (e.g., BP and / or HQ) in an amount of about 2 mole percent to about 40 mole percent, and in some embodiments about 5 mole percent to about 35 mole percent.

[0036] Of course, "low cycloalkane" liquid crystalline polymers can also be used in the composition, either alone or in combination with "high cycloalkane" liquid crystalline polymers. In such low cycloalkane polymers, the total amount of repeating units derived from cycloalkane hydroxycarboxylic acid and / or cycloalkane dicarboxylic acid (e.g., NDA, HNA, or a combination of HNA and NDA) is typically less than 10 mole percent of the polymer, in some embodiments about 8 mole percent or less, in some embodiments about 6 mole percent or less, and in some embodiments about 1 mole percent to about 5 mole percent.

[0037] Regardless of the specific composition and nature of the polymer, the liquid crystalline polymer can be prepared by first introducing aromatic monomers for forming ester repeat units (e.g., aromatic hydroxycarboxylic acids, aromatic dicarboxylic acids, etc.), and / or other repeat units (e.g., aromatic diols, aromatic amides, aromatic amines, etc.) into a reaction vessel to initiate a polycondensation reaction. The specific conditions and procedures used in such a reaction are well known and can be found in U.S. Patent No. 4,161,470 to Calundann, Linstid, III et al. U.S. Patent No. 5,616,680 to Linstid, III et al. U.S. Patent No. 6,114,492 to Shepherd et al. U.S. Patent No. 6,514,611 to Waggoner and WO 2004 / 058851. The vessel used for the reaction is not particularly limited, although it is generally desirable to use a vessel commonly used for high viscosity fluid reactions. Examples of such reaction vessels can include stirred tank type apparatus having an agitator with variable shaped agitator blades, such as anchor type, multiple stage type, ribbon type, helical shaft type, etc., or modified versions thereof. Further examples of such reaction vessels can include mixing apparatus commonly used in resin kneading, such as a kneader, roll mill, Banbury mixer, etc.

[0038] If desired, the reaction can be carried out by acetylation of the monomers as is known in the art. This can be accomplished by adding an acetylating agent (e.g., acetic anhydride) to the monomers. Acetylation is generally initiated at a temperature of about 90 °C. During the initial stages of acetylation, refluxing can be employed to maintain the gas phase temperature below the temperature at which acetic acid byproduct and anhydride begin to distill. The temperature during acetylation is generally between 90 °C and 150 °C, and in some embodiments between about 110 °C and about 150 °C. If refluxing is used, the gas phase temperature will generally exceed the boiling point of acetic acid, but still remain low enough to preserve residual acetic anhydride. For example, acetic anhydride vaporizes at a temperature of about 140 °C. It is therefore particularly desirable to provide a gas phase reflux to the reactor at a temperature of about 110 °C to about 130 °C. To ensure that the reaction is substantially complete, an excess of acetic anhydride can be used. The amount of excess anhydride will vary depending on the specific acetylation conditions used, including the presence or absence of refluxing. It is not uncommon to use an excess of about 1 mole % to about 10 mole % of acetic anhydride based on the total moles of reactant hydroxyl groups present.

[0039] Acetylation can occur in a separate reactor vessel, or it can occur in situ within the polymerization reactor vessel. When a separate reactor vessel is used, one or more monomers can be introduced into the acetylation reactor and subsequently transferred to the polymerization reactor. Likewise, one or more monomers can be introduced directly into the reactor vessel without pre-acetylation.

[0040] In addition to the monomers and optional acetylating agent, other components can be included in the reaction mixture to help facilitate polymerization. For example, a catalyst can optionally be used, such as metal salt catalysts (e.g., magnesium acetate, tin (I) acetate, tetrabutyl titanate, lead acetate, sodium acetate, potassium acetate, etc.) and organic compound catalysts (e.g., N-methyl imidazole). These catalysts are typically used in amounts of about 50 ppm to about 500 ppm, based on the total weight of the repeating unit precursors. When separate reactors are used, it is often desirable to apply the catalyst to the acetylation reactor rather than the polymerization reactor, although this is by no means necessary.

[0041] The reaction mixture is typically heated to an elevated temperature within the polymerization reactor vessel to initiate the melt polycondensation of the reactants. The polycondensation can occur, for example, in the temperature range of about 250 °C to about 380 °C, and in some embodiments, about 280 °C to about 380 °C. For example, one suitable technique for forming an aromatic polyester can include charging the precursor monomers and acetic anhydride into a reactor, heating the mixture to a temperature of about 90 °C to about 150 °C to acetylate (e.g., form acetoxy groups) the hydroxyl groups of the monomers, and then increasing the temperature to about 280 °C to about 380 °C to perform the melt polycondensation. As the final polymerization temperature is approached, the volatile byproducts of the reaction (e.g., acetic acid) can also be removed, such that the desired molecular weight can be readily achieved. The reaction mixture is typically agitated during polymerization to ensure good heat and mass transfer, and in turn, good material homogeneity. The rotational speed of the agitator can vary during the reaction, but is typically in the range of about 10 revolutions per minute to about 100 revolutions per minute (“rpm”), and in some embodiments, about 20 rpm to about 80 rpm. To increase the molecular weight in the melt, the polymerization reaction can also be performed under vacuum, the application of which helps to remove volatiles formed during the final stages of polycondensation. The vacuum can be generated by applying a suction pressure, for example, in the range of about 5 to about 30 pounds per square inch (“psi”), and in some embodiments, about 10 psi to about 20 psi.

[0042] After melt polymerization, the melt polymer can be discharged from the reactor, typically through an extrusion orifice fitted with a die of the desired configuration, cooled, and collected. Typically, the melt is discharged through a perforated die to form strands, which are then subjected to a water bath, pelletized, and dried. In some embodiments, the melt polymerized polymer can also be subjected to a subsequent solid state polymerization process to further increase its molecular weight. The solid state polymerization can be conducted in the presence of a gas (e.g., air, an inert gas, etc.). Suitable inert gases can include, for example, nitrogen, helium, argon, neon, krypton, xenon, and the like, and combinations thereof. The solid state polymerization reactor vessel can actually have any design that will allow the polymer to be maintained at the desired solid state polymerization temperature for the desired residence time. Examples of such vessels can be vessels having fixed beds, static beds, moving beds, fluidized beds, and the like. The temperature at which the solid state polymerization is conducted can vary, but is typically in the range of about 250 °C to about 350 °C. The polymerization time will of course vary depending on the temperature and the target molecular weight. However, in most cases, the solid state polymerization time will be in the range of about 2 hours to about 12 hours, and in some embodiments, about 4 hours to about 10 hours.

[0043] B. Other additives

[0044] In some cases, the liquid crystalline polymer can constitute the entire polymer composition (e.g., 100 wt. %). However, in certain embodiments it can be desirable to include one or more additives in the polymer composition to help achieve the target properties. In such embodiments, the polymer composition typically includes: one or more liquid crystalline polymers in an amount of about 30 wt. % to about 99 wt. %, in some embodiments about 40 wt. % to about 95 wt. %, and in some embodiments about 50 wt. % to about 90 wt. % of the entire polymer composition; and one or more additives in an amount of about 1 wt. % to about 70 wt. %, in some embodiments about 5 wt. % to about 60 wt. %, and in some embodiments about 10 wt. % to about 50 wt. % of the polymer composition.

