Dissolving microneedle patch for transdermal delivery of a peptide

Abstract

Aspects of the present disclosure relate to microneedle devices for transdermal delivery of peptides and methods thereof. In some embodiments, the devices comprise a microneedle array and a backing layer. The microneedle array, according to some embodiments, comprises a plurality of microneedles. The plurality of microneedles may be dissolvable, according to some embodiments. Additionally, in some cases, the plurality of microneedles may comprise a peptide, and optionally, one or more excipients. The microneedle array and the backing layer are at different pH values according to some embodiments, e.g., to prevent or limit back diffusion of the peptide into the backing layer. Other aspects of the disclosure relate to methods for making said microneedle devices.

Description

DISSOLVING MICRONEEDLE PATCH FOR TRANSDERMAL DELIVERY OF A PEPTIDEFIELD

[0001] The present disclosure is generally related to microneedle devices for transdermal delivery of peptides and uses thereof.BACKGROUND

[0002] Microneedle devices are commonly used to deliver drugs through the skin. In general, microneedle devices contain arrays of drug-loaded microneedles adhered to a substrate, e.g., a patch. Placement of the device onto a subject’s skin causes the microneedles containing the drug to penetrate through the stratum comeum of the skin and into the epidermis and / or upper dermis layer of the skin. Once the drug enters the epidermis / upper dermis, it can enter systemic circulation via the blood vessels in the dermis layer. The small size of microneedle patches may limit the total volume of drug that can be delivered. This is further complicated by the need for multiple excipients to form the microneedle itself (e.g., the microneedle shaft), which ultimately reduces the total amount of drug that can be loaded within a single device. Thus, improvements that allow for higher drug loading within microneedle devices are needed.SUMMARY

[0003] The present disclosure is generally related to microneedle devices for transdermal delivery of peptides and uses thereof. The subject matter of the present disclosure involves, in some cases, interrelated products, alternative solutions to a particular problem, and / or a plurality of different uses of one or more systems and / or articles.

[0004] Aspects of the disclosure relate to microneedle devices. In some embodiments, the devices comprise a microneedle array comprising a plurality of microneedles having a first end and a second end. The devices, in certain embodiments, further comprise a backing layer in contact with the second end of the microneedles of the microneedle array. In some embodiments, the at least some of the microneedles comprises a peptide, the peptide present at a concentration of between 15% and 85% (w / v).

[0005] In some embodiments, a microneedle device comprises a microneedle array comprising a plurality of microneedles having a first end and a second end and a backing layer in contact with the second end of the microneedles of the microneedle array. Additionally, in some embodiments, at least some of the microneedles comprises a peptide having a pl value. In somecases, the backing layer has a pH lower than the peptide pl value and the microneedle array has a pH higher than the peptide pl value.

[0006] In some embodiments, a microneedle device comprises a microneedle array comprising a plurality of microneedles having a first end and a second end. In some cases, at least some of the microneedles comprise tirzepatide at a concentration of between 15% and 85% (w / v).

[0007] Other aspects of the disclosure relate to methods of producing a microneedle patch disclosed herein. For example, in some embodiments, the methods comprise creating a negative mold of a microneedle array, the negative mold comprising a plurality of cavities. In certain embodiments, the methods further comprise adding a first solution at a first pH to the plurality of cavities of the negative mold wherein the first solution comprises a peptide. The method further comprises allowing the first solution to at least partially dry within the plurality of cavities of the negative mold to form a plurality of microneedles. In other embodiments, the methods further comprise adding a second solution at a second pH comprising a polymer to the negative mold, and allowing the second solution to dry within the negative mold to form a backing layer. Additionally, in some embodiments, the difference in the pH of the first and second solutions inhibits diffusion of the peptide from the first solution into the second solution.

[0008] Several methods are disclosed herein of administering a subject with a compound for prevention or treatment of a particular condition. It is to be understood that in each such aspect of the disclosure, the disclosure specifically includes, also, the compound for use in the treatment or prevention of that particular condition, as well as use of the compound for the manufacture of a medicament for the treatment or prevention of that particular’ condition.

[0009] In another aspect, the present disclosure encompasses methods of making one or more of the embodiments described herein, for example, a microneedle device. In still another aspect, the present disclosure encompasses methods of using one or more of the embodiments described herein, for example, a microneedle device.

[0010] Other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments of the disclosure when considered in conjunction with the accompanying figures.BRIEF DESCRIPTION OF DRAWINGS

[0011] Non-limiting embodiments of the present disclosure will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to bedrawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the disclosure shown where illustration is not necessary to allow those of ordinary skill in the art to understand the disclosure. In the figures:

[0012] FIG. 1 illustrates an overview of fabrication of molds used to make dissolving microneedle devices by indirect 3D printed methods, according to some embodiments.

[0013] FIG. 2 illustrates the fabrication of tirzepatide loaded dissolvable microneedle patches using the PDMS molds developed in FIG. 1, according to some embodiments.

[0014] FIG. 3 shows scanning electron micrographs of microneedle tips as a function of the printing angle (0 degrees, 30 degrees, 45 degrees, and 60 degrees) used to make a mold. Molds fabricated at an angle of 30 degrees produced tip diameters of 70.2 + / - 11.9 microns, at 0 degrees produced tip diameters of 85.5 + / - 3.1 microns, at 45 degrees produced tip diameters of 75.8 + / - 10.9 microns, and at 60 degrees produced tip diameters of 72.1 + / - 7.9 microns; according to some embodiments.

[0015] FIG. 4 illustrates microneedle devices fabricated at different excipient concentrations. All formulations had 10% (wt%) tirzepatide (TZP). The percent excipient list is in addition to the TZP. For example, the 0% excipient image corresponds to microneedles comprising 10% (wt) TZP + 0% excipients, according to some embodiments.

