Microneedle Components

Abstract

A microneedle assembly is provided capable of delivering drug compounds (e.g., vaccines) and / or detecting the presence of analytes. The assembly includes at least one microneedle extending outward from a support. The microneedle comprises a polymer composition containing a thermoplastic polymer with a melt temperature of about 250°C or higher. The polymer composition exhibits a melt viscosity of about 100 Pa⁻¹ or less and a tensile elongation of about 5% or less.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 016,560, filed April 28, 2020, and U.S. Provisional Patent Application No. 63 / 034,429, filed June 4, 2020, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0003] Most vaccines, due to their relatively high molecular weight and viscosity, require delivery to the recipient via oral, injection, or infusion. Unfortunately, these methods present problems for various reasons. For example, injections typically use small needles that can cause pain and may require prolonged periods of extremely high pressure to deliver the vaccine. Oral delivery similarly requires successful absorption of the vaccine through the epithelial layer of the digestive tract and avoidance of degradation by digestive substances. Injection and oral delivery also tend to deliver burst release and large fluctuations in systemic concentration of the vaccine, rather than the preferred steady-state delivery. Infusion therapy can also be used to deliver vaccines directly to blood vessels, muscles, or subcutaneous connective tissue. However, infusion therapy is invasive, increasing the risk of infusion site infection, and requires the use of pumps, percutaneous tubing, etc. Due to these issues, attempts have been made to deliver vaccines via percutaneous delivery devices. Unfortunately, due to the relatively small size of the delivery devices, manufacturing microneedles with consistent size and shape is often complex. Furthermore, microneedles are often not properly aligned, leading to inconsistent vaccine doses.

[0004] Therefore, there is a need for improved transdermal delivery devices. Summary of the Invention

[0005] According to one embodiment of the present invention, a microneedle assembly is disclosed, comprising at least one microneedle extending outwardly from a support. The microneedle comprises a polymer composition containing a thermoplastic polymer with a melt temperature of about 250°C or higher. The polymer composition exhibits a melt viscosity of about 100 Pa⁻⁶ or less and a tensile elongation of about 5% or less.

[0006] Other features and aspects of the invention are set forth in more detail below. Attached Figure Description

[0007] The remainder of the specification, including the accompanying drawings, sets forth a full and practical disclosure of the invention, including the best mode of carrying out the invention as will be apparent to those skilled in the art. In the drawings:

[0008] Figure 1 This is a SEM image of one embodiment of a microneedle assembly that can be formed according to the present invention;

[0009] Figure 2 This is a schematic plan view of one embodiment of a microneedle assembly that can be formed according to the present invention;

[0010] Figure 3 yes Figure 2 A schematic front view of a row of microneedles in the component shown;

[0011] Figure 4 yes Figure 2 A schematic front view of one embodiment of the microneedles shown in the components;

[0012] Figure 5 yes Figure 2 A schematic side view of one embodiment of the microneedles shown in the components; and

[0013] Figure 6 yes Figure 2 A schematic plan view of one embodiment of the microneedles shown in the components. Detailed Implementation

[0014] Those skilled in the art will understand that the discussion herein is merely a description of exemplary embodiments and is not intended to limit the broader aspects of the invention.

[0015] Generally, the present invention relates to a microneedle assembly capable of transdermal delivery of pharmaceutical compounds, such as vaccines, across the skin barrier of a subject (e.g., a human), and / or detection of the presence of analytes in the subject. The microneedles can be formed from a thermoplastic polymer composition having a sufficiently low melt viscosity to allow for easy molding into the small size required for the microneedles. For example, the polymer composition can have a melt viscosity of about 100 Pa⁻¹ or less, in some embodiments about 80 Pa⁻¹ or less, in some embodiments about 1 Pa⁻¹ to about 60 Pa⁻¹, and in some embodiments about 2 Pa⁻¹ to about 50 Pa⁻¹, as per ISO test 11443:2014 at 1000 s. -1 The shear rate was determined at a temperature about 30°C above the melt temperature (e.g., about 380°C). The polymer composition may also have a melt viscosity of about 150 Pa⁻¹ or less, in some embodiments about 100 Pa⁻¹ or less, in some embodiments about 5 Pa⁻¹ to about 90 Pa⁻¹, and in some embodiments about 10 Pa⁻¹ to about 70 Pa⁻¹, as per ISO test 11443:2014 at 400 s⁻¹. -1 The shear rate was measured at a temperature approximately 30°C above the melting temperature (e.g., approximately 380°C).

[0016] Typically, thermoplastic polymer compositions exhibiting such low melt viscosity are believed not to also possess sufficiently good thermal and mechanical properties to achieve good physical integrity for forming substantially aligned microneedles with consistent shape and size. However, contrary to conventional thinking, the inventors have discovered that by carefully controlling specific thermoplastic polymers and / or other optional materials used, the resulting polymer compositions can also possess excellent thermal and mechanical properties. More specifically, the polymer compositions comprise thermoplastic polymers having, for example, a melt temperature of about 250°C or higher as determined according to ISO 11357-2:2013, about 275°C or higher in some embodiments, about 300°C or higher in some embodiments, and about 320°C to about 450°C in some embodiments. Even at such melt temperatures, the ratio of deflection temperature under load (DTUL, a measure of short-term heat resistance) to melt temperature can remain relatively high, further allowing for the use of high-speed processes for forming microneedles. For example, the ratio can be from about 0.5 to 1.00, from about 0.65 to about 0.95 in some embodiments, and from about 0.75 to about 0.85 in some embodiments. For example, a specific DTUL value can be about 160°C or higher, from about 200°C to about 350°C in some embodiments, from about 220°C to about 320°C in some embodiments, and from about 250°C to about 300°C in some embodiments, for example, determined under a load of 1.8 MPa according to ISO Test 75-2:2013 (technically equivalent to ASTM D648-07).

[0017] The polymer composition can generally be rigid in nature to maintain the desired degree of physical integrity during microneedle formation. This rigidity is typically characterized by low tensile elongation and / or high tensile modulus. For example, tensile elongation can be about 5% or less, in some embodiments about 4% or less, in some embodiments about 0.1% to about 3.5%, in some embodiments about 0.2% to about 3%, and in some embodiments about 0.5% to about 2.5%, as determined, for example, according to ISO test 527:2012 at a temperature of about 23°C. Similarly, the tensile modulus can be about 7000 MPa or higher, in some embodiments about 7500 MPa or higher, in some embodiments about 8000 MPa to about 25000 MPa, in some embodiments about 8500 MPa to about 20000 MPa, and in some embodiments about 9000 MPa to about 15000 MPa, as determined, for example, according to ISO test 527:2012 at a temperature of about 23°C. The polymer composition may also exhibit other favorable mechanical properties. For example, the polymer composition may exhibit a tensile strength of about 10 MPa or higher, about 50 MPa or higher in some embodiments, about 70 MPa to about 300 MPa in some embodiments, and about 80 MPa to about 200 MPa in some embodiments, as measured, for example, at a temperature of about 23°C according to ISO test 527:2012.

[0018] The polymer composition may also exhibit: a flexural strength of about 40 MPa to about 500 MPa, in some embodiments about 50 MPa to about 300 MPa, and in some embodiments about 100 MPa to about 200 MPa; a flexural fracture strain of about 0.5% to about 15%, in some embodiments about 0.6% to about 10%, and in some embodiments about 1% to about 5%; and / or a flexural modulus of about 5000 MPa to about 20000 MPa, in some embodiments about 6000 MPa to about 15000 MPa, and in some embodiments about 8000 MPa to about 12000 MPa. Flexural properties can be determined at 23°C according to ISO Test 178:2010 (technically equivalent to ASTM D790-10). The composition may also exhibit a flexural strength of about 1 kJ / m² as determined at 23°C according to ISO Test 179-1:2010 (technically equivalent to ASTM D256-10e1). 2 Or greater, in some embodiments about 1.5 kJ / m 2 Approximately 30 kJ / m 2 and in some implementations approximately 2 kJ / m 2 Approximately 20 kJ / m 2Charpy unnotched and / or notched impact strength.

[0019] Various embodiments of the present invention will now be described in more detail.

[0020] I. polymer composition

[0021] A. thermoplastic polymers

[0022] Any of the various thermoplastic polymers having the above-described characteristics can be used in polymer compositions. Specific examples of such polymers may include, for example, fully aromatic polymers or partially aromatic polymers, such as polyarylethers (e.g., polyphenylene sulfide), polyamides (e.g., aromatic polyamides or semi-aromatic polyamides), polyarylene ketones (e.g., polyetheretherketones), liquid crystal polymers, etc., as well as aliphatic polymers, such as aliphatic polyamides.