[0045] In use, the specific properties of the additives can vary. For example, the polymer composition may contain mineral fillers, which may be in the form of granules (e.g., flakes, sheets, etc.), fibers, etc. In one embodiment, the mineral filler may include, for example, granular mineral fillers such as talc, halloysite, kaolinite, illite, montmorillonite, vermiculite, palygorskite, pyrophyllite, mica, diatomaceous earth, etc., and combinations thereof. Mica and / or talc may be particularly suitable. In use, the inventors have found that relatively small-sized granular mineral fillers better facilitate filling of the mold cavity and ensure proper alignment of the microneedles. In a particular embodiment, for example, the granular mineral filler (e.g., talc) may have a median size (e.g., D50 size) of about 10 micrometers or less, in some embodiments about 0.1 micrometers to about 8 micrometers, in some embodiments about 0.5 micrometers to about 5 micrometers, and in some embodiments about 0.6 micrometers to about 2.5 micrometers. Besides silicates, other suitable mineral filler particles may include: carbonates, such as calcium carbonate (CaCO3) or copper hydroxide (Cu2CO3(OH)2); fluorides, such as calcium fluoride (CaFl2); phosphates, such as calcium pyrophosphate (Ca2P2O7), anhydrous calcium hydrogen phosphate (CaHPO4), or hydrated aluminum phosphate (AlPO4·2H2O); glass (e.g., glass powder); and so on. Mineral fibers (also known as “whiskers”) may also be used as mineral fillers in polymer compositions. Examples of such mineral fibers include those derived from silicates, such as neosilicate, sorosilicate, inosilicate (e.g., calcium chain silicates, such as wollastonite; calcium-magnesium chain silicates, such as tremolite; calcium-magnesium-iron chain silicates, such as actinolite; magnesium-iron chain silicates, such as anthocyanin; etc.), phyllosilicate (e.g., aluminum chain silicates, such as palygorskite), tectosilicate, etc.); sulfates, such as calcium sulfate (e.g., dehydrated or anhydrous gypsum); mineral wool (e.g., rock wool or slag wool); glass; etc. Particularly suitable are chain silicates, for example, available from Nyco Minerals under the trade name... (For example, 4W 5 or 8) The wollastonite fibers obtained. In addition to having the size characteristics described above, the mineral fibers can also have a relatively high aspect ratio (average length divided by median width) to help further enhance mechanical properties. For example, the mineral fibers can have an aspect ratio of about 1 to about 50, in some embodiments about 2 to about 20, and in some embodiments about 4 to about 15. The volume average length of these mineral fibers can be, for example, in the range of about 1 micron to about 200 microns, in some embodiments about 2 microns to about 150 microns, in some embodiments about 5 microns to about 100 microns, and in some embodiments about 10 microns to about 50 microns.

[0046] If desired, a tribological additive material can also be used in the polymer composition to help achieve a good combination of low friction and good wear resistance for the microneedle assembly. In one embodiment, for example, the tribological additive material can include a fluorinated additive. Without being limited by theory, it is believed that the fluorinated additive can improve the processability of the composition, for example, by providing better mold filling, internal lubrication, demolding, and the like. In certain embodiments, the fluorinated additive can include a fluoropolymer, which contains a hydrocarbon backbone polymer in which some or all of the hydrogen atoms are replaced with fluorine atoms. The backbone polymer can be polyolefinic and formed from fluorine-substituted unsaturated olefin monomers. The fluoropolymer can be a homopolymer of such fluorine-substituted monomers, or a copolymer of fluorine-substituted monomers, or a mixture of fluorine-substituted monomers and non-fluorine-substituted monomers. In addition to fluorine atoms, the fluoropolymer can also be substituted with other halogen atoms, such as chlorine atoms and bromine atoms. Representative monomers suitable for forming the fluoropolymer for use in the present application are tetrafluoroethylene, vinylidene fluoride, hexafluoropropylene, chlorotrifluoroethylene, perfluoroethyl vinyl ether, perfluoromethyl vinyl ether, perfluoropropyl vinyl ether, and the like, as well as mixtures thereof. Specific examples of suitable fluoropolymers include polytetrafluoroethylene, perfluoroalkyl vinyl ether, poly(tetrafluoroethylene-co-perfluoroalkyl vinyl ether), fluorinated ethylene-propylene copolymer, ethylene-tetrafluoroethylene copolymer, polyvinylidene fluoride, polychlorotrifluoroethylene, and the like, as well as mixtures thereof. The fluorinated additive can include only the fluoropolymer, or it can also include other ingredients, such as those that facilitate its ability to disperse uniformly in the polymer composition. In one embodiment, for example, the fluorinated additive can include the fluoropolymer in combination with a plurality of carrier particles. In such embodiments, for example, the fluoropolymer can be coated onto the carrier particles. Silicate particles are particularly suitable for this purpose, such as talc, halloysite, kaolinite, illite, montmorillonite, vermiculite, palygorskite, pyrophyllite, calcium silicate, aluminum silicate, mica, diatomite, wollastonite, and the like. Mica, for example, can be particularly suitable for use in the present application. The carrier particles can have an average particle size of about 5 microns to about 50 microns in particle diameter, and in some embodiments about 10 microns to 20 microns. If desired, the carrier particles can also be in the shape of plate-like particles, in that they have a ratio of long axis to thickness of 2 or greater.

[0047] A variety of other additional additives can also be included in the polymer composition, such as lubricants, fibrous fillers (e.g., glass fibers), thermally conductive fillers, pigments, antioxidants, stabilizers, surfactants, waxes, flame retardants, anti-drip additives, nucleating agents (e.g., boron nitride), flow modifiers, coupling agents, antibacterial agents, pigments or other colorants, impact modifiers, and other materials added to enhance performance and processing properties.

[0048] II. Forming

[0049] The components used to form the polymer composition can be combined together using any of a variety of different techniques known in the art. In one particular embodiment, for example, the liquid crystalline polymer and other optional additives are melt processed as a mixture within an extruder to form the polymer composition. The mixture can be melt kneaded in a single-screw extruder or a multi-screw extruder at a temperature of about 200 °C to about 450 °C. In one embodiment, the mixture can be melt processed in an extruder comprising multiple temperature zones. The temperature of each zone is typically set in the range of about -60 °C to about 25 °C relative to the melting temperature of the polymer. By way of example, the mixture can be melt processed using a twin-screw extruder, such as a Leistritz 18-mm co-rotating intermeshing twin-screw extruder. A general purpose screw design can be used to melt process the mixture. In one embodiment, the mixture comprising all of the components can be fed through a volumetric feeder to a feed throat in a first barrel. In another embodiment, different components can be added at different addition points of the extruder, as is known. For example, the polymer can be applied at the feed throat, and certain additives (e.g., particulate fillers) can be supplied at the same or different temperature zones located downstream from the feed throat. Regardless, the resulting mixture can be melted and mixed, and then extruded through a die. The extruded polymer composition can then be quenched in a water bath to solidify and pelletized in a pelletizer, followed by drying.

[0050] The resulting polymer composition is typically formed to have a melt viscosity that is sufficiently low to enable it to be easily molded into the small dimensions required for microneedles. For example, the polymer composition can have a melt viscosity of about 100 Pa-s or less, in some embodiments about 80 Pa-s or less, in some embodiments about 1 Pa-s to about 60 Pa-s, and in some embodiments about 2 Pa-s to about 50 Pa-s, as determined according to ISO Test No. 11443:2014 at a shear rate of 1,000 sec -1 The polymer composition can also have a melt viscosity of about 150 Pa-s or less, in some embodiments about 100 Pa-s or less, in some embodiments about 5 Pa-s to about 90 Pa-s, and in some embodiments about 10 Pa-s to about 70 Pa-s, as determined according to ISO Test No. 11443:2014 at a shear rate of 400 sec -1 and a temperature that is about 30 °C higher than the melting temperature (e.g., about 380 °C).

[0051] Generally, it is believed that polymer compositions exhibiting such low melt viscosities would not also have sufficiently good thermal and mechanical properties to achieve good physical integrity for forming microneedles that are substantially aligned and have uniform shape and dimensions. However, contrary to conventional thinking, the present inventors have discovered that by careful control of the particular liquid crystalline polymer and / or other optional materials used, the resulting polymer composition can also have excellent thermal and mechanical properties. More particularly, the polymer composition typically has a melting temperature of about 280°C or more, in some embodiments about 300°C or more, in some embodiments about 320°C or more, and in some embodiments about 330°C to about 450°C, for example as determined according to ISO 11357-2:2013. Even at such melting temperatures, the ratio of the deflection temperature under load ("DTUL") (a measure of short term heat resistance) to the melting temperature can remain relatively high, which can allow for the use of high speed processes to form microneedles, among other things. For example, the ratio can be in the range of about 0.5 to about 1.00, in some embodiments about 0.65 to about 0.95, and in some embodiments about 0.75 to about 0.85. For example, the particular DTUL value can be about 160°C or more, in some embodiments about 200°C to about 350°C, in some embodiments about 220°C to about 320°C, and in some embodiments about 250°C to about 300°C, for example as determined according to ISO Test No. 75-2:2013 (technically equivalent to ASTM D648-07) at a load of 1.8 megapascals.