[0016] FIG. 5 show a high pressure liquid chromatography (HPLC) chromatograph illustrating the absence of a TZP degradation peak following fabrication of the devices described in FIG. 4, according to some embodiments.

[0017] FIG. 6 shows the backing layer of the devices, according to several embodiments.

[0018] FIG. 7 shows images of microneedle devices following placement on wet skin, dry skin, and SynDaver skin. The images show that the microneedles dissolve under the conditions tested, according to some embodiments.

[0019] FIG. 8 shows a table quantifying the percent dissolution as a function of excipient concentration, according to some embodiments.

[0020] FIG. 9 shows a table quantifying the percent of TZP recovered from pig tissue following placement of a device on pig skin, according to some embodiments.DETAILED DESCRIPTION

[0021] Aspects of the present disclosure relate to micronccdlc devices for transdcrmal delivery of peptides and methods thereof. In some embodiments, the devices comprise a microneedle array and a backing layer. The microneedle array, according to some embodiments, comprises a plurality of microneedles. The plurality of microneedles may be dissolvable, according to some embodiments. Additionally, in some cases, the plurality of microneedles may comprise a peptide, and optionally, one or more excipients. The microneedle array and the backing layer are at different pH values according to some embodiments, e.g., to prevent or limit back diffusion of the peptide into the backing layer. Other aspects of the disclosure relate to methods for making said microneedle devices.

[0022] Microneedle devices are devices that can be used for transdcrmal delivery of peptides and other large molecules that are normally incapable of permeating through the stratum comeum (e.g., the outer most skin layer). As stated above, microneedle devices may comprise a microneedle array disposed on a backing layer. The microneedle array may comprise one or a plurality of microneedles. Without wishing to be bound by any particular theory, pressing a microneedle device onto the skin of a subject can create micron-sized channels through the stratum corneum, via the plurality of microneedles, that lead to the epidermis and / or upper dermis layers (e.g., it allows drugs to by-pass the stratum comeum, the uppermost layer of the skin, and often the main barrier to entry of drugs into the body). Following the creation of such channels, the drugs within the microneedles may diffuse into the tissue (e.g., along a concentration gradient), through the micron-sized pathways, e.g., into the skin, and / or into the systemic circulation via blood vessels located in the dermis layer. In this regard, the tissue vasculature can act as a “sink” that depletes the local drug concentration at the delivery site, which in turn, drives the continuous release of the drug from the microneedles, e.g., until the reservoirs are depleted.

[0023] A current problem is that a limited amount of drug can be loaded into the microneedle device. This is at least, in part, due to the limited dimensions of the microneedles themselves.

[0024] A common theme amongst existing microneedle devices is the use of excipients to create the plurality of microneedles. As used herein, the term “excipient” refers to any material of the microneedle device that is not the active therapeutic drug. Without wishing to be bound by any particular theory, it is believed that the excipients can be useful in certain circumstances foroptimizing certain device parameters and / or design performance. For example, one motivation for using micronccdlc patches is to avoid the pain associated with administering a drug via hypodermic needles. The shape of the microneedle (e.g., conic vs pyramidal) and / or the needle sharpness (e.g., tip diameter) may be factors in determining pain. Thus, materials capable of making microneedles in different shapes and sharpness may be used.

[0025] Common excipients used to fabricate microneedles, include but are not limited to, silicon, metal (e.g., stainless-steel, titanium, palladium, nickel, palladium-cobalt alloys, etc.), ceramic (e.g., alumina, gypsum, brushite, etc.), silica glass (e.g., borosilicate glass), carbohydrates (e.g., maltose, mannitol, trehalose, sucrose, xylitol, galactose, etc.), and polymers (e.g., poly (methyl methacrylate) (PMMA), polylactic acid (PLA), poly (lactic-co-glycolic acid) (PLGA), polyglycolic acid (PGA), poly (carbonate), cyclic-olefin copolymer, poly (vinylpyrrolidone) (PVP), poly (vinyl alcohol) (PVA), polystyrene (PS), poly (methyl vinyl ether-co-maleic anhydride, SU-8 photoresist, etc.). A drug may be encapsulated within the microneedle and / or coated onto an outer surface of the microneedle.

[0026] Some embodiments are generally directed to the fabrication of the microneedles using the drug as the primary excipient. This may allow microneedle devices having relatively high drug loading capabilities (e.g., 1 mg / cm2to 10 mg / cm2). In some embodiments. u the drug loading may be at least 1 mg / cm2, at least 2 mg / cm2, at least 3 mg / cm2, at least 4 mg / cm2, at least 5 mg / cm-, at least 6 mg / cm', at least 7 mg / cm , at least 8 mg / cm , at least 9 mg / cm , at least 10 mg / cm2, etc., and / or no more than 10 mg / cm2, no more than 9 mg / cm2, no more than 8 mg / cm2, no more than 7 mg / cm2, no more than 6 mg / cm2, no more than 5 mg / cm2, no more than 4 mg / cm2, no more than 3 mg / cm2, no more than 2 mg / cm2, no more than 1 mg / cm2, etc. In one exemplary embodiment, a microneedle patch with 1 cm2area and a total microneedle volume of 9pL has a total drug loading of 9 mg / patch. Combinations of any of these are also possible in some cases. Additionally, certain embodiments are directed to systems and methods for fabricating the devices in such a way that allow the microneedle properties (e.g., shape, tip sharpness, spacing, height, aspect ratio, permeability, dis solvability, etc.) to be readily tuned. Those of ordinary skill in the art will understand and appreciate that such improvements may permit systemic delivery of a target drug at therapeutic levels over controlled time scales.