[0023] Aromatic polymers are particularly suitable for use in this polymer composition. Aromatic polymers can be substantially semi-crystalline or crystalline. An example of a suitable semi-crystalline aromatic polymer is, for example, an aromatic polyamide. Aromatic polyamides typically contain repeating units linked together by amide bonds (NH-CO) and are synthesized by the polycondensation of dicarboxylic acids (e.g., aromatic dicarboxylic acids), diamines (e.g., aliphatic diamines), etc. For example, aromatic polyamides can contain aromatic repeating units derived from aromatic dicarboxylic acids, such as terephthalic acid, isophthalic acid, 2,6-naphthalenedicarboxylic acid, 2,7-naphthalenedicarboxylic acid, 1,4-naphthalenedicarboxylic acid, 1,4-phenylenedioxy-diacetic acid, 1,3-phenylenedioxy-diacetic acid, biphenyl dicarboxylic acid, 4,4'-oxybenzoic acid, diphenylmethane-4,4'-dicarboxylic acid, diphenyl sulfone-4,4'-dicarboxylic acid, 4,4'-biphenyl dicarboxylic acid, etc., and combinations thereof. Terephthalic acid is particularly suitable. Of course, it should also be understood that other types of acid units can also be used, such as aliphatic dicarboxylic acid units, polyfunctional carboxylic acid units, etc. Aromatic polyamides can also contain aliphatic repeating units derived from aliphatic diamines, which typically have 4 to 14 carbon atoms. Examples of such diamines include: straight-chain aliphatic alkylene diamines, such as 1,4-tetramethylenediamine, 1,6-hexanediamine, 1,7-heptanediamine, 1,8-octanediamine, 1,9-nonanediamine, 1,10-decanediamine, 1,11-undecanediamine, 1,12-dodecanediamine, etc.; branched-chain aliphatic alkylene diamines, such as 2-methyl-1,5-pentanediamine, 3-methyl-1,5-pentanediamine, 2,2,4-trimethyl-1,6-hexanediamine, 2,4,4-trimethyl-1,6-hexanediamine, 2,4-dimethyl-1,6-hexanediamine, 2-methyl-1,8-octanediamine, 5-methyl-1,9-nonanediamine, etc.; and combinations thereof. Repeating units derived from 1,9-nonanediamine and / or 2-methyl-1,8-octanediamine are particularly suitable. Of course, other diamine units can also be used, such as alicyclic diamines, aromatic diamines, etc.

[0024] Particularly suitable aromatic polyamides may include: poly(nonamethylene terephthalamide) (PA9T), poly(nonamethylene terephthalamide / nonamethylene decanediamide) (PA9T / 910), poly(nonamethylene terephthalamide / nonamethylene dodecanediamide) (PA9T / 912), poly(nonamethylene terephthalamide / 11-aminoundecanediamide) (PA9T / 11), poly(nonamethylene terephthalamide / 12-aminododecanediamide) (PA9T / 12), poly(decamethylene terephthalamide / 11-aminoundecanediamide) (PA10T / 11), poly(decamethylene terephthalamide / 12-aminododecanediamide) (PA10T / 12), poly(decamethylene terephthalamide / decamethylene do ... Examples of suitable aromatic polyamides include poly(decamethylene terephthalamide / decamethylene dodecylamide) (PA10T / 1010), poly(decamethylene terephthalamide / decamethylene dodecylamide) (PA10T / 1012), poly(decamethylene terephthalamide / tetramethylene hexadecanamide) (PA10T / 46), poly(decamethylene terephthalamide / caprolactam) (PA10T / 6), poly(decamethylene terephthalamide / hexamethylene hexadecanamide) (PA10T / 66), poly(dodecylethylene terephthalamide / dodecyl dodecylamide) (PA12T / 1212), poly(dodecylethylene terephthalamide / caprolactam) (PA12T / 6), and poly(dodecylethylene terephthalamide / hexamethylene hexadecanamide) (PA12T / 66). Other examples of suitable aromatic polyamides are described in U.S. Patent No. 8,324,307 to Harder et al.

[0025] Another suitable semi-crystalline aromatic polymer that can be used in this invention is polyaryletherketone. Particularly suitable polyaryletherketones are those that mainly comprise a phenyl moiety along with a ketone and / or ether moiety. Examples of such polymers include polyetheretherketone (PEEK), polyetherketone (PEK), polyetherketoneketone (PEKK), polyetherketoneetherketoneketone (PEKEKK), polyetheretherketoneketone (PEEKK), polyether-diphenyl-ether-ether-diphenyl-ether-phenyl-ketone-phenyl, etc., as well as blends and copolymers thereof.

[0026] In addition to the polymers mentioned above, crystalline polymers may also be used in polymer compositions. Particularly suitable thermoplastic polymers for use in polymer compositions are liquid crystal polymers. Liquid crystal polymers are generally classified as "thermotropic" because they can possess a rod-like structure and exhibit crystalline behavior in their molten state (e.g., a thermotropic nematic state). Such polymers can be formed from one or more types of repeating units known in the art. Liquid crystal polymers may, for example, contain one or more aromatic ester repeating units typically represented by the following formula (I):

[0027]

[0028] in,

[0029] Ring B is a substituted or unsubstituted 6-membered aryl group (e.g., 1,4-phenylene or 1,3-phenylene), a substituted or unsubstituted 6-membered aryl group fused with a substituted or unsubstituted 5- or 6-membered aryl group (e.g., 2,6-naphthalene), or a substituted or unsubstituted 6-membered aryl group linked to a substituted or unsubstituted 5- or 6-membered aryl group (e.g., 4,4-biphenylene); and

[0030] Y1 and Y2 are independently O, C(O), NH, C(O)HN or NHC(O).

[0031] Typically, at least one of Y1 and Y2 is C(O). Examples of such aromatic ester repeating units may include, for example, aromatic dicarboxyl repeating units (Y1 and Y2 in Formula I are C(O)), aromatic hydroxycarboxyl repeating units (Y1 in Formula I is O and Y2 is C(O)), and various combinations thereof.

[0032] For example, repeating aromatic hydroxycarboxyl units derived from aromatic hydroxycarboxylic acids can be used, such as 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, etc., as well as their alkyl, alkoxy, aryl, and halogen substituents and combinations thereof. Particularly suitable aromatic hydroxycarboxylic acids are 4-hydroxybenzoic acid (HBA) and 6-hydroxy-2-naphthoic acid (HNA). When used, repeating units derived from hydroxycarboxylic acids (e.g., HBA and / or HNA) typically constitute about 20 mol.% or more of the polymer, in some embodiments about 25 mol.% or more, in some embodiments about 30 mol.% or more, in some embodiments about 40 mol.% or more, in some embodiments about 50 mol.% or more, in some embodiments about 55 mol.% to 100 mol.%, and in some embodiments about 60 mol.% to about 95 mol.%

[0033] Alternatively, aromatic dicarboxylic acid derivatives derived from repeating aromatic dicarboxylic acid units, such as terephthalic acid, isophthalic acid, 2,6-naphthalenedicarboxylic acid, diphenyl ether-4,4'-dicarboxylic acid, 1,6-naphthalenedicarboxylic acid, 2,7-naphthalenedicarboxylic acid, 4,4'-dicarboxybiphenyl, bis(4-carboxyphenyl) ether, bis(4-carboxyphenyl)butane, bis(4-carboxyphenyl)ethane, bis(3-carboxyphenyl) ether, bis(3-carboxyphenyl)ethane, etc., and their alkyl, alkoxy, aryl, and halogen substituted derivatives, as well as combinations thereof, may be used. Particularly suitable aromatic dicarboxylic acids may include, for example, terephthalic acid (TA), isophthalic acid (IA), and 2,6-naphthalenedicarboxylic acid (NDA). When used, repeating units derived from aromatic dicarboxylic acids (e.g., IA, TA, and / or NDA) typically constitute about 1 mol.% to about 40 mol.% of the polymer, in some embodiments about 2 mol.% to about 30 mol.% and in some embodiments about 5 mol.% to about 25 mol.%.

[0034] Other repeating units may also be used in the polymer. In some embodiments, repeating units derived from aromatic diols may be used, such as hydroquinone, resorcinol, 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 their alkyl, alkoxy, aryl, and halogen substituents, and combinations thereof. Particularly suitable aromatic diols may include, for example, hydroquinone (HQ) and 4,4'-biphenol (BP). When used, repeating units derived from aromatic diols (e.g., HQ and / or BP) typically constitute about 1 mol.% to about 50 mol.% of the polymer, in some embodiments about 1 mol.% to about 40 mol.%, in some embodiments about 2 mol.% to about 40 mol.%, in some embodiments about 5 mol.% to about 35 mol.%, and in some embodiments about 5 mol.% to about 25 mol.%.