[0052] The polymer composition can generally be hard in nature, such that it is able to maintain a desired degree of physical integrity during microneedle formation. Such hardness can generally be characterized by a low tensile elongation and / or a high tensile modulus. For example, the tensile elongation can be about 5% or less, in some embodiments about 4% or less, in some embodiments from about 0.1% to about 3.5%, in some embodiments from about 0.2% to about 3%, and in some embodiments from about 0.5% to about 2.5%, for example as determined according to ISO Test No. 527:2012 at a temperature of about 23 °C. The tensile modulus likewise can be about 7,000 MPa or more, in some embodiments about 7,500 MPa or more, in some embodiments from about 8,000 MPa to about 25,000 MPa, in some embodiments from about 8,500 MPa to about 20,000 MPa, and in some embodiments from about 9,000 MPa to about 15,000 MPa, for example as determined according to ISO Test No. 527:2012 at a temperature of about 23 °C. The polymer composition can also exhibit other good mechanical properties. For example, the polymer composition can exhibit a tensile strength of about 10 MPa or more, in some embodiments about 50 MPa or more, in some embodiments from about 70 MPa to about 300 MPa, and in some embodiments from about 80 MPa to about 200 MPa, for example as determined according to ISO Test No. 527:2012 at a temperature of about 23 °C.

[0053] The polymer composition can also exhibit a flexural strength of from about 40 MPa to about 500 MPa, in some embodiments from about 50 MPa to about 300 MPa, and in some embodiments from about 100 MPa to about 200 MPa; a flexural strain at break of from about 0.5% to about 15%, in some embodiments from about 0.6% to about 10%, and in some embodiments from about 1% to about 5%; and / or a flexural modulus of from about 5,000 MPa to about 20,000 MPa, in some embodiments from about 6,000 MPa to about 15,000 MPa, and in some embodiments from about 8,000 MPa to about 12,000 MPa. Flexural properties can be determined according to ISO Test No. 178:2010 (technically equivalent to ASTM D790-10) at 23 °C. The composition can also exhibit a Charpy unnotched and / or notched impact strength of about 1 kJ / m 2 or more, in some embodiments from about 1.5 kJ / m 2 to about 30 kJ / m 2 , and in some embodiments from about 2 kJ / m 2 to about 20 kJ / m 2measured at 23 °C according to ISO Test No. 179-1 :2010 (technically equivalent to ASTM D256-10e1).

[0054] III. Microneedle assembly

[0055] The microneedle assembly generally includes one or more microneedles extending outwardly from a support. The microneedles can be formed using any of a variety of techniques, such as embossing (e.g., hot embossing, roll-to-roll molding, etc.); molding, such as micro-molding, injection molding (e.g., low pressure injection molding, gas injection molding, foam injection molding, etc.), compression molding (e.g., extrusion compression molding), extrusion molding; printing (e.g., three-dimensional printing); and the like. For example, an injection molding system can be employed that includes a mold into which a polymeric composition can be injected. The time within the injector can be controlled and optimized so that the polymeric matrix is not pre-solidified. When the cycle time is reached and the barrel is full to discharge, a piston can be used to inject the composition into the mold cavity. A compression molding system can also be used. As with injection molding, the polymeric composition is shaped into the desired article within a mold. The composition can be placed into the compression mold using any known technique, such as by robotic arm pick-up. The temperature of the mold can be maintained at or above the solidification temperature of the polymeric matrix for a desired period of time to allow for solidification. The molded product can then be solidified by placing the molded product at a temperature below the melting temperature. The resulting product can be de-molded. The cycle time of each molding process can be adjusted to accommodate the polymeric matrix to achieve sufficient bonding and to improve the productivity of the overall process.

[0056] For example, with reference to Figures 1-4 a particular embodiment of a microneedle assembly 100 is shown in greater detail that includes a plurality of microneedles 110 (e.g., a microneedle array) extending outwardly from a surface 121 of a support 120. The support 120 can also be formed from a polymeric composition as well as from a rigid or flexible sheet of metal, ceramic, plastic, or other material. The thickness of the support 120 can vary to meet the needs of a particular application, such as about 1,000 micrometers or less, in some embodiments from about 1 micrometer to about 500 micrometers, and in some embodiments from about 10 micrometers to about 200 micrometers.

[0057] The microneedles 110 can be arranged in a variety of patterns on the support 120. As shown, for example, the microneedles 110 can be arranged in an array that includes one or more predetermined geometric patterns. The predetermined patterns can vary as desired, such as straight lines, circles, rectangles, squares, parabolas, and the like. The array can also include combinations of these patterns, such as a plurality of lines arranged in a grid, concentric circles, and the like. For example, in some embodiments, the microneedles 110 can be arranged in a pattern that includes a plurality of lines arranged in a grid, such as a plurality of lines extending in a first direction and a plurality of lines extending in a second direction that is perpendicular to the first direction. In some embodiments, the microneedles 110 can be arranged in a pattern that includes a plurality of lines arranged in a grid, such as a plurality of lines extending in a first direction and a plurality of lines extending in a second direction that is parallel to the first direction. In some embodiments, the microneedles 110 can be arranged in a pattern that includes a plurality of lines arranged in a grid, such as a plurality of lines extending in a first direction and a plurality of lines extending in a second direction that is non-parallel to the first direction. Figures 1-2 Figure 2 ​In this pattern, the array is a grid comprising lines 102 extending along a first direction "B" and lines 104 extending along a second direction "W," which is typically perpendicular to the first direction "B." The spacing of the microneedles 110 within a given pattern can depend on many factors, including the height and width of the microneedles 110, and the amount and type of material intended to move through the microneedles. For example, the spacing between the tips of the microneedles 110 ( Figure 1 The distance between the bases of the microneedles 110 can be about 20 micrometers or larger, in some embodiments about 60 micrometers to about 800 micrometers, and in some embodiments about 100 micrometers to about 600 micrometers. The spacing between the bases of the microneedles 110 can be the same as or different from the spacing between the tips. In some embodiments, for example, the spacing between the bases of the microneedles can be about 50 micrometers or larger, in some embodiments about 100 micrometers to about 1,000 micrometers, and in some embodiments about 200 micrometers to about 800 micrometers. The density of the microneedles 110 within the array can also vary, for example, per square centimeter (cm²). 2 The number of microneedles 110 used in component 100 may range from about 2,000 to about 10,000 in some embodiments, from about 3,000 to about 25,000 microneedles per square centimeter, and from about 5,000 to about 20,000 microneedles per square centimeter in some embodiments.

[0058] Microneedles typically consist of a base and a tip. The specific geometries of these portions (e.g., shape and size) can vary as is known in the art. For example, see reference... Figures 3-4 The diagram illustrates one embodiment of a microneedle 110 extending in a longitudinal direction “y” and comprising a base 113 and a tip 112. The base 113 has a width or diameter “D” extending in a transverse direction “x” (generally perpendicular to the longitudinal direction “y”) and is defined between two substantially parallel side surfaces. The base 113 may generally include: a lower portion 115 located near a support 120; and an opposing upper portion 117 extending from the lower portion 115 in the longitudinal direction “y” and located near the tip 112. In some embodiments, the upper portion 117 is defined as follows: Figure 3 The upper edge 114 is shown; however, the tip 112 may also be formed as an integral structure with the upper portion 117, so that there is no separate edge. The tip 112 of the microneedle extends longitudinally "y" from the upper portion 117 of the base 113 and terminates at the edge 111.