[0027] FIG. 10 shows an exemplary microneedle device, e.g., as disclosed herein. In some embodiments, the microneedle device comprises a microneedle array comprising a plurality ofmicroneedles. The microneedles may have a first end (e.g., a tip end) and a second end (e.g., end adjacent the backing layer). In some embodiments, the devices may further comprise a backing layer. In some cases, the backing layer is in contact with the second end of the plurality of microneedles of the microneedle array (e.g., the microneedle array is disposed onto the backing layer).

[0028] In some embodiments, at least some of the microneedles comprise a peptide. In some embodiments, the peptide is present in at least some of the microneedles at a concentration of between 0% (e.g., not present in the microneedle) and 100% w / v (e.g., only the compound is present in the microneedle). In some embodiments, the peptide is present in at least some of the microneedles at a concentration of between 15% and 85% (w / v). In other embodiments, the peptide is present in at least some of the microneedles at a concentration of between 80% and 90% (w / v). In some embodiments, the peptide is present in at least some of the microneedles at a concentration of greater than or equal to 0%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, greater than or equal to 85%, greater than or equal to 90%, or greater than or equal to 100%. In some embodiments, the peptide is present in at least some of the microneedles at a concentration of less than or equal to 100%, less than or equal to 90%, less than or equal to 85%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 15%, less than or equal to 10%, or less than or equal to 0%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments the peptide is present in at least some of the microneedles at a concentration of greater than or equal to 15% and less than or equal to 85%.

[0029] Certain embodiments are directed toward reducing back diffusion of a peptide from a microneedle into a backing layer (e.g., in contact with a second end of the microneedle).Without wishing to be bound by any particular theory, it is generally known in the art that peptides have a pl value (isoelectric point), which is an inherent property of the peptide that represents the pH at which the peptide carries no net electrical charge. The pl may be calculated empirically from the mean of the pKa’s (i.e., the acid dissociation constants). It is well known that at a pH below the pl, the peptide (or protein) carries a net positive charge, and conversely, ata pH above the pl a peptide (or protein) carries a net negative charge. As a result, peptides and proteins may be more soluble at pHs above their pl than pHs at or below their pl. Importantly, when the pH=pI, the peptide usually precipitates out of solution.

[0030] Accordingly, in some embodiments, a backing layer has a pH lower than the peptide pl value and the microneedle array has a pH higher than the peptide pl value. As will be discussed in more detail below, it is generally believed that such configurations may prevent or inhibit dissolution of the peptide in the backing layer during the fabrication process.

[0031] Those of ordinary skill in the ail will understand, however, that some peptide may still back diffuse into the backing layer. Accordingly, in some embodiments, a backing layer may comprise between 1% and 20% (w / v) of a peptide loaded into a microneedle device. In some embodiments, the backing layer comprises less than 1%, less than 5%, less than 10%, less than 15%, or less than 20% of the peptide loaded into a microneedle device. In some embodiments, a backing layer comprises less than 10% of the peptide loaded into the microneedle device.

[0032] In some embodiments, a microneedle array comprising a plurality of microneedles that have a pH value of between 1 and 10. In some embodiments, the pH of the microneedle array comprising the plurality of microneedles is greater than or equal to 1 , greater than or equal to 2, greater than or equal to 3, greater than or equal to 4, greater than or equal to 5, greater than or equal to 6, greater than or equal to 7, greater than or equal to 8, greater than or equal to 9, or greater than or equal to 10. In some embodiments, the pH of the microneedle array comprising the plurality of microneedles is less than or equal to 10, less than or equal to 9, less than or equal to 8, less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0033] In some embodiments, a backing layer has a pH value of between 1 and 10. In some embodiments, the pH of the backing layer is greater than or equal to 1, greater than or equal to 2, greater than or equal to 3, greater than or equal to 4, greater than or equal to 5, greater than or equal to 6, greater than or equal to 7, greater than or equal to 8, greater than or equal to 9, or greater than or equal to 10. In some embodiments, the pH of the backing layer is less than or equal to 10, less than or equal to 9, less than or equal to 8, less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0034] In some embodiments, a peptide has a pl value of between 1 and 10, of between 1 and 9, of between 1 and 8, of between 1 and 7, of between 1 and 6, of between 1 and 5, of between 1 and 4, of between 1 and 3, of between 1 and 2, of between 2 and 10, of between 2 and 9, of between 2 and 8, of between 2 and 7, of between 2 and 6, of between 2 and 5, of between 2 and4, of between 2 and 3, of between 3 and 10, of between 3 and 9, of between 3 and 8, of between 3 and 7, of between 3 and 6, of between 3 and 5, of between 3 and 4, of between 4 and 10, of between 4 and 9, of between 4 and 8, of between 4 and 7, of between 4 and 6, of between 4 and5, of between 5 and 10, of between 5 and 9, of between 5 and 8, of between 5 and 7, of between 5 and 6, of between 6 and 10, of between 6 and 9, of between 6 and 8, of between 6 and 7, of between 7 and 10, of between 7 and 9, of between 7 and 8, of between 8 and 10, of between 8 and 9, or between 9 and 10. In some embodiments, the peptide pl is between 4 and 5.

[0035] In some embodiments, at least some of the microneedles further comprise one or more excipients (e.g., in addition to the drug). Exemplary excipients include but are not limited to comprises glycerol, polyvinylpyrrolidone K30 (PVPK30), or trehalose.