[0035] Repeating units derived from aromatic amides (e.g., acetaminophen (APAP)) and / or aromatic amines (e.g., 4-aminophenol (AP), 3-aminophenol, 1,4-phenylenediamine, 1,3-phenylenediamine, etc.) may also be used. When used, repeating units derived from aromatic amides (e.g., APAP) and / or aromatic amines (e.g., AP) typically comprise about 0.1 mol.% to about 20 mol.% of the polymer, about 0.5 mol.% to about 15 mol.% in some embodiments, and about 1 mol.% to about 10 mol.% in some embodiments. It should also be understood that various other monomer repeating units can be incorporated into the polymer. For example, in some embodiments, the polymer may contain one or more repeating units derived from non-aromatic monomers (e.g., aliphatic or alicyclic hydroxycarboxylic acids, dicarboxylic acids, diols, amides, amines, etc.). Of course, in other embodiments, if the polymer lacks repeating units derived from non-aromatic (e.g., aliphatic or alicyclic) monomers, the polymer may be "fully aromatic".

[0036] In some embodiments, the liquid crystal polymer can be considered a "high-cycloalkane" polymer in terms of containing 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 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 about 55 mol.% to about 95 mol.%. Without being theoretically limited, it is believed that such "high-cycloalkane" polymers can reduce the water absorption tendency of polymer compositions, which can contribute to the processability and accurate alignment of microneedles. In other words, according to ISO 62-1:2008, after immersion in water for 24 hours, this high-cycloalkane polymer typically has a water absorption rate of about 0.015% or less, in some embodiments about 0.01% or less, and in some embodiments about 0.0001% to about 0.008%. According to ISO 62-4:2008, after exposure to a humid atmosphere (50% relative humidity) at 23°C, the high-cycloalkane polymer may also have a moisture absorption rate of about 0.01% or less, in some embodiments about 0.008% or less, and in some embodiments about 0.0001% to about 0.006%.

[0037] For example, in one embodiment, repeating units derived from HNA may constitute about 30 mol.% or more of the polymer, in some embodiments about 40 mol.% or more, in some embodiments about 45 mol.% or more, in some embodiments 50 mol.% or more, in some embodiments about 55 mol.% or more, and in some embodiments about 55 mol.% to about 95 mol.%. In such embodiments, the liquid crystal polymer may contain various other monomers, such as: aromatic hydroxycarboxylic acids (e.g., HBA) in an amount of about 1 mol.% to about 50 mol.%, and in some embodiments about 1 mol.% to about 20 mol.%, and in some embodiments about 2 mol.% to about 10 mol.%; aromatic dicarboxylic acids (e.g., IA and / or TA) in an amount of about 1 mol.% to about 40 mol.%, and in some embodiments about 5 mol.% to about 25 mol.%; and / or aromatic diols (e.g., BP and / or HQ) in an amount of about 1 mol.% to about 40 mol.%, and in some embodiments about 5 mol.% to about 25 mol.%. In another embodiment, repeating units derived from NDA may constitute 10 mol.% or more of the polymer, in some embodiments about 12 mol.% or more, in some embodiments about 15 mol.% or more, and in some embodiments about 18 mol.% to about 95 mol.% of the polymer. In such embodiments, the liquid crystal polymer may also contain various other monomers, such as: aromatic hydroxycarboxylic acids (e.g., HBA) in an amount of about 20 mol.% to about 60 mol.% of the polymer, and in some embodiments about 30 mol.% to about 50 mol.% of the polymer; aromatic dicarboxylic acids (e.g., IA and / or TA) in an amount of about 2 mol.% to about 30 mol.% of the polymer, and in some embodiments about 5 mol.% to about 25 mol.% of the polymer; and / or aromatic diols (e.g., BP and / or HQ) in an amount of about 2 mol.% to about 40 mol.% of the polymer, and in some embodiments about 5 mol.% to about 35 mol.% of the polymer.

[0038] Of course, "low-cycloalkane" liquid crystal polymers can also be used alone or in combination with "high-cycloalkane" liquid crystal polymers in compositions. In such low-cycloalkane polymers, the total amount of repeating units derived from cycloalkane hydroxycarboxylic acids and / or cycloalkane dicarboxylic acids (e.g., NDA, HNA, or a combination of HNA and NDA) is typically less than 10 mol.% of the polymer, in some embodiments about 8 mol.% or less, in some embodiments about 6 mol.% or less, and in some embodiments about 1 mol.% to about 5 mol.%.

[0039] Regardless of the specific composition and properties of the polymer, liquid crystal polymers can be prepared by first introducing aromatic monomers (e.g., aromatic hydroxycarboxylic acids, aromatic dicarboxylic acids, etc.) for forming ester repeating units and / or aromatic monomers (e.g., aromatic glycols, aromatic amides, aromatic amines, etc.) into a reactor vessel to initiate a polycondensation reaction. The specific conditions and steps used in such reactions are well known and can be described in more detail in: U.S. Patent No. 4,161,470 to Calundann; U.S. Patent No. 5,616,680 to Linstid, III et al.; U.S. Patent No. 6,114,492 to Linstid, III et al.; U.S. Patent No. 6,514,611 to Shepherd et al.; and WO2004 / 058851 to Waggoner. There are no particular limitations on the vessel used for the reaction, although it is generally desirable to use vessels typically used for reactions of high-viscosity fluids. Examples of such reaction vessels may include stirred tank type equipment, the agitator of which has variable-shaped stirring blades, such as anchor type, multi-stage type, spiral ribbon type, screw shaft type, etc., or modified shapes thereof. Other examples of such reaction vessels may include mixing equipment commonly used for resin kneading, such as kneaders, roller mills, Banbury mixers, etc.

[0040] If desired, the reaction can be carried out by acetylation of a monomer known in the art. This can be done by adding an acetyling agent (e.g., acetic anhydride) to the monomer. Acetylation typically begins at a temperature of about 90°C. During the initial stage of acetylation, reflux can be used to keep the vapor phase temperature below the temperature at which the acetic acid byproducts and anhydride begin to distill. The temperature during acetylation is typically from 90°C to 150°C, and in some embodiments, from about 110°C to about 150°C. If reflux is used, the vapor phase temperature will typically exceed the boiling point of acetic acid, but will still remain low enough to retain residual acetic anhydride. For example, acetic anhydride evaporates at a temperature of about 140°C. Therefore, a vapor phase reflux providing the reactor with a temperature of about 110°C to about 130°C is particularly desirable. 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 employed (including the presence or absence of reflux). It is not uncommon to use an excess of about 1 mol% to about 10 mol% of acetic anhydride based on the total number of moles of hydroxyl groups present in the reactants.

[0041] Acetylation can be carried out in a separate reactor vessel, or it can be carried out in situ within a polymerization reactor vessel. When using a separate reactor vessel, one or more monomers can be introduced into the acetylation reactor and subsequently transferred to the polymerization reactor. Similarly, one or more monomers can be introduced directly into the reactor vessel without pre-acetylation.

[0042] In addition to the monomer and optional acetylation agent, other components may be included in the reaction mixture to aid in promoting polymerization. For example, catalysts may be optionally 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-methylimidazole). Such catalysts are typically used in amounts from about 50 ppm to about 500 ppm based on the total weight of the repeating unit precursors. When using a separate reactor, it is generally desirable to apply the catalyst to the acetylation reactor rather than the polymerization reactor, although this is by no means necessary.

[0043] Typically, the reaction mixture is heated to a high temperature within the polymerization reactor vessel to initiate melt polycondensation of the reactants. For example, polycondensation can be carried out in a temperature range of about 250°C to about 380°C, and in some embodiments, in a temperature range of about 280°C to about 380°C. For example, a suitable technique for forming aromatic polyesters may include: charging a precursor monomer and acetic anhydride into a reactor, heating the mixture to a temperature of about 90°C to about 150°C to acetylate the hydroxyl groups of the monomer (e.g., to form acetoxy groups), and then raising the temperature to about 280°C to about 380°C for melt polycondensation. As the final polymerization temperature approaches, volatile byproducts of the reaction (e.g., acetic acid) can also be removed, thereby readily achieving the desired molecular weight. The reaction mixture is typically stirred during polymerization to ensure good heat and mass transfer, and thus good material homogeneity. The rotational speed of the stirrer can vary during the reaction, but is typically in the range of about 10 rpm to about 10 rpm, and in some embodiments, from about 20 rpm to about 80 rpm. To increase the molecular weight of the melt, the polymerization reaction can also be carried out under a vacuum. The application of a vacuum is beneficial for removing volatiles formed in the final stage of polycondensation. A vacuum can be generated by applying suction pressure, for example, in the range of about 5 pounds per square inch (psi) to about 30 psi, and in some embodiments, about 10 psi to about 20 psi.