[0059] The tip 112 generally has a width or diameter "Dl" and a length "LI" which can vary depending on the particular application. For example, the length of the tip 112 can range from about 5 nanometers to about 500 nanometers, in some embodiments from about 10 nanometers to about 200 nanometers, and in some embodiments from about 20 nanometers to about 100 nanometers, while the width of the tip can range from about 0.5 micrometers to about 5 micrometers, in some embodiments from about 0.6 micrometers to about 4 micrometers, and in some embodiments from about 1 micrometer to about 3.5 micrometers. The base 113 likewise has a width or diameter "D" and a length "L2". Generally, the length of the base is greater than the length of the tip. The width of the base 113 can be equal to or greater than the width of the tip 112. For example, the length of the base of the microneedle can range from about 10 nanometers to about 1,000 nanometers, in some embodiments from about 20 nanometers to about 500 nanometers, and in some embodiments from about 30 nanometers to about 100 nanometers; while the width of the base can range from about 5 nanometers to about 100 nanometers, in some embodiments from about 10 nanometers to about 80 nanometers, and in some embodiments from about 20 nanometers to about 70 nanometers. The aspect ratio of the cross-sectional length:width of the base can likewise be relatively high, for example about 2: 1 or greater, in some embodiments from about 2: 1 to about 20: 1, and in some embodiments from about 3: 1 to about 10: 1.

[0060] In certain embodiments, the microneedle can have a generally convex profile. The convex profile can extend the entire length of the microneedle or only a portion of the microneedle. For example, in Figure 1 the convex profile tapers in a gradual manner from the edge 111 of the tip 112 to the lower portion of the base 113. However, in other embodiments, the convex profile need not be present over the entire length of the microneedle. For example, in Figures 3-4 the convex profile extends only from the edge 111 of the tip 112 to the upper portion 117 of the base 113. Regardless of the specific geometry, the degree of the convex profile can vary and can be characterized as a cone angle "a" which is the angle measured between the outer surface of the tip 112 and a centerline "C" extending through the center of the base 113 in the longitudinal direction "y". For microneedles having a purely conical profile, the cone angle a will generally be constant along the length of the protrusion 110. However, in other cases, the cone angle a can vary along the length of the protrusion 110. For example, the cone angle a can range from about 0 degrees to 20 degrees, in some embodiments from about 0 degrees to 15 degrees, in some embodiments from about 1 degree to about 15 degrees, and in some embodiments from about 2 degrees to about 10 degrees. If desired, the microneedle can also include a stepped portion to help ensure a more consistent penetration depth. The stepped portion generally provides an offset distance from the outer surface of the tip and the outer surface of the base. Again referring to Figures 3-4For example, step portions can be provided on the upper surface 114 of the base 113. The offset distance of each of these portions can vary, but is typically from 0.1 microns to about 100 microns, in some embodiments from about 0.2 microns to about 50 microns, and in some embodiments from about 0.5 microns to about 25 microns.

[0061] Each microneedle can have an overall length "L" that is sized to penetrate at least the outermost layer of the epidermis (i.e., the stratum corneum), but optionally not so large that they penetrate the dermis. For example, the length can be from about 10 nanometers to about 1,200 nanometers, in some embodiments from about 20 nanometers to about 600 nanometers, and in some embodiments from about 30 nanometers to about 200 nanometers. It should be noted that while the above figures illustrate bases and tips that contain only a single portion, each of these components can also be formed from multiple segments. For example, in certain embodiments, the base can be formed from a first segment located proximate the support and a second segment that covers the first segment. The tip typically covers the second segment, which can have the same or different size and / or shape as the first segment.

[0062] Regardless of the particular geometry employed, the present inventors have discovered that by selectively controlling the particular components of the polymeric composition employed in the microneedle, the resulting microneedle can exhibit a high degree of physical alignment. The physical alignment of the microneedle can be characterized in a number of ways. For example, one method for determining the physical alignment of the microneedle is through the "offset factor" k, which is determined according to the following equation:

[0063] k = O / ((Li + L2) / D)

[0064] wherein,

[0065] O is the distance that the tip (e.g., the tip edge) is offset from the centerline "C" in the lateral direction "x" that is typically perpendicular to the longitudinal direction "y" ( Figure 3 and Figure 5 );

[0066] Li is the length of the tip ( Figure 3 );

[0067] L2 is the length of the base ( Figure 3 ); and

[0068] D is the width or diameter of the microneedle ( Figure 3 ).

[0069] Figure 5The offset distance is explained in more detail. That is, for illustrative purposes, the edge 111 of the tip 112 is shown offset from the centerline "C" by a distance "O" in the lateral direction "x". Due to the alignment of the height achieved in the present application, the offset factor is relatively small, such as about 20 or less, in some embodiments about 15 or less, in some embodiments about 10 or less, in some embodiments about 5 or less, and in some embodiments from 0 to about 4. The actual value of the offset distance "O" can vary, but is typically about 100 microns or less, in some embodiments about 80 microns or less, in some embodiments about 50 microns or less, in some embodiments about 25 microns or less, in some embodiments about 15 microns or less, in some embodiments about 10 microns or less, in some embodiments about 5 microns or less, in some embodiments less than about 1 micron or less, and in some embodiments about 0.5 microns or less. Likewise, in the illustrated diagram, the edge 111 of the tip 112 is oriented at an angle β of about 15 degrees or less, in some embodiments about 10 degrees or less, and in some embodiments about 5 degrees or less, relative to the centerline "C". Figure 5

[0070] Another method for determining the physical alignment of a plurality of microneedles is by measuring the distance that the tip (e.g., the tip edge) is spaced apart from a desired predetermined geometric pattern (e.g., a line) of the array (in which the microneedles are arranged). Again referring to Figure 2 , for example, the microneedles 110 within the predetermined line 102 are generally arranged such that each tip 111 can be offset from the line 102 in a "W" direction, which is generally perpendicular to the direction "B" in which the line 102 extends. Similar to the offset factor "k", the degree of physical alignment of the microneedles relative to the predetermined geometric pattern can be characterized by an offset factor "p", as determined according to the following equation:

[0071] p = G / ((L1+L2) / D)

[0072] wherein,

[0073] G is the distance that the tip (e.g., the tip edge) is offset from the predetermined geometric pattern (e.g., the line 102 and / or 104 in Figure 2 );

[0074] L1 is the length of the tip ( Figure 3 );

[0075] L2 is the length of the base ( Figure 3 ); and

[0076] D is the width or diameter of the microneedle ( Figure 3 ). ​

[0077] Again, since high alignment is achieved in the present application, the offset factor "p" can be relatively small, such as about 20 or less, in some embodiments about 15 or less, in some embodiments about 10 or less, in some embodiments about 5 or less, and in some embodiments from 0 to about 4. The actual value of the offset distance "G" can vary, but is typically about 100 microns or less, in some embodiments about 80 microns or less, in some embodiments about 50 microns or less, in some embodiments about 25 microns or less, in some embodiments about 15 microns or less, in some embodiments about 10 microns or less, in some embodiments about 5 microns or less, in some embodiments less than about 1 micron or less, and in some embodiments about 0.5 microns or less. Again, the microneedles 110 within the predetermined line 104 are typically arranged such that each of the tips 111 is offset from the second line 104 in the "B" direction by only about 5 microns or less, in some embodiments less than about 1 micron or less, and in some embodiments about 0.5 microns or less.

[0078] The manner in which the microneedle assembly delivers the pharmaceutical compound can vary as known in the art. In certain embodiments, for example, the pharmaceutical compound can be coated onto the surface of the microneedles. Various coating techniques can be employed, such as dipping, spraying, printing (e.g., inkjet printing, spotting, non-contact printing, drop-on-demand piezoelectric microdispensing, etc.), and the like. For example, the microneedles can be dipped into a reservoir of the pharmaceutical compound through a dipping aperture that is spaced according to the microneedle array. The microneedles can also be sprayed with the pharmaceutical compound and then dried with a gas. In yet another embodiment, the microneedles can be coated with the pharmaceutical compound through a printing technique. For example, in Wang et al. Various suitable printing techniques are described in U.S. Patent Publication No. 2018 / 0326726 to Kwon et al., the entirety of which is incorporated by reference herein. For example, a piezoelectric stack actuator can be used as a drive assembly that dispenses a fluid pharmaceutical compound (or a fluid containing the compound) from a pump chamber through a two-dimensional array of nozzles. The nozzles are aligned with the microneedles such that the dispensed fluid is coated onto the surface of the microneedles.