[0036] In some embodiments, one or more excipients comprises glycerol. In some embodiments, glycerol is present in at least some of the microneedles at a concentration of between 1% and 3% (w / v). In some embodiments, the glycerol is present in at least some of the microneedles at a concentration of greater than or equal to 1%, greater than or equal to 2% or greater than or equal to 3%. In some embodiments, the glycerol is present in at least some of the microneedles at less than or equal to 3%, less than or equal to 2%, or less than or equal to 1%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments, the glycerol is present in at least some of the microneedles at greater than or equal to 1% and less than or equal to 3%.

[0037] In some embodiments, one or more excipients comprises PVP, for example, PVP30K. In some embodiments, PVP30K is present in at least some of the microneedles at a concentration of between 8% and 40% (w / v). In some embodiments, the PVP30K is present in at least some of the microneedles at a concentration of greater than or equal to 8%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 35%, or greater than or equal to 40%. In some embodiments, the PVP30K is present in at least some of the microneedles at less than or equal to 40%, less than or equal to 35%, less than or equal to 30%, less than or equal to 25%, less than orequal to 20%, less than or equal to 15%, less than or equal to 10% or less than or equal to 8%. Combinations of the above recited ranges arc also possible in some embodiments. For example, in some embodiments, the PVP30K is present in at least some of the microneedles at greater than or equal to 8% and less than or equal to 40%.

[0038] In some embodiments, one or more excipients comprises trehalose. In some embodiments, trehalose is present in at least some of the microneedles at a concentration of between 1% and 10% (w / v). In some embodiments, the trehalose is present in at least some of the microneedles at a concentration of greater than or equal to 1%, greater than or equal to 2%, greater than or equal to 3%, greater than or equal to 4%, greater than or equal to 5%, greater than or equal to 6%, greater than or equal to 7%, greater than or equal to 8%, greater than or equal to 9%, or greater than or equal to 10%. In some embodiments, the trehalose is present in at least some of the microneedles at less than or equal to 10%, less than or equal to 9%, less than or equal to 8%, less than or equal to 7%, less than or equal to 6%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, or less than or equal to 1%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments, the trehalose is present in at least some of the microneedles at greater than or equal to 1% and less than or equal to 10%.

[0039] In some embodiments, one or more excipients comprises glycerol, PVP30K, and trehalose wherein the glycerol is present at a concentration of between 1% and 3% (w / v), PVPK30 is present at a concentration of between 8% and 40% (w / v), and trehalose is present at a concentration of between 2% and 10% (w / v).

[0040] Other excipients are possible in other embodiments. For example, in some embodiments, the one or more excipients comprises a carbohydrate (e.g., sugar). In some embodiments, the carbohydrate comprises a polymeric carbohydrate. Exemplary embodiments of polymeric carbohydrates include, but are not limited to, xanthan gum, dextran, alginate, gellan, gelatin, pullulan, mannan, hyaluronan, chitin, chitosan, agarose, and guar gum. In some embodiments, the carbohydrate comprises simple sugars. Exemplary embodiments of simple sugars include but are not limited to sucrose, maltose, mannitol, xylitol, aspartame, sucralose, trehalose, glucose, galactose, and the like. In some embodiments, carbohydrate is present in at least some of the microneedles at a concentration of between 1% and 10% (w / v). In some embodiments, the carbohydrate is present in at least some of the microneedles at a concentration of greater than orequal to 1 %, greater than or equal to 2%, greater than or equal to 3%, greater than or equal to 4%, greater than or equal to 5%, greater than or equal to 6%, greater than or equal to 7%, greater than or equal to 8%, greater than or equal to 9%, or greater than or equal to 10%. In some embodiments, the carbohydrate is present in at least some of the microneedles at less than or equal to 10%, less than or equal to 9%, less than or equal to 8%, less than or equal to 7%, less than or equal to 6%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, or less than or equal to 1%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments, the carbohydrate is present in at least some of the microneedles at greater than or equal to 1% and less than or equal to 10%.

[0041] Similarly, in some embodiments, the one or more excipients comprises a polymer, such as PVP30K or PVP90K. However, other polymers are also contemplated in other embodiments. Exemplary embodiments of polymers contemplated herein include, but are not limited to, polyvinylpyrrolidone, poly (methyl methacrylate) (PMMA), polylactic acid (PLA), poly (lactic - co-glycolic acid) (PLGA), polyglycolic acid (PGA), poly (carbonate), cyclic-olefin copolymer, poly (vinylpyrrolidone) (PVP), poly (vinyl alcohol) (PVA), polystyrene (PS), poly (methyl vinyl ether-co-maleic anhydride, SU-8 photoresist, or polydimethylsiloxane (PDMS). In some embodiments, the polymer is present in at least some of the microneedles at a concentration of between 8% and 40% (w / v). In some embodiments, the polymer is present in at least some of the microneedles at a concentration of greater than or equal to 8%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 35%, or greater than or equal to 40%. In some embodiments, the polymer is present in at least some of the microneedles at less than or equal to 40%, less than or equal to 35%, less than or equal to 30%, less than or equal to 25%, less than or equal to 20%, less than or equal to 15%, less than or equal to 10% or less than or equal to 8%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments, the polymer is present in at least some of the microneedles at greater than or equal to 8% and less than or equal to 40%.

[0042] The polymer may be of any suitable molecular weight (MW of 1000 g / mol = IK). For example, in some embodiments, the polymer has a molecular weight of greater than or equal to IK, greater than or equal to 5K, greater than or equal to 10K, greater than or equal to 15K,greater than or equal to 20K, greater than or equal to 25K, greater than or equal to 30K, greater than or equal to 40K, greater than or equal to 50K, greater than or equal to 60K, greater than or equal to 70K, greater than or equal to 80K, or greater than or equal to 90K. In some embodiments, the polymer has a molecular weight of less than or equal to 90K, less than or equal to 80K, less than or equal to 70K, less than or equal to 60K, less than or equal to 50K, less than or equal to 40K, less than or equal to 30K, less than or equal to 25K, less than or equal to 20K, less than or equal to 15K, less than or equal to 10K, less than or equal to 5K, or less than or equal to IK. Combination of the recited ranges are also possible in some embodiments. For example, in some embodiments, the polymer has a molecular weight of greater than or equal to IK and less than or equal to 90K. As a further example, PVP, for instance, may be present as PVP10K, PVP30K, or PVP90K, or any other molecular weights described herein.