[0044] Following melt polymerization, the molten polymer is typically discharged from the reactor 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 a filament, which is then placed in a water bath, granulated, and dried. In some embodiments, the melt-polymerized polymer may also undergo subsequent solid-state polymerization to further increase its molecular weight. Solid-state polymerization can be carried out in the presence of a gas (e.g., air, inert gas, etc.). Suitable inert gases may include, for example, nitrogen, helium, argon, neon, krypton, xenon, etc., and combinations thereof. The solid-state polymerization reactor vessel can be virtually any design capable of maintaining the polymer at the desired solid-state polymerization temperature for the desired residence time. Examples of such vessels include those with fixed beds, static beds, moving beds, fluidized beds, etc. The temperature at which solid-state polymerization takes place can vary, but is typically in the range of about 250°C to about 350°C. The polymerization time will, of course, vary based on temperature and target molecular weight. However, in most cases, the solid-state polymerization time will be about 2 to about 12 hours, and in some embodiments, about 4 to about 10 hours.

[0045] B. Other additives

[0046] In some cases, a thermoplastic polymer may constitute the entire polymer composition (e.g., 100 wt.%). However, in some embodiments, it may be necessary to include one or more additives in the polymer composition to help achieve the desired properties. In such embodiments, the polymer composition typically comprises: one or more thermoplastic polymers (e.g., liquid crystal polymers) in an amount of about 30 wt.% to about 99 wt.% of the entire polymer composition, in some embodiments about 40 wt.% to about 95 wt.%, and in some embodiments about 50 wt.% to about 90 wt.%; and one or more additives in an amount of about 1 wt.% to about 70 wt.% of the polymer composition, in some embodiments about 5 wt.% to about 60 wt.%, and in some embodiments about 10 wt.% to about 50 wt.%.

[0047] The specific properties of the additives may vary during use. For example, the polymer composition may contain mineral fillers, which may be in the form of particles (e.g., flakes, scaly, etc.), fibers, etc. In one embodiment, the mineral filler may include, for example, particulate 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. When used, the inventors have found that particulate mineral fillers with relatively small sizes better facilitate filling of the mold cavity and ensure accurate micro-alignment. In a particular embodiment, for example, the particulate mineral filler (e.g., talc) may have a median particle size (e.g., D50 size) of about 10 micrometers or less, from about 0.1 micrometers to about 8 micrometers in some embodiments, from about 0.5 micrometers to about 5 micrometers in some embodiments, and from about 0.6 micrometers to about 2.5 micrometers in some embodiments. 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 dicalcium 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 can include, for example, those derived from: silicates, such as neosilicates, tansilicates, chain silicates (e.g., calcium chain silicate, such as wollastonite; calcium magnesium chain silicate, such as tremolite; calcium magnesium iron chain silicate, such as actinolite; magnesium iron chain silicate, such as anthocyanin; etc.), foli silicates (e.g., aluminum foli silicate, such as palygorskite), reticulate silicates, etc.; sulfates, such as calcium sulfate (e.g., dehydrated or anhydrous gypsum); mineral wool (e.g., rock wool or slag wool); glass, etc. Chain silicates are particularly suitable, for example, those available from NycoMinerals under the trade name... (For example, 4W 5 or 8) Wollastonite fibers. In addition to the dimensional characteristics described above, the mineral fibers may also have a relatively high aspect ratio (average length divided by median width) to further improve mechanical properties. For example, the aspect ratio of the mineral fibers may be from about 1 to about 50, from about 2 to about 20 in some embodiments, and from about 4 to about 15 in some embodiments. The volume average length of such mineral fibers may, for example, be from about 1 micrometer to about 200 micrometers, from about 2 micrometers to about 150 micrometers in some embodiments, from about 5 micrometers to about 100 micrometers in some embodiments, and in the range of about 10 micrometers to about 50 micrometers in some embodiments.

[0048] If desired, tribological additives may also be used in the polymer composition to help achieve a good combination of low friction and good wear resistance for microneedle components. In one embodiment, for example, the tribological additive may include a fluorinated additive. Without being theoretically limited, it is believed that fluorinated additives can, among other things, improve the processability of the composition by providing better mold filling, internal lubrication, demolding, etc. In some embodiments, the fluorinated additive may include a fluoropolymer containing a hydrocarbon backbone polymer in which some or all of its hydrogen atoms are replaced by fluorine atoms. The backbone polymer may be a polyolefin and formed from fluorinated unsaturated olefin monomers. The fluoropolymer may be a homopolymer of such fluorinated monomers or a copolymer of fluorinated monomers or a mixture of fluorinated and non-fluorinated monomers. Along with the fluorine atoms, the fluoropolymer may also be substituted with other halogen atoms (e.g., chlorine and bromine atoms). Representative monomers suitable for forming the fluoropolymers used in this invention are tetrafluoroethylene, vinylidene fluoride, hexafluoropropylene, chlorotrifluoroethylene, perfluoroethyl vinyl ether, perfluoromethyl vinyl ether, perfluoropropyl vinyl ether, and mixtures thereof. Specific examples of suitable fluoropolymers include polytetrafluoroethylene, perfluoroalkyl vinyl ethers, poly(tetrafluoroethylene-co-perfluoroalkyl vinyl ethers), fluorinated ethylene-propylene copolymers, ethylene-tetrafluoroethylene copolymers, polyvinylidene fluoride, polychlorotrifluoroethylene, and mixtures thereof. Fluorinated additives may contain only fluoropolymers, or they may include other components, such as those that contribute to their ability to be uniformly dispersed within the polymer composition. In one embodiment, for example, the fluorinated additive may comprise a fluoropolymer combined with a plurality of carrier particles. In such an embodiment, for example, the fluoropolymer may 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, diatomaceous earth, wollastonite, etc. For example, mica may be a mineral particularly suitable for use in this application. The average particle size of the carrier particles may be from about 5 micrometers to about 50 micrometers, and in some embodiments from about 10 micrometers to 20 micrometers. If desired, the carrier particles can also be in the shape of sheet particles, since the ratio of their main axis to thickness is 2 or greater.

[0049] Many other additives may also be included in the polymer composition, such as lubricants, fiber fillers (e.g., glass fibers), thermally conductive fillers, pigments, antioxidants, stabilizers, surfactants, waxes, flame retardants, anti-dripping additives, nucleating agents (e.g., boron nitride), flow modifiers, coupling agents, antimicrobial agents, pigments or other colorants, impact modifiers, and other materials added to enhance properties and processability.

[0050] II.

[0051] The components used to form the polymer composition can be combined using any of a variety of different techniques known in the art. In one particular embodiment, for example, the thermoplastic 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 or 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 that includes multiple temperature zones. The temperature of each zone is typically set between about -60°C and about 25°C relative to the melt temperature of the polymer. For example, the mixture can be melt-processed using a twin-screw extruder (e.g., a Leistritz 18mm co-rotating fully intermeshing twin-screw extruder). A general screw design can be used to melt-process the mixture. In one embodiment, the mixture comprising all components can be fed into a feed throat in a first barrel via a volumetric feeder. In another embodiment, as is known, different components can be added at different points of addition within the extruder. 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 downstream therefrom. In any case, 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, granulated in a granulator, and then dried.

[0052] III. microneedle components

[0053] Microneedle assemblies typically consist of one or more microneedles extending outward from a support. Microneedles can be formed using any of a variety of techniques, such as embossing (e.g., thermoforming, roll-to-roll molding, etc.); molding, such as micromolding; injection molding (e.g., low-pressure injection molding, gas injection molding, foam injection molding, etc.); compression molding (e.g., extrusion compression molding); extrusion; printing (e.g., 3D printing); and so on. For example, an injection molding system including a mold into which a polymer composition can be injected can be used. The time within the syringe can be controlled and optimized so that the polymer matrix is ​​not pre-cured. When the cycle time is reached and the syringe is full for discharge, a piston can be used to inject the composition into the mold cavity. Compression molding systems can also be used. As with injection molding, the molding of the polymer composition into the desired article also occurs within the mold. Any known technique can be used, such as placing the composition into a compression mold by an automated robotic arm. The temperature of the mold can be maintained at or above the curing temperature of the polymer matrix for the required duration to allow curing. The molded product can then be cured by bringing it to a temperature below its melt temperature. The resulting product can be demolded. The cycle time of each molding process can be adjusted to suit the polymer matrix to achieve sufficient bonding and improve overall process yield.