[0079] In embodiments where the pharmaceutical compound is coated onto the surface of the microneedles, the microneedles can be solid in nature, as described above, and thus lack hollow channels and / or pores for fluid delivery. In such embodiments, the microneedle assembly does not require conventional components (e.g., a drug reservoir, a release member, etc.) to drive delivery of the pharmaceutical compound. Examples of such solid microneedles are described in, for example, U.S. Patent Publication No. 2018 / 0264244 to Kwon et al., the entirety of which is incorporated by reference herein. Meliga et al.

[0080] ​Of course, in alternative embodiments, one or more microneedles can include one or more channels of a particular size such that passive capillary flow can drive delivery of the pharmaceutical compound. For example, the microneedle can define at least one channel in fluid communication with the pharmaceutical compound, such as through an aperture of the support. Such channels can be located on the outer surface and / or inner surface of the microneedle. The size of the channel is specifically selected in the present application to induce capillary flow of the pharmaceutical compound. Capillary flow generally occurs when the adhesion of the fluid to the channel wall is greater than the cohesive forces between the liquid molecules. Specifically, the capillary pressure is inversely proportional to the cross-sectional size of the channel and directly proportional to the product of the liquid surface tension and the cosine of the contact angle of the material forming the channel when in contact with the fluid. Thus, to promote capillary flow, the cross-sectional size (e.g., width, diameter, etc.) of the channel can be selectively controlled, with smaller sizes generally resulting in higher capillary pressures. For example, in some embodiments, the cross-sectional size of the channel can range from about 1 micron to about 100 microns, in some embodiments from about 5 microns to about 50 microns, and in some embodiments from about 10 microns to about 30 microns. The size can be constant or it can vary with the length of the channel. The length of the channel can also vary to accommodate different volumes, flow rates, and residence times of the pharmaceutical compound. For example, the length of the channel can range from about 10 microns to about 800 microns, in some embodiments from about 50 microns to about 500 microns, and in some embodiments from about 100 microns to about 300 microns. The cross-sectional area of the channel can also vary. For example, the cross-sectional area can range from about 50 square microns to about 1,000 square microns, in some embodiments from about 100 square microns to about 500 square microns, and in some embodiments from about 150 square microns to about 350 square microns. Furthermore, the aspect ratio (length / cross-sectional size) of the channel can range from about 1 to about 50, in some embodiments from about 5 to about 40, and in some embodiments from about 10 to about 20. In the case where the cross-sectional size (e.g., width, diameter, etc.) and / or length varies with length, the aspect ratio is determined by the average size.

[0081] Regardless of the type employed, the microneedle assembly can deliver a controlled volume of the pharmaceutical compound through the skin. For example, the microneedle assembly can be placed in proximity to the skin of a subject (e.g., a human) and pressure can be applied to the skin such that the microneedles penetrate at least into the stratum corneum layer of the epidermis.

[0082] If desired, the microneedle assembly can be placed in fluid communication with a reservoir, which can initially retain the pharmaceutical compound, particularly in those embodiments employing one or more channels. The term "reservoir" generally refers to a designated region or chamber configured to retain a fluid pharmaceutical compound. The reservoir can be an open volume space, a gel, a solid structure, etc. In most embodiments, however, the reservoir is a solid matrix through which the pharmaceutical compound is able to flow. The selection of the desired material for the matrix generally depends on the solubility and diffusivity of the target pharmaceutical compound and the time period for which release is sought. In one embodiment, for example, the solid matrix is generally impermeable to the pharmaceutical compound, and the material used to form the matrix is selected so that the pharmaceutical compound is able to diffuse from the matrix. In other embodiments, however, the solid matrix can be permeable or semi-permeable to the pharmaceutical compound, such that the pharmaceutical compound can simply flow through the pores of the solid matrix. Examples of such solid matrices include porous fiber webs (e.g., woven or nonwoven), porous films, foams, sponges, etc. Regardless of its specific form, a polymeric material is generally used to form the solid matrix, such as silicone, acrylic resin, olefin polymer (e.g., ethylene-vinyl acetate), plasticized polyvinyl acetate / polyvinyl chloride resin, plasticized hydrolyzed polyvinyl alcohol, rubber-based adhesive (e.g., polyisobutylene thickened with a solvent such as mineral oil), plasticized polyvinyl chloride, polyethylene glycol and polypropylene glycol of different molecular weights, cellulose ester, etc.

[0083] Multiple reservoirs can also be employed to store multiple delivery materials in certain embodiments. The reservoirs can be positioned adjacent to one another in a vertical or horizontal relationship. For example, a first reservoir can contain a pharmaceutical compound and a second reservoir can contain an excipient (e.g., a delivery carrier such as an alcohol, water, etc.; a buffer; etc.). In one particular embodiment, for example, a first reservoir can contain a lyophilized powder of a pharmaceutical compound and a second reservoir can contain an aqueous solution for reconstituting the powder. Alternatively, multiple reservoirs can be used, each containing a pharmaceutical compound. The different materials can be mixed prior to delivery.

[0084] In certain embodiments, the microneedle assembly and drug reservoir can be integrated together in the form of a transdermal delivery device (e.g., a patch). This approach can also include other elements to help maintain the desired flow of the drug compound. For example, the drug reservoir can be in fluid communication with a rate control membrane that helps control the flow rate of the drug compound by regulating the pressure downstream of the reservoir. The rate control membrane can help slow the flow rate as the drug compound is released. Specifically, the fluid drug compound passing from the drug reservoir to the microneedle assembly can experience a drop in pressure that results in a reduced flow rate. If this difference is too great, some back pressure can be created that impedes the flow of the compound and can potentially overcome the capillary pressure of the fluid through the microfluidic channel. Thus, the use of a rate control membrane can ameliorate this pressure differential and allow the drug compound to be introduced to the microneedles at a more controlled flow rate. The specific material, thickness, etc. of the rate control membrane can vary based on a variety of factors, such as the viscosity of the drug compound, the desired delivery time, etc. The rate control membrane can, for example, include a permeable, semi-permeable, or microporous material. Suitable membrane materials include, for example, fibrous webs (e.g., woven or nonwoven), apertured films, foams, sponges, etc. that are formed from polymers such as polyethylene, polypropylene, polyvinyl acetate, ethylene-vinyl acetate copolymer, and the like.

[0085] If desired, the transdermal delivery device can include additional layers or materials that provide various benefits. For example, the assembly can include an adhesive layer that can help facilitate attachment of the delivery device to the user's skin during use. Although not required, the adhesive layer is typically disposed above the reservoir. The adhesive layer typically uses an adhesive coated on a backing material. The backing can be made from a material (e.g., a polymer, a metal foil, etc.) that is substantially impermeable to the drug compound. Suitable polymers can include, for example, polyethylene terephthalate, polyvinyl chloride, polyethylene, polypropylene, polycarbonate, polyesters, and the like. The adhesive can be a pressure sensitive adhesive known in the art. Suitable adhesives can include, for example, solvent-based acrylic adhesives, solvent-based rubber adhesives, silicone adhesives, and the like.

[0086] The release member can also be positioned adjacent to the microneedle assembly such that the release member is adjacent to the support and optional rate controlling membrane of the microneedle assembly. It should be appreciated, however, that the release layer need not contact such layers and in fact other layers can be positioned between the release member and the support and / or rate controlling membrane. Regardless, the release member can comprise a material that is substantially impermeable to the drug compound, such as a polymeric material, metal, and the like. The material is also desirably hydrophobic. Suitable polymeric materials can include, for example, polyethylene terephthalate, polyvinyl chloride, polyethylene, polypropylene, polycarbonate, polyesters, metal foils, and the like. Because the release member is generally impermeable, the release member can initially seal the aperture in the support, thereby limiting the flow of the drug compound from the aperture. In this manner, the release member can act as a barrier to the flow of the drug compound and thus inhibit premature leakage. When use of the delivery device is desired, the user can apply a force to at least partially separate the release member, thereby breaking the seal. Separation of the release member can be accomplished in a variety of ways. For example, a portion of the release member can simply separate (e.g., split, rupture, etc.). Thus, the flow of the drug compound can be "passively" induced - i.e., without the need for a traditional active displacement mechanism, such as a liquid pump, actuator, plunger, finger pressure, etc. This allows the delivery device to be placed on the skin prior to activation, thereby limiting potential spillage of the drug compound. Passive delivery of the drug compound is also simple to use, which allows it to be used by a wide range of consumers and not just medical professionals.