[0043] Other contemplated formulations are shown in Table 1.Table 1. Composition of formulations used to fabricate microneedle arrays of microneedle devices contemplated herein.

[0044] It should be understood that while some of the devices disclosed herein may comprise one or more excipients, the presence of an excipient is not required in all embodiments.

[0045] As stated elsewhere herein, in some cases, at least some of the microneedles (e.g., of a microneedle array) comprise a peptide. Any suitable peptide may be used. In some embodiments, the peptide includes tirzepatide (TZP), disclosed in U.S. Patent 9,474,780, entitled “GIP and GLP-1 Co-Agonist Compounds” issued on October 25, 2016, U.S. Patent 11,357,820, entitled “GIP / GLP1 Agonist Compositions” issued on June 14, 2022, and U.S. Patent 11,918,623, entitled “GIP / GLP1 Agonist Compositions” issued on March 5, 2024, each of whichthe entire contents are incorporated herein by reference. In other embodiments, the peptide includes rctatrutidc, disclosed in U.S. Patent 11,542,313, entitled “Incrctin Analogs and Uses Thereof’ issued on January 3, 2023, and U.S. Patent Application 2024 / 0173250, entitled “Incretin Analog-Containing Compositions and Uses Thereof’ published on May 30, 2024, each of which the entire contents are incorporated herein by reference. However, it should be understood that any suitable peptide capable of forming the microneedles can be used herein.

[0046] In some embodiments, TZP is present in at least some of the microneedles at a concentration of between 0% (e.g., not present in microneedle) and 100% w / v (e.g., only compound present in microneedle). In some embodiments, TZP is present in at least some of the microneedles at a concentration of between 15% and 85% (w / v). In other embodiments, TZP is present in at least some of the microneedles at a concentration of between 80% and 90% (w / v). In some embodiments, TZP is present in at least some of the microneedles at a concentration of greater than or equal to 0%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, greater than or equal to 85%, greater than or equal to 90%, or greater than or equal to 100%. In some embodiments, TZP is present in at least some of the microneedles at a concentration of less than or equal to 100%, less than or equal to 90%, less than or to 85%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 15%, less than or equal to 10%, or less than or equal to 0%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments, TZP is present in at least some of the microneedles at a concentration of greater than or equal to 15% and less than or equal to 85%.

[0047] In some embodiments, a backing layer comprises one or more excipients. Any suitable excipient may be used to form the backing layer (e.g., elastic materials). In some embodiments, the excipient is a polymer. Exemplary polymers that may be used include, but are not limited to, polyvinylpyrrolidone K90 (PVPK90), poly (methyl methacrylate) (PMMA), polylactic acid (PLA), poly (lactic-co-glycolic acid) (PLGA), polyglycolic acid (PGA), poly (carbonate), cyclic- olefin copolymer, poly (vinylpyrrolidone) (PVP), poly (vinyl alcohol) (PVA), polystyrene (PS), poly (methyl vinyl ether-co-maleic anhydride, SU-8 photoresist, polydimethylsiloxane (PDMS),xanthan gum, dextran, alginate, gellan, gelatin, pullulan, mannan, hyauronan, chitin, chitosan, agarose, guar gum, hyaluronic acid, or carboxymethyl cellulose, etc.

[0048] In some embodiments, one or more excipients is present in a backing layer at a concentration of greater than or equal to 8%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 35%, or greater than or equal to 40%. In some embodiments, the one or more excipients is present in the backing layer at less than or equal to 40%, less than or equal to 35%, less than or equal to 30%, less than or equal to 25%, less than or equal to 20%, less than or equal to 15%, less than or equal to 10% or less than or equal to 8%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments, the one or more excipients is present in the backing layer at greater than or equal to 8% and less than or equal to 40%. In some embodiments, at least some microneedles in a microneedle array are configured to dissolve when placed onto a subjects skin. In some embodiments, the percent dissolution is between 80% and 100% within 24 hours of placing a microneedle device onto a subject’s skin. In some embodiments, the percent dissolution is between 80% and 100% after about 2 hours, after about 4 hours, after about 6 hours, after about 8 hours, after about 10 hours, after about 12 hours, after about 14 hours, after about 16 hours, after about 18 hours, after about 20 hours, after about 22 hours or after about 24 hours.

[0049] However, it should be understood that the dissolution rate may be accelerated or retarded, as appropriate, for example, by applying the device to wet skin (e.g., accelerated dissolution) or by applying the device to dry skin (e.g., retarded dissolution).

[0050] Some embodiments are directed toward a microneedle device comprising a microneedle array, a backing layer, and a reservoir layer. In some embodiments, the microneedle array is on a first side of the reservoir layer and the backing layer is on a second, opposing side, of the reservoir layer. In certain embodiments, the microneedle array further comprises a plurality of microneedles having a first end (e.g., tip end) and a second end, the second end being adjacent the reservoir layer. In some embodiments, the reservoir layer comprises a peptide. In other embodiments, the microneedles comprise a peptide. In other embodiments, still, both the reservoir and the microneedles comprise the peptide. In some embodiments, the microneedles are dissolvable.