[0054] For example, refer to Figures 1 to 6 A more detailed embodiment of a microneedle assembly 500 is shown, comprising a plurality of microneedles 510 (e.g., a microneedle array) extending outwardly from a support 520. As described above, one or more microneedles 510 may be formed from the polymer composition of the present invention. The support 520 may also be formed from a polymer composition, as well as from a rigid or flexible sheet of metal, ceramic, plastic, or other materials. The thickness of the support 520 may vary to meet the needs of specific drug delivery applications, for example, about 1000 micrometers or less, from about 1 micrometer to about 500 micrometers in some embodiments, and from about 10 micrometers to about 200 micrometers in some embodiments.

[0055] The density of the microneedles 510 can be varied as needed, for example, per square centimeter (cm²). 2 Approximately 2000 microneedles or more, in some implementations, per cm 2 Approximately 3,000 to approximately 25,000 microneedles, and in some implementations, per cm 2Approximately 5,000 to approximately 20,000 microneedles. The number of microneedles 510 used in component 500 can, for example, range from approximately 500 to approximately 10,000, in some embodiments from approximately 2,000 to approximately 8,000, and in some embodiments from approximately 4,000 to approximately 6,000. The microneedles 510 can be arranged on support 520 in various patterns. For example, the microneedles can be spaced evenly, such as in a rectangular or square grid or concentric circles, or they can be arranged in one or more rows. Although various arrangements are possible, Figure 2 A particularly suitable embodiment is shown, in which the microneedles 510 are arranged in straight, spaced rows. The spacing can depend on many factors, including the height and width of the microneedles 510, and the amount and type of substance intended to be moved by the microneedles. For example, the spacing between the tips of the microneedles 510 ( Figure 2 S1 in the microneedles 510 can be about 20 micrometers or larger, about 60 micrometers to about 800 micrometers in some embodiments, and about 100 micrometers to about 600 micrometers in some embodiments, while the spacing between the bases of the microneedles 510 ( Figure 2 S2 in the figure can be about 50 micrometers or larger, about 100 micrometers to about 1000 micrometers in some embodiments, and about 200 micrometers to about 800 micrometers in some embodiments.

[0056] The size and shape of the microneedle 510 can also be varied as needed. For example, the microneedle 510 is shown to have a conical hexagonal shape, comprising a tip 611 and a base 612. The base 612 has two substantially parallel sides 621 and 622, which have, as shown in... Figure 5 The small draft angle indicated by α1 extends to the transition point 613, where the angle increases, such as... Figure 5 As shown in α2. Although this example depicts a significant increase in angle at transition point 613, it should be noted that the increase in angle may be more gradual than depicted. For example, the draft angle α1 can range from about 0 degrees to 20 degrees, from about 0 degrees to 15 degrees in some embodiments, from about 1 degree to about 15 degrees in some embodiments, and from about 2 degrees to about 10 degrees in some embodiments. Similarly, the transition point angle α2 can range from about 20 degrees to 70 degrees, from about 20 degrees to 60 degrees in some embodiments, from about 25 degrees to about 55 degrees in some embodiments, and from about 25 degrees to about 45 degrees in some embodiments. In alternative embodiments, the ends of the microneedles may be blunt to provide an extended octagonal profile. While the profile of the microneedles can be defined as an extended hexagonal or octagonal shape, the edges of the profile may be slightly rounded depending on the manufacturing method of the microneedles and the microneedle array.

[0057] Each microneedle 510 terminates at a slender edge at its tip 611. The tip 611 has a width W. 尖端 and length L 尖端 The length of the tip 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 612 has a thickness T. 基部 and length L 基部 Its length is greater than that of the tip 611. For example, the length of the base of the microneedle can be from about 10 nanometers to about 1000 nanometers, from about 20 nanometers to about 500 nanometers in some embodiments, and from about 30 nanometers to about 100 nanometers in some embodiments, while the thickness of the base can be from about 5 nanometers to about 100 nanometers, from about 10 nanometers to about 80 nanometers in some embodiments, and from about 20 nanometers to about 70 nanometers in some embodiments. Cross-sectional length of base 612: thickness aspect ratio (L) 基部 :T 基部 The ratio can also be relatively large, for example, about 2:1 or greater, in some embodiments about 2:1 to about 20:1, and in some embodiments about 3:1 to about 10:1. Each microneedle also has a total height H, the length of which is sufficient to penetrate at least the outermost layer of the epidermis (i.e., the stratum corneum), but optionally not long enough for them to penetrate the dermis. For example, the height can be about 10 nanometers to about 1000 nanometers, in some embodiments about 20 nanometers to about 500 nanometers, and in some embodiments about 30 nanometers to about 100 nanometers.

[0058] The manner in which microneedle assemblies deliver drug compounds can vary as is known in the art. In some embodiments, for example, the drug 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, dotting, non-contact printing, on-demand inkjet piezoelectric microdispensing, etc.), and so on. For example, microneedles can be dipped into a drug compound reservoir through dipping orifices spaced apart according to an array of microneedles. Microneedles can also be sprayed with a drug compound and then dried with gas. In yet another embodiment, microneedles can be coated with a drug compound using printing techniques. For example, various suitable printing techniques are described in U.S. Patent Publication No. 2018 / 0326726 by Wang et al., which is incorporated herein by reference in its entirety. For example, a piezoelectric multilayer actuator can be used as a drive element that dispenses a fluid drug 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.

[0059] In embodiments where the drug compound is coated onto the surface of the microneedle, such as those described above, the microneedle can be solid in nature and therefore lack hollow channels and / or holes for fluid delivery. In such embodiments, the microneedle assembly does not require conventional components (e.g., drug reservoirs, release members, etc.) to drive the delivery of the drug compound. Examples of such solid microneedles are described, for example, in U.S. Patent Publication No. 2018 / 0264244 to Meliga et al., which is incorporated herein by reference in its entirety.

[0060] Of course, in alternative embodiments, one or more microneedles may include one or more channels of a specific size, such that passive capillary flow can drive the delivery of the drug compound. For example, the microneedle may define at least one channel in fluid communication with the drug compound, for example, through the pores of a support. See again Figure 3For example, channel 511 is located on the outer surface of microneedle 510. Although shown on the outer surface, the channel can be located in various different locations, such as inside the microneedle. The channel size is specifically chosen in this invention to induce capillary flow of the drug compound. Capillary flow typically occurs when the adhesion force of the fluid to the channel walls is greater than the cohesive force between liquid molecules. Specifically, capillary pressure is inversely proportional to the cross-sectional size of the channel multiplied by the cosine of the contact angle of the fluid in contact with the material forming the channel, and directly proportional to the surface tension of the liquid multiplied by the cosine of the contact angle of the fluid in contact with the material forming the channel. Therefore, to promote capillary flow, the cross-sectional size of the channel (e.g., width, diameter, etc.) can be selectively controlled; smaller sizes generally result in higher capillary pressure. For example, in some embodiments, the cross-sectional size of the channel can range from about 1 micrometer to about 100 micrometers, in some embodiments from about 5 micrometers to about 50 micrometers, and in some embodiments from about 10 micrometers to about 30 micrometers. The size can be constant or it can vary depending on the channel length. The length of the channel can also be varied to accommodate different volumes, flow rates, and residence times of the drug compound. For example, the channel length can be from about 10 micrometers to about 800 micrometers, in some embodiments from about 50 micrometers to about 500 micrometers, and in some embodiments from about 100 micrometers to about 300 micrometers. The cross-sectional area of ​​the channel can also be varied. For example, the cross-sectional area can be from about 50 square micrometers to about 1000 square micrometers, in some embodiments from about 100 square micrometers to about 500 square micrometers, and in some embodiments from about 150 square micrometers to about 350 square micrometers. Furthermore, the aspect ratio (length / cross-sectional dimension) 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. When the cross-sectional dimensions (e.g., width, diameter, etc.) and / or the length varies with the length, the aspect ratio is determined by the average dimension.

[0061] Regardless of the type used, microneedle components can deliver controlled volumes of drug compounds through the skin. For example, a microneedle component can be placed near the skin of an object (e.g., a person), and pressure can be applied to the microneedle component so that the microneedles penetrate at least into the stratum corneum of the epidermis.