[0087] There is no particular limitation on the pharmaceutical compounds that can be delivered using the microneedle assemblies of the present application. Suitable compounds can include, for example, protein compounds such as insulin, immunoglobulins (e.g., IgG, IgM, IgA, IgE), TNF-alpha, anti-viral drugs, and the like; polynucleotide agents such as plasmids, siRNA, RNAi, nucleoside anticancer drugs, vaccines, and the like; small molecule agents such as alkaloids, glycosides, phenolics, and the like; anti-infective agents, hormones, drugs that modulate cardiac action or blood flow, pain control agents; vaccines; and the like. A non-limiting list of agents includes anti-angiogenic agents, anti-depressants, anti-diabetic agents, anti-histamines, anti-inflammatory agents, butorphanol, calcitonin and analogs, COX-II inhibitors, dermatological agents, dopamine agonists and antagonists, enkephalins and other opioid peptides, epidermal growth factor, erythropoietin and analogs, follicle stimulating hormone, glucagon, growth hormone and analogs (including growth hormone releasing hormone), growth hormone antagonists, heparin, hirudin and hirudin analogs (e.g., lepirudin), IgE inhibitors and other protein inhibitors, immunosuppressants, insulin, insulinotropins and analogs, interferons, interleukins, luteinizing hormone, luteinizing hormone releasing hormone and analogs, monoclonal or polyclonal antibodies, motion sickness preparations, muscle relaxants, narcotic analgesics, nicotine, non-steroidal anti-inflammatory agents, oligosaccharides, parathyroid hormone and analogs, parathyroid hormone antagonists, prostaglandin antagonists, prostaglandins, scopolamine, sedatives, serotonin agonists and antagonists, sexual dysfunction agents, tissue plasminogen activators, tranquilizers, vaccines with or without carriers / adjuvants, vasodilators, major diagnostic agents such as tuberculin and other hypersensitivity agents.

[0088] The microneedle assemblies can be particularly advantageous for delivering high molecular weight pharmaceutical compounds. The term "high molecular weight" generally refers to compounds having a molecular weight of about 1 kilodalton ("kDa") or greater, in some embodiments about 10 kDa or greater, in some embodiments about 20 kDa to about 250 kDa, and in some embodiments greater than about 40 kDa to about 150 kDa. Examples of such high molecular weight compounds include protein therapeutics, which refers to any biologically active protein compound, including but not limited to, natural, synthetic, and recombinant compounds, fusion proteins, peptides, chimeras, and the like, as well as compounds including 20 standard amino acids and / or synthetic amino acids.

[0089] In one particular embodiment, the pharmaceutical compound can include a vaccine antigen, which is a substance that stimulates an immune response (e.g., T cell activation and / or antibody production) when introduced into the body to prevent a virus. Vaccine antigens can include a natural, whole pathogen (e.g., a bacterium or virus), a live attenuated virus, or a portion and / or subunit of a pathogen (e.g., a single viral or bacterial protein). Vaccine antigens can also include cancer antigens or fragments thereof. In one particular embodiment, for example, the vaccine antigen can be a coronavirus vaccine antigen, which is used to prevent a coronavirus (e.g., SARS-CoV-1, SARS-CoV-2, MERS-CoV, etc.). Such vaccine antigens can be derived from a coronavirus or other types of viruses. Particular examples of such coronavirus vaccine antigens can include, for example, mRNA-1273 (a novel lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine), BNT162 (an LNP-encapsulated mRNA-based vaccine), Ad5-nCoV (a recombinant type 5 adenovirus vector), ChAdOxl (an adenovirus viral vector capable of producing SARS-CoV-2 spike protein), bacTRL-Spike (a live Bifidobacterium longum bacterium that has been engineered to deliver a plasmid containing synthetic DNA encoding SARS-CoV-2 spike protein), BCG (prepared from a strain of attenuated (reduced virulence) live Mycobacterium bovis, a bovine Mycobacterium), AdCovid (an intranasal vaccine), NVX-CoV2373 (a recombinant spike protein nanoparticle), SARS recombinant spike protein plus delta inulin (a protein subunit), SARS VLPs protein and influenza Ml protein, DNA vaccine VRC-SRSDNA015-00-VP (DNA), replicative and / or non-replicative viral vectors expressing SARS-CoV S (e.g., VEEV replicon particles expressing SARS-CoV S or LV-SMENP (modified dendritic cells with lentiviral vectors expressing CoV-19 minor

[0090] Other suitable viral vaccine antigens can be derived from and / or used to prevent an adenovirus, an arenavirus, a bunyavirus, a flavivirus, a hantavirus, a hepadnavirus, a herpesvirus, a papillomavirus, a paramyxovirus, a parvovirus, a picornavirus, a poxvirus, an orthomyxovirus, a retrovirus, a reovirus, a rhabdovirus, a rotavirus, a spongiform virus, or a togavirus. Examples of such vaccine antigens can include peptides expressed by, for example, a CMV, an EBV, an influenza virus, a hepatitis A virus, a hepatitis B virus, or a hepatitis C virus, a herpes simplex virus, an HIV, an influenza virus, a Japanese encephalitis virus, a measles virus, a poliovirus, a rabies virus, a respiratory syncytial virus, a rubella virus, a smallpox virus, a varicella zoster virus, a West Nile virus, and / or a Zika virus. CMV vaccine antigens include envelope glycoprotein B and CMV pp65; EBV vaccine antigens include EBV EBNAI, EBV P18, and EBV P23; hepatitis vaccine antigens include S protein, M protein, L protein of hepatitis B virus, hepatitis B virus pre-S antigen, HBCAG DELTA, HBV HBE, hepatitis C virus RNA, HCV NS3, and HCV NS4; herpes simplex vaccine antigens include immediate early protein and glycoprotein D; human immunodeficiency virus (HIV) vaccine antigens include gene products of gag, pol, and env genes, such as HIV gp32, HIV gp41, HIV gp120, HIV gp160, HIV P17 / 24, HIV P24, HIV P55 GAG, HIV P66 POL, HIV TAT, HIV GP36, Nef protein, and reverse transcriptase; human papillomavirus (HPV) viral antigens include LI protein; influenza vaccine antigens include hemagglutinin and neuraminidase; Japanese encephalitis vaccine antigens include protein E, protein M-E, protein M-E-NS1, protein NS1, protein NS1-NS2A, and 80% E; malaria vaccine antigens include Plasmodium circumsporozoite protein (CSP), glutamate dehydrogenase, lactate dehydrogenase, and fructose diphosphate aldolase; measles vaccine antigens include measles virus fusion protein; rabies vaccine antigens include rabies glycoprotein and rabies nucleoprotein; respiratory syncytial vaccine antigens include RSV fusion protein and M2 protein; rotavirus vaccine antigens include VP7sc; rubella vaccine antigens include proteins El and E2; varicella zoster vaccine antigens include gpl and gpll; Zika vaccine antigens include pre-membrane, envelope (E), domain III of E protein, and non-structural proteins 1-5.

[0091] In the above embodiments, the microneedle assembly of the present application is generally used to deliver a pharmaceutical compound to a subject. In addition to and / or instead of pharmaceutical delivery, the microneedle assembly can also be used as a sensor. For example, the microneedle assembly can be used as a sensor only, or in other cases it can be used as a sensor to determine the dosage of a pharmaceutical compound to be delivered. Regardless, the microneedle can be placed in contact with the skin of a subject and allowed to remain in contact for a period of time sufficient to contact a bodily fluid (e.g., blood) of the subject containing an analyte of interest. The fluid can be withdrawn and tested. Alternatively, a detection system can be connected to the microneedle assembly, such as incorporated into the outer surface of a microneedle (e.g., a solid microneedle) or the interior of a microneedle (e.g., a microneedle having a hollow channel), such that the fluid can be allowed to contact the microneedle only for testing. Various examples of such sensors are known in the art and described, for example, in U.S. Patent Publication No. 2020 / 0015751 to Chickering et al., U.S. Patent Publication No. 2013 / 0225956 to Huang et al., the entireties of which are incorporated herein by reference.