[0051] Without wishing to be bound by any particular theory, it is generally believed that such configurations may increase peptide loading and result in delivery of higher concentrations of peptide drug to the target tissue. This is possible in certain embodiments, for example, when using microneedles configured to dissolve following placement onto a subject’s skin, because as the microneedle dissolves, the peptide may be released and may partition into the surrounding tissue. Once at least a portion of the microneedles have dissolved, peptide from the reservoir layer may diffuse into the tissue via the pores created by the microneedles under certain conditions. This may be possible due, in part, to the fact that the channels created by the microneedles may remain for relatively long periods of time, e.g., at least 24 hours.

[0052] In some embodiments, the peptide is present in a reservoir at a concentration of between 0% (e.g., not present in the reservoir) and 100% w / v (e.g., only the compound is present in the reservoir). In some embodiments, the peptide is present in the reservoir at a concentration of between 15% and 85% (w / v). In other embodiments, the peptide is present in the reservoir at a concentration of between 80% and 90% (w / v). In some embodiments, the peptide is present in the reservoir at a concentration of greater than or equal to 0%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, greater than or equal to 85%, greater than or equal to 90%, or greater than or equal to 100%. In some embodiments, the peptide is present in the reservoir at a concentration of less than or equal to 100%, less than or equal to 90%, less than or equal to 85%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 15%, less than or equal to 10%, or less than or equal to 0%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments the peptide is present in the reservoir at a concentration of greater than or equal to 15% and less than or equal to 85%. In some embodiments, the peptide is TZP, or others such as any of those described herein.

[0053] In some embodiments, one or more excipients is present in a reservoir. The reservoir may comprise any excipient disclosed herein, at any suitable concentration, according to some embodiments. For example, in some embodiments, the one or more excipients is present in a reservoir at a concentration of between 0% (e.g., not present in the reservoir) and 85% w / v. Insome embodiments, the one or more excipients is present in the reservoir at a concentration of between 15% and 85% (w / v). In some embodiments, the one or more excipients is present in the reservoir at a concentration of greater than or equal to 0%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, or greater than or equal to 85%. In some embodiments the one or more excipients is present in the reservoir at a concentration of less than or equal to 85%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 15%, less than or equal to 10%, or less than or equal to 0%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments the peptide is present in the reservoir at a concentration of greater than or equal to 0% and less than or equal to 85%.

[0054] In some embodiments, a microneedle device further comprises an anti-inflammatory agent. For instance, in some embodiments, the microneedle array, reservoir, and / or backing layer may comprise one or more other agents, such as a numbing or an anti-inflammatory agent. Without wishing to be bound by any particular theory, it is generally believed that devices comprising numbing agents and / or anti-inflammatory agents may reduce redness and / or irritation as a result of use of the device. Any suitable numbing and / or anti-inflammatory agent known to one of ordinary skill in the art may be used in the devices as contemplated herein. Exemplary numbing agents include, for example, benzocaine, dibucane, lidocaine, phenol, pramoxine, and prilocaine, among others. Exemplary inflammatory agents include, but are not limited to, known nonsteroidal anti-inflammatory drugs (e.g., NSAIDs such as aspirin, ibuprofen, ketoprofen, celecoxib, diclofenac, ketorolac, naproxen, etc.), steroidal agents (e.g., hydrocortisone, prednisone, cortisone, betamethasone, dexamethasone, etc.), or the like.

[0055] Other aspects of the disclosure relate to one or more methods. In some embodiments, the methods relate to manufacturing a microneedle device as disclosed herein. In some cases, the methods comprise creating a negative mold of a microneedle array. It will be understood that the term “negative mold” means that the mold may comprise a plurality of cavities corresponding to the plurality of microneedles of the array (see FIG. 1, PDMS mold). Any suitable method for making the negative mold may be employed herein.

[0056] FIG. 1 illustrates one exemplary method in which a three-dimensional SLA printer is used to first create a positive mold. The positive mold is then used to produce a negative mold, for example, using solution casting. The positive mold has a plurality of columns that correspond to the plurality of microneedles. In this approach, for example, the tip geometry of the final microneedle product can be manipulated by mold design (e.g., channel geometries) and / or the printer process (e.g., printing angle). For example, it is known in the art that printing the mold at an angle can increase the sharpness of the microneedle tip.

[0057] Accordingly, in some embodiments, the methods comprise using a 3D printing process to make a positive mold of the microneedle device. The mold may be printed at any suitable angle, relative to an axis that is parallel to the printing platform. In some embodiments, the mold is printed at a 0 degree, 30 degree, 45 degree, or a 60 degree angle, relative to the printing platform. In some embodiments, the mold is printed at a 30 degree angle, relative to the printing platform.

[0058] After creating the negative mold, the methods, according to some embodiments, further comprise adding a first solution (e.g., comprising a peptide) at a first pH to the plurality of cavities of the negative mold (see FIG. 2) and allowing the first solution (e.g., comprising the peptide) to at least partially dry within the plurality of cavities of the negative mold to form a plurality of microneedles. In some embodiments, the pH of the first solution is higher than a pl of the peptide in the first solution.

[0059] In some embodiments, the methods further comprise adding a second solution at a second pH comprising an excipient to the negative mold (e.g., on top of the partially dried microneedle array), and allowing the second solution to dry within the negative mold to from a backing layer. In some embodiments, the pH of the second solution is lower than the pl of the peptide in the first solution. In some embodiments, the difference in pH of the first and second solutions inhibits diffusion of the peptide from the first solution into the second solution.