[0062] If desired, the microneedle assembly can be positioned in fluid communication with a reservoir that can initially hold the drug compound, particularly in embodiments employing one or more channels. The term "reservoir" generally refers to a designated area or chamber configured to hold a fluid drug compound. A reservoir can be an open volume space, a gel, a solid structure, etc. However, in most embodiments, the reservoir is a solid matrix through which the drug compound can flow. The choice of the desired matrix material typically depends on the solubility and diffusivity of the target drug compound and the desired release time. In one embodiment, for example, the solid matrix is ​​typically impermeable to the drug compound, and the material used to form the matrix is ​​selected to allow the drug compound to diffuse through the matrix. However, in other embodiments, the solid matrix can be permeable or semi-permeable to the drug compound so that the drug compound can simply flow through the pores of the matrix. Examples of such solid matrices include porous fiber webs (e.g., woven or non-woven), open-cell membranes, foams, sponges, etc. Regardless of their specific form, polymeric materials are commonly used to form solid matrices, such as silicones, acrylic resins, olefin polymers (e.g., ethylene vinyl acetate), plasticized polyvinyl acetate / polyvinyl chloride resins, plasticized hydrolyzed polyvinyl alcohol, rubber-based adhesives (e.g., polyisobutylene swollen with solvents such as mineral oil), plasticized polyvinyl chloride, polyethylene glycol and polypropylene glycol of different molecular weights, cellulose esters, etc.

[0063] In some embodiments, multiple reservoirs may be used to store various delivery materials. The reservoirs may be arranged adjacent to each other in a vertical or horizontal relationship. For example, a first reservoir may contain a pharmaceutical compound, while a second reservoir may contain excipients (e.g., delivery solvents, such as alcohols, water, etc.; buffers; etc.). In a particular embodiment, for example, a first reservoir may contain a lyophilized powder of a pharmaceutical compound, while a second reservoir may contain an aqueous solution for reconstitution of the powder. Alternatively, multiple reservoirs may be used, each containing a pharmaceutical compound. Different materials may be mixed prior to delivery.

[0064] In some implementations, the microneedle assembly and drug reservoir can be integrated together as a percutaneous delivery device (e.g., a patch). This pathway may also include other elements to help maintain the desired flow of the drug compound. For example, the drug reservoir may 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 of the drug compound during release. Specifically, the fluid drug compound delivered from the drug reservoir to the microneedle assembly may experience a pressure drop that results in a reduced flow rate. If this difference is too large, it may create back pressure that impedes the flow of the compound and may overcome the capillary pressure of the fluid passing through the microfluidic channel. Therefore, using a rate control membrane can mitigate this pressure difference and allow the drug compound to be introduced into 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 may, for example, comprise permeable, semi-permeable, or microporous materials. Suitable membrane materials include, for example, fiber webs (e.g., woven or nonwoven), open-cell membranes, foams, sponges, etc., which are formed from polymers such as polyethylene, polypropylene, polyvinyl acetate, ethylene-butyl acetate, and ethylene-vinyl acetate copolymers.

[0065] If desired, the transdermal delivery device may include additional layers or materials that provide various benefits. For example, the component may include an adhesive layer that helps facilitate adhesion of the delivery device to the user's skin during use. Although not essential, the adhesive layer is typically positioned above the reservoir. The adhesive layer typically uses an adhesive applied to a backing material. The backing may be made of a material that is substantially impermeable to the drug compound, such as polymers, metal foils, etc. Suitable polymers may include, for example, polyethylene terephthalate, polyvinyl chloride, polyethylene, polypropylene, polycarbonate, polyester, etc. The adhesive may be a pressure-sensitive adhesive known in the art. Suitable adhesives may include, for example, solvent-based acrylic adhesives, solvent-based rubber adhesives, silicone adhesives, etc.

[0066] The release member can also be positioned adjacent to the microneedle assembly, such that it is close to the support and optional rate control membrane of the microneedle assembly. However, it should be understood that the release layer does not need to contact these layers, and other layers can indeed be positioned between the release member and the support and / or rate control membrane. In any case, the release member can comprise a material that is substantially impermeable to the drug compound, such as polymeric materials, metals, etc. Ideally, the material should also be hydrophobic. Suitable polymeric materials may include, for example, polyethylene terephthalate, polyvinyl chloride, polyethylene, polypropylene, polycarbonate, polyester, metal foil, etc. Because it is generally impermeable, the release member can initially seal the pores in the support, thereby restricting the flow of the drug compound through it. In this way, the release member can act as a barrier to the flow of the drug compound and thus inhibit premature leakage. When the delivery device is required, the user can apply force to at least partially separate the release member, thereby breaking the seal. Separation of the release member can be achieved in a variety of ways. For example, a portion of the release member can be easily separated (e.g., detached, ruptured, etc.). Therefore, the flow of drug compounds can be induced "passively"—that is, without the need for traditional active displacement mechanisms such as liquid pumps, actuators, plungers, finger pressure, etc. This allows the delivery device to be placed on the skin before activation, thus limiting the potential spillage of drug compounds. Passive delivery of drug compounds is also simple and easy to use, making it accessible to a wide range of consumers, not just medical professionals.

[0067] There are no particular limitations on the drug compounds that can be delivered using the microneedle components of this invention. Suitable compounds may include, for example: protein compounds, such as insulin, immunoglobulins (e.g., IgG, IgM, IgA, IgE), TNF-α, antiviral drugs, etc.; polynucleotide reagents, such as plasmids, siRNA, RNAi, nucleoside anticancer drugs, vaccines, etc.; small molecule reagents, such as alkaloids, glycosides, phenols, etc.; anti-infective agents, hormones, drugs that regulate cardiac activity or blood flow, and drugs that control pain; vaccines; and so on. The non-restricted list of reagents includes: anti-angiogenic agents, antidepressants, antidiabetic agents, antihistamines, anti-inflammatory agents, butorphanol, calcitonin and analogues, COX-II inhibitors, dermatological reagents, dopamine agonists and antagonists, enkephalins and other opioid peptides, epidermal growth factor, erythropoietin and analogues, follicle-stimulating hormone, glucagon, growth hormone and analogues (including growth hormone-releasing hormone), growth hormone antagonists, heparin, hirudin and hirudin analogues such as hirudin, IgE inhibitors and other protein inhibitors, immunosuppressants, insulin, and other similar drugs. Insulin and its analogues, interferon, interleukin, luteinizing hormone, luteinizing hormone-releasing hormone and its analogues, monoclonal or polyclonal antibodies, motion sickness preparations, muscle relaxants, anesthetic analgesics, nicotine, nonsteroidal anti-inflammatory agents, oligosaccharides, parathyroid hormone and its analogues, parathyroid hormone antagonists, prostaglandin antagonists, prostaglandins, scopolamine, sedatives, serotonin agonists and antagonists, hypoactive agents, tissue plasminogen activators, tranquilizers, vaccines with or without carriers / adjuvants, vasodilators, tuberculin and other major diagnostic agents, as well as other hypersensitivity agents.

[0068] Microneedle components are particularly advantageous for delivering high molecular weight drug compounds. The term "high molecular weight" generally refers to compounds with 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 refer to any biologically active protein compound, including but not limited to natural, synthetic, and recombinant compounds, fusion proteins, peptides, chimeras, etc., and compounds comprising 20 standard amino acids and / or synthetic amino acids.

[0069] In one particular embodiment, the pharmaceutical compound may include a vaccine antigen, a substance that, when introduced into the body, stimulates an immune response such as T-cell activation and / or antibody production to prevent the virus. The vaccine antigen may include a naturally occurring intact pathogen (e.g., bacteria or virus), an attenuated live virus, or a portion and / or subunit of a pathogen, such as a monoviral or bacterial protein. The vaccine antigen may also include a cancer antigen or fragment thereof. In one particular embodiment, for example, the vaccine antigen may be a coronavirus vaccine antigen used to prevent coronaviruses such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV. Such vaccine antigens may be derived from coronaviruses or other types of viruses. Specific examples of such coronavirus vaccine antigens may include, for example, mRNA-1273 (a novel lipid nanoparticle (LNP) encapsulated mRNA-based vaccine), BNT162 (LNP-encapsulated mRNA-based vaccine), Ad5-nCoV (recombinant adenovirus type 5 vector), ChAdOx1 (an adenovirus vector capable of producing the SARS-CoV-2 spike protein), bacTRL-Spike (a live Bifidobacterium longum bacterium engineered to deliver a plasmid containing synthetic DNA encoding the SARS-CoV-2 spike protein), BCG (prepared from attenuated (reduced virulence) live Mycobacterium bovis strain), AdCovid (an intranasal vaccine), NVX-CoV2373 (recombinant spike protein nanoparticles), SARS recombinant spike protein plus δ-inulin (protein subunit), SARS VLPs S protein and influenza M1 protein, DNA vaccine VRC-SRSDNA015-00-VP (DNA), and replicating and / or non-replicating viral vectors expressing SARS-CoV S (e.g., expressing SARS-CoV S). VEEV replicon particles or LV-SMENP (dendritic cells modified with a lentiviral vector expressing the CoV-19 small gene SMENP and an immunomodulatory gene), inactivated SARS-CoV-2 virus or viral vector, attenuated live SARS-CoV-2 virus, etc.