[0092] Examples of target analytes that can be detected using the sensor include, but are not limited to, pH or metal ions, proteins, nucleic acids (e.g., DNA, RNA, etc.), drugs, sugars (e.g., glucose), hormones (e.g., estradiol, estrone, progesterone, progestogens, testosterone, androstenedione, etc.), carbohydrates, or other analytes of interest. Other conditions that can be determined can include pH changes, which can be indicative of disease, yeast infection, periodontal disease of the mucosal surface, oxygen or carbon monoxide levels (indicative of lung dysfunction), and drug levels (e.g., legal prescription levels of drugs such as coumarin, other drugs such as nicotine, or illegal drugs such as cocaine). Further examples of analytes include those indicative of disease, such as cancer-specific markers (e.g., CEA and PSA), viral and bacterial antigens, and autoimmune indicators (e.g., antibodies to double-stranded DNA). Still other cases include exposure to elevated carbon monoxide, which can be from external sources or due to sleep apnea, overheating (important for infants who are not fully self-regulating for internal temperature control), or fever. Other possible suitable analytes include various pathogens, such as bacteria or viruses, and / or markers produced by such pathogens. As additional non-limiting examples, the sensor can include antibodies capable of interacting with markers of a disease state, enzymes capable of detecting glucose (e.g., glucose oxidase or glucose 1-dehydrogenase), etc. The analyte can be determined quantitatively or qualitatively, and / or in some cases the presence or absence of the analyte in the withdrawn fluid can be determined.

[0093] The particular detection system used in conjunction with the microneedle assembly to detect the analyte can vary as understood by those skilled in the art. For example, various non-limiting examples of sensor technology include pressure or temperature measurements, spectroscopy such as infrared, absorption, fluorescence, UV / visible, FTIR (“Fourier Transform Infrared Spectroscopy”), or Raman; piezoelectric measurements; immunoassays; electrical measurements, electrochemical measurements (e.g., ion-specific electrodes); magnetic measurements, optical measurements (e.g., optical density measurements); circular dichroism; light scattering measurements (such as quasi-electron light scattering); polarization assays; refractometry; chemical indicators (such as dyes); or turbidity measurements, including nephelometry. For example, in one particular embodiment, the sensor can rely on electrochemical impedance for detection, and thus include at least one working electrode, which is typically located on, inside, or otherwise in fluid contact with the first microneedle. For example, the working electrode can be a metal (e.g., gold) deposited on the surface of the microneedle. The sensor can also include at least one reference electrode, which is located on, inside, or otherwise in fluid contact with the second microneedle, and / or at least one counter electrode, which is located on, inside, and / or otherwise in fluid contact with the third microneedle. For example, the reference and counter electrodes can also be made of a metal (e.g., gold) deposited on the surface of the respective microneedle. The impedance value can be detected to assess the concentration of the analyte. If desired, the sensitivity of the detection system can be increased by accumulating trace amounts of the target molecule at the electrodes. For specificity, the microneedle (e.g., the working electrode) can be surface-modified, for example, with enzymes, antibodies, aptamers, single-chain variable fragments (ScFv), carbohydrates, and combinations thereof. For example, in one embodiment, the working electrode can be modified with glucose oxidase (GOx) for glucose detection.

[0094] The application can be better understood with reference to the following examples.

[0095] Test methods

[0096] Melt Viscosity: Melt viscosity (Pa-s) can be determined according to ISO Test No. 11443:2005 at a shear rate of 400 s -1 or 1,000 s -1 and a temperature of 15 °C above the specific melting temperature (e.g., about 350 °C) using a Dynisco LCR7001 capillary rheometer. The rheometer orifice (die) has a diameter of 1 mm, a length of 20 mm, an aspect ratio of 20.1, and an entrance angle of 180°. The barrel has a diameter of 9.55 mm ± 0.005 mm, and the rod has a length of 233.4 mm.

[0097] Melting temperature: The melting temperature (“Tm”) can be determined by differential scanning calorimetry (“DSC”) as known in the art. The melting temperature is the peak melting temperature by differential scanning calorimetry (DSC) determined according to ISO Test No. 11357-2:2013. Under the DSC procedure, the sample is heated and cooled at 20 °C per minute using DSC measurements on a TA Q2000 instrument as specified in ISO Standard 10350.

[0098] Deflection temperature under load (“DTUL”): The deflection temperature under load can be determined according to ISO Test No. 75-2:2013 (technically equivalent to ASTM D648-07). More specifically, an edge-wise three-point bend test can be performed on a test bar sample having a length of 80 mm, a thickness of 10 mm, and a width of 4 mm, with a specified load (maximum outer fiber stress) of 1.8 megapascals. The test specimen can be placed in a silicone oil bath, with the temperature raised at 2 °C per minute until the test specimen deflects 0.25 mm (0.32 mm for ISO Test No. 75-2:2013).

[0099] Tensile modulus, tensile stress, and tensile elongation: Tensile properties can be tested according to ISO Test No. 527:2012 (technically equivalent to ASTM D638-14). Modulus and strength measurements can be performed on the same test bar sample having a length of 80 mm, a thickness of 10 mm, and a width of 4 mm. The test temperature can be 23 °C, and the test speed can be 1 mm / min or 5 mm / min.

[0100] Flexural modulus, flexural stress, and flexural elongation: Flexural properties can be tested according to ISO Test No. 178:2010 (technically equivalent to ASTM D790-10). The test can be performed on a 64 mm support span. The test can be performed on the center portion of an ISO 3167 multipurpose bar that is not notched. The test temperature can be 23 °C, and the test speed can be 2 mm / min.

[0101] Unnotched and notched Charpy impact strength: Charpy properties can be tested according to ISO Test No. ISO 179-1:2010 (technically equivalent to ASTM D256-10, Method B). The test can be performed using Type 1 specimen dimensions (length of 80 mm, width of 10 mm, thickness of 4 mm). When testing notched impact strength, the notch can be a Type A notch (0.25 mm bottom radius). The specimen can be cut from the center of a multipurpose bar using a single-tooth milling machine. The test temperature can be 23 °C.

[0102] Example 1

[0103] Samples 1-5 and control samples were formed for microneedle assemblies. The samples contained various combinations of liquid crystalline polymer (LCP 1 or LCP 2), talc (TALC 1 or TALC 2), and / or polytetrafluoroethylene (PTFE). LCP 1 was formed from 60% HBA, 4% HNA, 18% BP, and 18% TA. LCP 2 was formed from 48% HNA, 2% HBA, 25% BP, and 25% TA. TALC 1 had a median particle size of 4 microns and TALC 2 had a median particle size of 1 micron. Compounding was performed using an 18 mm single screw extruder. The samples were injection molded into plaques (60 mm x 60 mm). Formulations are shown below.

[0104] Control Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 LCP 1 100 - - - - - LCP 2 - 100 79 89 79 99 TALC 1 - - 21 11 - - TALC 2 - - - - 21 - PTFE - - - - - 1

[0105] Thermal and mechanical properties of samples 1-5 were tested. Results are shown below.

[0106]

[0107] Example 2

[0108] Samples 6-10 were formed for microneedle assemblies. The samples contained various combinations of liquid crystalline polymer (LCP 2), talc (TALC 1 or TALC 2), and / or polytetrafluoroethylene (PTFE). LCP was formed from 48% HNA, 2% HBA, 25% BP, and 25% TA. Compounding was performed using an 18 mm single screw extruder. The samples were injection molded into plaques (60 mm x 60 mm). Formulations are shown below.

[0109] Sample 6 Sample 7 Sample 8 Sample 9 Sample 10 LCP 2 78 88 100 58 58 TALC 1 - - - 41 - TALC 2 21 11 - - 41 PTFE 1 1 - 1 1

[0110] Thermal and mechanical properties of samples 6-10 were tested. Results are shown below.

[0111]

[0112] These and other modifications and variations to the applications can be practiced by those of ordinary skill in the art, without departing from the spirit and scope of the applications. In addition, it should be understood that aspects of the various embodiments can be interchanged both in whole and in part. In addition, it will be appreciated that those skilled with ordinary skill in the art will be able to devise many embodiments that, although not explicitly described or shown herein, embody the principles of the application and are included within its spirit and scope.