[0060] Such configurations may be advantageous in certain embodiments for preventing, or inhibiting, dissolution of the dried peptide (e.g., the microneedle) and / or its subsequent diffusion into the backing layer. As mentioned above, peptides and proteins may be more water soluble at pHs above their respective pl and less water soluble at pHs below their pl. Because the pH of the backing layer can be less than the pl of the peptide, the dried peptide (e.g., at the interface between the second end of the microneedle and the backing layer) may not be readily soluble in the backing layer solution. This may slow dissolution under certain circumstances, and / orsubsequent diffusion, of the peptide into the backing layer solution. Importantly, by manipulating the pH of the backing layer solution to approximate the pl of the peptide, the solubility in the peptide in the backing layer may be reduced under certain conditions. In some embodiments, this may occur because most peptides are insoluble when the pH is equal to or close to the pl of the peptide.

[0061] As discussed elsewhere herein, such configurations can produce a pH gradient at the interface between the microneedle array and the backing layer. At some point within this pH gradient, the pH may approach the pl of the peptide, which may cause the peptide to precipitate out of solution, resulting in a pseudo-diffusion barrier that prevents further diffusion of peptide from the microneedle into the backing layer.

[0062] Thus, in some embodiments, the peptide is soluble in the first solution. In other embodiments the peptide is at least partially insoluble in the second solution. In some embodiments, a diffusional barrier is formed by the partial precipitation of the peptide in the second solution.

[0063] In some embodiments, a first solution has a pH value of between 1 and 10. In some embodiments, the pH of the first solution is greater than or equal to 1, greater than or equal to 2, greater than or equal to 3, greater than or equal to 4, greater than or equal to 5, greater than or equal to 6, greater than or equal to 7, greater than or equal to 8, greater than or equal to 9, or greater than or equal to 10. In some embodiments, the pH of the first solution is less than or equal to 10, less than or equal to 9, less than or equal to 8, less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, less than or equal to 3, less than or equal to 2, or less than or equal to 1. In some embodiments, the first solution has a pH value of between 8 and 9.

[0064] In some embodiments, a second solution has a pH value of between 1 and 10. In some embodiments, the pH of the second solution is greater than or equal to 1, greater than or equal to 2, greater than or equal to 3, greater than or equal to 4, greater than or equal to 5, greater than or equal to 6, greater than or equal to 7, greater than or equal to 8, greater than or equal to 9, or greater than or equal to 10. In some embodiments, the pH of the second solution is less than or equal to 10, less than or equal to 9, less than or equal to 8, less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, less than or equal to 3, less than orequal to 2, or less than or equal to 1 . Tn some embodiments, the second solution has a pH of between 4 and 6.

[0065] In some embodiments, the first solution comprises a peptide. In some embodiments, the peptide is present in the first solution at a concentration of between 0% (e.g., not present in microneedle) and 100% w / v (e.g., only compound present in microneedle). In some embodiments, the peptide is present in the first solution at a concentration of between 15% and 85% (w / v). In other embodiments, the peptide is present in the first solution at a concentration of between 80% and 90% (w / v). In some embodiments, the peptide is present in the first solution at a concentration of greater than or equal to 0%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, greater than or equal to 85%, greater than or equal to 90%, or greater than or equal to 100%. In some embodiments, the peptide is present in the first solution at a concentration of less than or equal to 100%, less than or equal to 90%, less than or equal to 85%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 20%, less than or equal to 15%, less than or equal to 10%, or less than or equal to 0%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments the peptide is present in the first solution at a concentration of greater than or equal to 15% and less than or equal to 85%. In some embodiments, the peptide is Tirzepatide.

[0066] In some embodiments, the first solution may further comprise one or more excipients (e.g., in addition to the drug). Exemplary excipients include but are not limited to comprises glycerol, polyvinylpyrrolidone K30 (PVPK30), or trehalose, etc.

[0067] In some embodiments, one or more excipients comprises glycerol. In some embodiments, glycerol is present in the first solution at a concentration of between 1% and 3% (w / v). In some embodiments, the glycerol is present in the first solution at a concentration of greater than or equal to 1%, greater than or equal to 2% or greater than or equal to 3%. In some embodiments, the glycerol is present in the first solution at less than or equal to 3%, less than or equal to 2%, or less than or equal to 1%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments, the glycerol is present in the first solution at greater than or equal to 1% and less than or equal to 3%.

[0068] In some embodiments, one or more excipients comprises PVP30K. In some embodiments, PVP30K is present in the first solution at a concentration of between 8% and 40% (w / v). In some embodiments, the PVP30K is present in the first solution at a concentration of greater than or equal to 8%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 35%, or greater than or equal to 40%. In some embodiments, the PVP30K is present in the first solution at less than or equal to 40%, less than or equal to 35%, less than or equal to 30%, less than or equal to 25%, less than or equal to 20%, less than or equal to 15%, less than or equal to 10% or less than or equal to 8%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments, the PVP30K is present in the first solution at greater than or equal to 8% and less than or equal to 40%.

[0069] In some embodiments, one or more excipients comprises trehalose. In some embodiments, trehalose is present in the first solution at a concentration of between 1% and 10% (w / v). In some embodiments, the trehalose is present in the first solution at a concentration of greater than or equal to 1%, greater than or equal to 2%, greater than or equal to 3%, greater than or equal to 4%, greater than or equal to 5%, greater than or equal to 6%, greater than or equal to 7%, greater than or equal to 8%, greater than or equal to 9%, or greater than or equal to 10%. In some embodiments, the trehalose is present in the first solution at less than or equal to 10%, less than or equal to 9%, less than or equal to 8%, less than or equal to 7%, less than or equal to 6%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, or less than or equal to 1%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments, the trehalose is present in the first solution at greater than or equal to 1% and less than or equal to 10%.