[0070] Other suitable viral vaccine antigens may be derived from and / or used to prevent adenoviruses, arenaviruses, Bunyaviruses, flaviviruses, hantaviruses, hepatotropic DNA viruses, herpesviruses, papillomaviruses, paramyxoviruses, parvoviruses, picornaviruses, poxviruses, orthomyxoviruses, retroviruses, reoviruses, rhabdoviruses, rotaviruses, spongiviruses, or tunica albuginea viruses. Examples of such vaccine antigens may include peptides expressed by viruses such as CMV, EBV, influenza virus, hepatitis A, B, or C virus, herpes simplex virus, HIV, influenza virus, Japanese encephalitis virus, measles virus, poliovirus, rabies virus, respiratory syncytial virus, rubella virus, smallpox virus, varicella-zoster virus, West Nile virus, and / or Zika virus. CMV vaccine antigens include envelope glycoprotein B and CMV pp65; EBV vaccine antigens include EBVEBNAI, EBV P18, and EBV P23; hepatitis vaccine antigens include hepatitis B virus S, M, and L proteins, 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 protein and glycoprotein D; human immunodeficiency virus (HIV) vaccine antigens include gag, pol, and env genes (e.g., HIV gp32, HIV gp41, HIV gp120, HIV gp160, HIV P17 / 24, HIV P24, HIV P55GAG, HIV P66POL, HIV...). The vaccine antigens include the gene products of TAT and HIVGP36, Nef protein, and reverse transcriptase; human papillomavirus (HPV) antigens include L1 protein; influenza vaccine antigens include hemagglutinin and neuraminidase; Japanese encephalitis vaccine antigens include proteins E, ME, ME-NS1, NS1, NS1-NS2A, and 80%E; malaria vaccine antigens include Plasmodium circospore protein (CSP), glutamate dehydrogenase, lactate dehydrogenase, and fructose-2-phosphate 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 E1 and E2; varicella-zoster vaccine antigens include gpl and gpll; and Zika vaccine antigens include the promembrane, envelope (E), E protein domain III, and non-structural proteins 1-5.

[0071] In the above embodiments, the microneedle assembly of the present invention is generally used for delivering a pharmaceutical compound to a subject. In addition to and / or instead of drug delivery, the microneedle assembly can also be used as a sensor. For example, the microneedle assembly can be used solely as a sensor, or in other cases, it can be used as a sensor to determine the dose of the pharmaceutical compound to be delivered. In any case, the microneedle can be positioned to contact the subject's skin and allowed to remain in contact with the subject's bodily fluids (e.g., blood) containing the target analyte for a sufficient period of time. The fluid can be aspirated and tested. Alternatively, a detection system can be coupled to the microneedle assembly, for example, incorporated into the outer surface of the microneedle (e.g., a solid microneedle) or the interior of the microneedle (e.g., a microneedle with a hollow channel), so that fluid can be easily brought into contact with the microneedle for testing. Various examples of such sensors are known in the art and are described, for example, in U.S. Patent Publication No. 2020 / 0015751 to Chickering et al. and U.S. Patent Publication No. 2013 / 0225956 to Huang et al., which are incorporated herein by reference in their entirety.

[0072] Examples of target analytes that can be detected using sensors 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, progesterone, testosterone, androstenedione, etc.), carbohydrates, or other target analytes. Other conditions that can be identified may include pH changes (which can indicate disease), yeast infections, periodontal disease on mucosal surfaces, oxygen or carbon monoxide levels (indicating lung dysfunction), and drug levels, such as drugs like coumarin, other drugs like nicotine, or legally prescribed levels of illicit drugs like cocaine. Other examples of analytes include those that indicate disease, such as cancer-specific biomarkers (e.g., CEA and PSA), viral and bacterial antigens, and autoimmune indicators (e.g., antibodies against double-stranded DNA). Other conditions include exposure to elevated carbon monoxide (which may be from external sources or due to sleep apnea), overheating (important for infants whose internal temperature control is not fully self-regulated), or fever. Other potentially suitable analytes include various pathogens, such as bacteria or viruses, and / or biomarkers produced by such pathogens. As other non-limiting examples, the sensor may include antibodies capable of interacting with biomarkers of disease states, enzymes capable of detecting glucose (e.g., glucose oxidase or glucose 1-dehydrogenase), and so on. The analyte can be measured quantitatively or qualitatively, and / or in some cases, the presence or absence of the analyte in the extracted fluid can be determined.

[0073] The specific detection system used in conjunction with the microneedle assembly to detect an analyte can vary as those skilled in the art will understand. For example, various non-limiting examples of sensor technologies 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-electro-optical scattering; polarization measurements; refractive index measurements; chemical indicators, such as dyes; or turbidity measurements, including turbidimetry. For example, in one particular embodiment, the sensor may rely on electrochemical impedance spectroscopy for detection, thus the sensor includes at least one working electrode, which is typically located on, within, or otherwise fluidically contacted with the first microneedle. For example, the working electrode may be a metal (e.g., gold) deposited on the surface of the microneedle. The sensor may also include at least one reference electrode located on, within, or otherwise in fluid contact with the second microneedle, and / or at least one counter electrode located on, within, and / or otherwise in fluid contact with the third microneedle. For example, the reference and counter electrodes may also be made of a metal (e.g., gold) deposited on the surface of the respective microneedles. Impedance values ​​can be detected to assess the concentration of the analyte. If desired, the sensitivity of the detection system can be improved by accumulating trace amounts of the target molecule at the electrodes. Regarding specificity, the microneedles (e.g., the working electrode) can be surface-modified, for example, with enzymes, antibodies, aptamers, single-stranded variable fragments (ScFv), carbohydrates, and combinations thereof. For example, in one embodiment, the working electrode may be modified with glucose oxidase (GOx) for glucose detection.

[0074] The present invention can be better understood by referring to the following embodiments.

[0075] Test methods

[0076] Melt viscosity: can be measured according to ISO test 11443:2005 at 400s. -1 Or 1000s -1 The melt viscosity (Pa·s) was determined using a Dynisco LCR7001 capillary rheometer at a shear rate and a temperature 15°C above the melting temperature (e.g., approximately 350°C). The rheometer orifice (die) had a diameter of 1 mm, a length of 20 mm, an L / D ratio of 20.1, and an inlet angle of 180°. The barrel diameter was 9.55 mm ± 0.005 mm, and the rod length was 233.4 mm.

[0077] Melting temperature: The melting temperature (Tm) can be determined by differential scanning calorimetry (DSC) as known in the art. As determined by ISO test 11357-2:2013, the melting temperature is the peak melting temperature of the differential scanning calorimetry (DSC). Under DSC procedure, using DSC measurements performed on a TA Q2000 instrument, the sample is heated and cooled at 20°C per minute as described in ISO standard 10350.

[0078] Temperature Flexural Deflection Under Load (DTUL): The temperature flexural deformation under load can be determined according to ISO Test 75-2:2013 (technically equivalent to ASTM D648-07). More specifically, a three-point bending test along the edge can be performed on a test strip sample with a length of 80 mm, a thickness of 10 mm, and a width of 4 mm, where the specified load (maximum outer fiber stress) is 1.8 MPa. The sample can be lowered into a silicone oil bath, where the temperature is increased at 2°C per minute until it flexes to 0.25 mm (0.32 mm for ISO Test 75-2:2013).

[0079] Tensile modulus, tensile stress, and tensile elongation: Tensile properties can be tested according to ISO Test 527:2012 (technically equivalent to ASTM D638-14). Modulus and strength measurements can be performed on identical test strips with 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.

[0080] Flexural modulus, flexural stress, and flexural elongation: Flexural properties can be tested according to ISO Test 178:2010 (technically equivalent to ASTM D790-10). This test can be performed on a 64 mm support span. The test can be performed on the center portion of an uncut ISO 3167 multipurpose bar. The test temperature can be 23°C and the test speed can be 2 mm / min.

[0081] Notched and Unnotched Charpy Impact Strength: Charpy characteristics can be tested according to ISO test ISO 179-1:2010 (technically equivalent to ASTM D256-10, Method B). This test can be performed using a Type 1 specimen size (80 mm length, 10 mm width, and 4 mm thickness). When testing notched impact strength, the notch can be a Type A notch (0.25 mm base circle radius). The specimen can be cut from the center of a multi-purpose bar using a single-tooth milling machine. The test temperature can be 23°C.