Claims

1. A microneedle assembly comprising an array of microneedles arranged in at least one predetermined geometric pattern on a support, wherein the microneedle comprises a base comprising a lower portion located in proximity to the support and an opposing upper portion extending from the lower portion in a longitudinal direction, wherein a tip extends from the upper portion of the base in the longitudinal direction and terminates in an edge, the tip, the base, or a combination thereof comprising a polymer composition comprising a liquid crystalline polymer having a melting temperature above 300 °C, wherein a ratio of a deflection temperature under load measured according to ISO Test No. 75-2:2013 at a load of 1.8 megapascals to the melting temperature is from 0.75 to 1, and wherein, a centerline extends through the base in a longitudinal direction, and further wherein the microneedle exhibits an offset factor k of 20 or less determined according to the following equation: k = O / ((LI + L2) / D) wherein, O is a distance that the edge of the tip is offset from the centerline in a transverse direction that is perpendicular to the longitudinal direction; LI is a length of the tip; and L2 is a length of the base; and D is a width of the base.

2. The microneedle assembly of claim 1, wherein the distance O is 100 micrometers or less.

3. The microneedle assembly of claim 1, wherein the length of the tip is 5 nanometers to 500 nanometers.

4. The microneedle assembly of claim 1, wherein the width of the tip is 0.5 micrometers to 5 micrometers.

5. The microneedle assembly of claim 1, wherein the length of the base is 10 nanometers to 1,000 nanometers.

6. The microneedle assembly of claim 1, wherein the width of the base is 5 micrometers to 100 micrometers.

7. The microneedle assembly of claim 1, wherein the length of the microneedle is 10 nanometers to 1,200 nanometers.

8. The microneedle assembly of claim 1, wherein the tip is offset from the predetermined geometric pattern by a distance of only 100 micrometers or less.

9. The microneedle assembly of claim 1, wherein the predetermined geometric pattern is a first line extending in a first direction, wherein the tip of the microneedle in the first line is offset from the first line by a distance in a second direction that is perpendicular to the first direction of only 100 micrometers or less.

10. The microneedle assembly of claim 9, wherein the array includes a second line extending in a second direction, wherein the tip of the microneedle in the second line is offset from the second line by a distance in the first direction of only 100 micrometers or less.

11. The microneedle assembly of claim 1, wherein the edge of the tip is oriented at an angle of 15 degrees or less relative to the centerline.

12. The microneedle assembly of claim 1, wherein the polymer composition exhibits a melt viscosity of 100 Pa-s or less as determined in accordance with ISO Test No. 11443:2014 at a shear rate of 1,000 seconds-1 and a temperature that is 30°C higher than the comparative melting temperature. 1 of 100 Pa-s or less as determined in accordance with ISO Test No. 11443:2014 at a shear rate of 1,000 seconds-1 and a temperature that is 30°C higher than the comparative melting temperature.

13. The microneedle assembly of claim 1, wherein the liquid crystal polymer has a melting temperature of 320 °C or more.

14. The microneedle assembly of claim 1, wherein the polymer composition exhibits a tensile elongation of 5% or less as determined according to ISO Test No. 527:2012 at a temperature of 23 °C.

15. The microneedle assembly of claim 1, wherein the polymer composition exhibits a load deflection temperature of 250 °C or more as determined according to ISO Test No. 75-2:2013 at a load of 1.8 megapascals.

16. The microneedle assembly of claim 15, wherein the ratio of the load deflection temperature to the melting temperature is 0.75 to 0.

95.

17. The microneedle assembly of claim 1, wherein the polymer composition exhibits a tensile modulus of 7,000 MPa or more as determined according to ISO Test No. 527:2012 at a temperature of 23 °C.

18. The microneedle assembly of claim 1, wherein the liquid crystalline polymer comprises repeat units derived from one or more aromatic dicarboxylic acids, one or more aromatic hydroxycarboxylic acids, or a combination thereof.

19. The microneedle assembly of claim 18, wherein the aromatic hydroxycarboxylic acid comprises 4-hydroxybenzoic acid, 6-hydroxy-2-naphthoic acid, or a combination thereof.

20. The microneedle assembly of claim 18, wherein the aromatic hydroxycarboxylic acid comprises terephthalic acid, isophthalic acid, 2,6-naphthalene dicarboxylic acid, or a combination thereof.

21. The microneedle assembly of claim 20, wherein the liquid crystalline polymer further comprises repeat units derived from one or more aromatic diols.

22. The microneedle assembly of claim 21, wherein the aromatic diol comprises hydroquinone, 4,4'-biphenol, or a combination thereof.

23. The microneedle assembly of claim 1, wherein the liquid crystalline polymer is wholly aromatic.

24. The microneedle assembly of claim 1, wherein the liquid crystalline polymer comprises repeat units derived from a cycloalkane hydroxycarboxylic acid and / or a cycloalkane dicarboxylic acid in an amount of 10 mole percent or more.

25. The microneedle assembly of claim 1, wherein the liquid crystalline polymer comprises repeat units derived from 6-hydroxy-2-naphthoic acid in an amount of 30 mole percent or more.

26. The microneedle assembly of claim 1, wherein liquid crystalline polymer comprises 30 to 99 weight percent of the polymer composition.

27. The microneedle assembly of claim 1, wherein the polymer composition further comprises a mineral filler.

28. The microneedle assembly of claim 27, wherein the mineral filler is in particulate form.

29. The microneedle assembly of claim 28, wherein the particulate has a median size of 10 micrometers or less.

30. The microneedle assembly of claim 28, wherein the particulate has a median size of 0.6 to 2.5 micrometers.

31. The microneedle assembly of claim 28, wherein the particulate comprises talc.

32. The microneedle assembly of claim 1, wherein the polymer composition further comprises a tribological additive material.

33. The microneedle assembly of claim 32, wherein the tribological additive material comprises a fluoropolymer.

34. The microneedle assembly of claim 1, wherein the base comprises the polymer composition.

35. The microneedle assembly of claim 1, wherein the tip comprises a polymer composition.

36. The microneedle assembly of claim 1, wherein the assembly is configured to deliver a pharmaceutical compound.

37. The microneedle assembly of claim 36, wherein the pharmaceutical compound comprises a protein compound, a polynucleotide agent, a vaccine, a small molecule agent, an anti-infective agent, a hormone, a drug that modulates cardiac action or blood flow, or a combination thereof.

38. The microneedle assembly of claim 36, wherein the pharmaceutical compound has a molecular weight of 1 kDa or greater.

39. The microneedle assembly of claim 36, wherein the pharmaceutical compound comprises a viral vaccine antigen.

40. The microneedle assembly of claim 39, wherein the vaccine antigen is a coronavirus vaccine antigen.

41. The microneedle assembly of claim 39, wherein the vaccine antigen is a viral vector, live attenuated virus, or inactivated virus.

42. The microneedle assembly of claim 39, wherein the viral vaccine antigen comprises mRNA-1273, BNT162, Ad5-nCoV, ChAdOxl, bacTRL-Spike, BCG, AdCovid, NVX-CoV2373, LV-SMENP, SARS recombinant spike protein plus delta inulin, SARS VLPs S protein and influenza Ml protein, DNA vaccine VRC-SRSDNA015-00-VP, VEEV replicon particles expressing SARS-CoV S, inactivated SARS-CoV-2 virus or viral vectors, live attenuated SARS-CoV-2 virus, or combinations thereof.

43. The microneedle assembly of claim 39, wherein the viral vaccine antigen is derived from and / or used to prevent an adenovirus, arenavirus, bunyavirus, flavivirus, hantavirus, hepadnavirus, herpesvirus, papillomavirus, paramyxovirus, parvovirus, picornavirus, poxvirus, orthomyxovirus, retrovirus, reovirus, rhabdovirus, rotavirus, spongiform virus, togavirus, or combinations thereof.

44. The microneedle assembly of claim 36, wherein the pharmaceutical compound is coated onto a surface of the microneedle.

45. The microneedle assembly of claim 44, wherein the microneedle is solid.

46. The microneedle assembly of claim 36, wherein the microneedle comprises at least one channel through which the pharmaceutical compound can flow.

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