[0082] Example 1

[0083] Samples 1 through 5 and a control sample were prepared for use in microneedle assemblies. The samples comprised various combinations of liquid crystal polymers (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. The median particle size of TALC 1 was 4 μm, and that of TALC 2 was 1 μm. Blending was performed using an 18-mm single-screw extruder. The samples were injection molded into sheets (60 mm × 60 mm). The formulations are described below.

[0084]

[0085]

[0086] The thermal and mechanical properties of samples 1 through 5 were tested. The results are shown below.

[0087]

[0088] Example 2

[0089] Samples 6 to 10 were formed for use in microneedle assemblies. The samples comprised various combinations of liquid crystal polymer (LCP 2), talc (TALC 1 or TALC 2), and / or polytetrafluoroethylene (PTFE). The LCP was formed from 48% HNA, 2% HBA, 25% BP, and 25% TA. Blending was performed using an 18-mm single-screw extruder. The samples were injection molded into sheets (60mm × 60mm). The formulation is described below.

[0090] LCP 2 78 88 100 58 58 TALC 1 - - - 41 - TALC 2 21 11 - - 41 PTFE 1 1 - 1 1

[0091] The thermal and mechanical properties of samples 6 to 10 were tested. The results are shown below.

[0092]

[0093] These and other modifications and variations can be made to the invention by those skilled in the art without departing from the spirit and scope of the invention. Furthermore, it should be understood that aspects of the various embodiments can be interchanged entirely or partially. In addition, those skilled in the art will understand that the foregoing description is merely exemplary and is not intended to limit the invention as further described in the appended claims.

Claims

1. A microneedle assembly comprising at least one microneedle extending outwardly from a support, wherein the microneedle comprises a polymer composition comprising a thermoplastic polymer having a melt temperature of 300°C or higher, wherein the polymer composition exhibits a melt temperature of 1000 s according to ISO test 11443:2014. -1 The shear rate and melt viscosity of 100 Pa-s or less as measured at a temperature 30°C above the melt temperature, wherein the ratio of the flexural temperature under load to the melt temperature as measured according to ISO Test 75-2:2013 at a load of 1.8 MPa is 0.75 to 1, wherein the polymer composition exhibits an elongation at a temperature of 5% or less as measured according to ISO Test 527:2012 at a temperature of 23°C, and wherein the thermoplastic polymer comprises a liquid crystal polymer containing 30 mol.% or more of repeating units derived from cycloalkane hydroxycarboxylic acids, cycloalkane dicarboxylic acids or combinations thereof.

2. The microneedle assembly according to claim 1, wherein, The polymer composition exhibits performance according to ISO test 11443:2014 at 400 seconds. -1 The shear rate and the melt viscosity of 150 Pa-s or less, measured at a temperature 30°C above the melting temperature.

3. The microneedle assembly according to claim 1, wherein, The polymer composition exhibits a flexural temperature of 160°C or higher under a load of 1.8 MPa, as determined by ISO Test 75-2:2013.

4. The microneedle assembly according to claim 3, wherein, The ratio of the flexural temperature to the melting temperature under load is 0.75 to 0.

95.

5. The microneedle assembly according to claim 1, wherein, The polymer composition exhibits a tensile modulus of 7000 MPa or greater as determined according to ISO test 527:2012 at 23°C.

6. The microneedle assembly according to claim 1, wherein, The liquid crystal polymer comprises repeating units derived from 4-hydroxybenzoic acid, 6-hydroxy-2-naphthoic acid, or combinations thereof.

7. The microneedle assembly according to claim 1, wherein, The liquid crystal polymer comprises repeating units derived from terephthalic acid, isophthalic acid, 2,6-naphthalenedicarboxylic acid, or combinations thereof.

8. The microneedle assembly according to claim 1, wherein, The liquid crystal polymer further comprises repeating units derived from one or more aromatic diols.

9. The microneedle assembly according to claim 8, wherein, The aromatic diols include hydroquinone, 4,4'-biphenol, or combinations thereof.

10. The microneedle assembly according to claim 1, wherein, The liquid crystal polymer is fully aromatic.

11. The microneedle assembly according to claim 1, wherein, The liquid crystal polymer contains 40 mol.% or more of repeating units derived from cycloalkane hydroxycarboxylic acids and / or cycloalkane dicarboxylic acids.

12. The microneedle assembly according to claim 1, wherein, The liquid crystal polymer contains 30 mol.% or more of repeating units derived from 6-hydroxy-2-naphthoic acid.

13. The microneedle assembly according to claim 1, wherein, The thermoplastic polymer accounts for 30 wt.% to 99 wt.% of the polymer composition.

14. The microneedle assembly according to claim 1, wherein, The polymer composition also contains mineral fillers.

15. The microneedle assembly according to claim 14, wherein, The mineral filler is in granular form.

16. The microneedle assembly according to claim 15, wherein, The particles have a median particle size of 10 micrometers or less.

17. The microneedle assembly according to claim 15, wherein, The particles have a median particle size of 0.6 micrometers to 2.5 micrometers.

18. The microneedle assembly according to claim 15, wherein, The particles include talc.

19. The microneedle assembly according to claim 1, wherein, The polymer composition also includes tribological additive materials.

20. The microneedle assembly according to claim 19, wherein, The tribological additive material includes fluoropolymers.

21. The microneedle assembly according to claim 1, wherein, The component includes a plurality of microneedles arranged in an array on the support.

22. The microneedle assembly according to claim 1, wherein, The microneedle has a tip and a base.

23. The microneedle assembly according to claim 22, wherein, The tip has a length of 5 nanometers to 500 nanometers and a width of 0.5 micrometers to 5 micrometers.

24. The microneedle assembly according to claim 22, wherein, The base has a length of 10 nanometers to 1000 nanometers and a thickness of 5 micrometers to 100 micrometers.

25. The microneedle assembly according to claim 1, wherein, The microneedles have a height of 10 nanometers to 1000 nanometers.

26. The microneedle assembly according to claim 1, wherein, The component is configured to deliver a drug compound.

27. The microneedle assembly according to claim 26, wherein, The pharmaceutical compounds include protein compounds, polynucleotide reagents, small molecule reagents, or combinations thereof.

28. The microneedle assembly according to claim 26, wherein, The pharmaceutical compounds include vaccines, anti-infective agents, hormones, drugs that regulate cardiac activity or blood flow, or combinations thereof.

29. The microneedle assembly according to claim 26, wherein, The drug compound has a molecular weight of 1 kDa or higher.

30. The microneedle assembly according to claim 26, wherein, The drug compound includes viral vaccine antigens.

31. The microneedle assembly according to claim 30, wherein, The viral vaccine antigen mentioned is a coronavirus vaccine antigen.

32. The microneedle assembly according to claim 31, wherein, The coronavirus vaccine antigen is a viral vector, a live attenuated virus, or an inactivated virus.

33. The microneedle assembly according to claim 31, wherein, The coronavirus vaccine antigens include mRNA-1273, BNT162, Ad5-nCoV, ChAdOx1, bacTRL-Spike, BCG, AdCovid, NVX-CoV2373, LV-SMENP, SARS recombinant spike protein plus δ-inulin, SARS VLPs S protein and influenza M1 protein, DNA vaccine VRC-SRSDNA015-00-VP, VEEV replicon particles expressing SARS-CoV S, inactivated SARS-CoV-2 virus or viral vector, attenuated live SARS-CoV-2 virus or combinations thereof.

34. The microneedle assembly according to claim 30, wherein, The viral vaccine antigen is derived from and / or used to prevent adenovirus, arenavirus, Bunyavirus, flavivirus, hantavirus, hepatotropic DNA virus, herpesvirus, papillomavirus, paramyxovirus, parvovirus, piconemavirus, poxvirus, orthomyxovirus, retrovirus, reovirus, rhabdovirus, rotavirus, spongivirus, cloacal virus, or combination thereof.

35. The microneedle assembly according to claim 26, wherein, The drug compound coats the surface of the microneedles.

36. The microneedle assembly according to claim 35, wherein, The microneedles are solid.

37. The microneedle assembly according to claim 26, wherein, The microneedle contains at least one channel through which the drug compound can flow.

38. A transdermal delivery device comprising a microneedle assembly according to claim 37 and a drug reservoir in fluid communication with the channel, wherein the drug compound is located within the reservoir.

39. The transdermal delivery device of claim 38 further includes an additional reservoir containing excipients.

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