[0070] In some embodiments, a first solution further comprises glycerol, PVP30K, and trehalose (e.g., in addition to the peptide). In some embodiments, the glycerol is present at a concentration of between 1% and 3% (w / v), PVPK30 is present at a concentration of between 8% and 40% (w / v), and trehalose is present at a concentration of between 2% and 10% (w / v).

[0071] In some embodiments, a second solution comprises an excipient. In some embodiments, one or more excipients comprises PVP90K. In some embodiments, PVP90K is present in the second solution at a concentration of between 8% and 40% (w / v). In some embodiments, the PVP90K is present in the second solution at a concentration of greater than or equal to 8%,greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 35%, or greater than or equal to 40%. In some embodiments, the PVP90K is present in the second solution at less than or equal to 40%, less than or equal to 35%, less than or equal to 30%, less than or equal to 25%, less than or equal to 20%, less than or equal to 15%, less than or equal to 10% or less than or equal to 8%. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments, the PVP90K is present in the second solution at greater than or equal to 8% and less than or equal to 40%.

[0072] In some embodiments, a microneedle device as disclosed herein has a drug loading capacity of between 0.1 and 10 mg / microliters / square cm. In some embodiments, the loading capacity is greater than or equal to 0.1 mg / microliters / square cm, greater than or equal to 0.05 mg / microliters / square cm, greater than or equal to 1 mg / microliters / square cm, greater than or equal to 2 mg / microliters / square cm, greater than or equal to 3 mg / microliters / square cm, greater than or equal to 4 mg / microliters / square cm, greater than or equal to 5 mg / microliters / square cm, greater than or equal to 6 mg / microliters / square cm, greater than or equal to 7 mg / microliters / square cm, greater than or equal to 8 mg / microliters / square cm, greater than or equal to 9 mg / microliters / square cm, or greater than or equal to 10 mg / microliters / square cm. In some embodiments, the loading capacity is less than or equal to 10 mg / microliters / square cm, less than or equal to 9 mg / microliters / square cm, less than or equal to 8 mg / microliters / square cm, less than or equal to 7 mg / microliters / square cm, less than or equal to 6 mg / microliters / square cm, less than or equal to 5 mg / microliters / square cm, less than or equal to 4 mg / microliters / square cm, less than or equal to 3 mg / microliters / square cm, less than or equal to 2 mg / microliters / square cm, less than or equal to 1 mg / microliters / square cm, less than or equal to 0.5 mg / microliters / square cm, or less than or equal to 0.1 mg / microliters / square cm. Combinations of the above recited ranges are also possible in some embodiments. For example, in some embodiments, the loading capacity is greater than or equal to 0.1 mg / microliters / square cm and less than or equal to 10 mg / microliters / square cm.

[0073] The following examples are intended to illustrate certain embodiments of the present disclosure, but do not exemplify the full scope of the disclosure.EXAMPLES

[0074] Example 1. This example describes one embodiment for preparing the molds to make microneedle devices. For example, FIG. 1 shows a schematic overview of an exemplary process used to fabricate molds used to make dissolving microneedle devices, as contemplated in this example, by indirect 3D printed methods, according to some embodiments. See FIG. 1 for details.

[0075] Example 2. This example illustrates the fabrication of the microneedle devices from the molds described in Example 1. See FIG. 2 for details.

[0076] Example 3. This example illustrates the tunablity of the microneedle properties using the processes shown in Examples 1 and 2. For example FIG. 3 shows scanning electron micrographs of microneedle tips as a function of the printing angle (0 degrees, 30 degrees, 45 degrees, and 60 degrees) used to make the mold. Molds printed at an angle of 30 degrees produced tip diameters of 70.2 + / - 11.9 microns, at 0 degrees produced tip diameters of 85.5 + / - 3.1 microns, at 45 degrees produced tip diameters of 75.8 + / - 10.9 microns, and at 60 degrees produced tip diameters of 72.1 + / - 7.9 microns; according to some embodiments. See FIG. 3.Table 2. Tip diameters as a function of printing degree for positive molds.

[0077] Example 4. This example illustrates the fabrication and tirzepatide (TZP) loading of microneedle devices at different excipient concentrations and their subsequent degradation profile. As shown in FIG. 5, high pressure liquid chromatography (HPLC) chromatograph was used to show the absence of a TZP degradation peak following fabrication of the devices described in FIG. 4, according to some embodiments. The percent degradation for each formulation is shown in Table 3.Table 3. Percent degradation of TZP drug following encapsulation with microneedle devicesDMNs formulation Drug amount (mg) Degradation (%)10% TZP-no excipient 1.52 < 0.310% TZP- 12% excipient 1.41 < 0.310% TZP-24% excipient 1.54 < 0.610% TZP-36% excipient 1.30 < 0.610% TZP-48% excipient 1.15 < 0.7

[0078] Example 6. This example illustrates the flexibility and diffusional barrier properties of the backing layer, according to some embodiments. FIG. 6 shows a micrograph of a device loaded with peptide having a flexible backing layer. Manipulation of the relative pH values between the microneedle and the backing layer, c.g., during device fabrication, inhibits back diffusion of the peptide into the backing layer, as shown in Table 4.Table 4. Loading and back diffusion of TZP in microneedle devices.

[0079] Example 7. This example shows images of microneedle devices following placement on wet skin, dry skin, and SynDaver skin. FIG. 7 shows that the microneedles used in this example dissolve under all conditions tested, according to some embodiments. FIG. 8 shows that the majority of the microneedle dissolves within 2 hours of administration.

[0080] Example 8. This example shows the ability of certain microneedle devices to deliver a peptide drug to the skin in a pig model. FIG. 9 shows that the amount of drug delivered was similar between devices having microneedles comprising TZP only versus those comprising TZP plus excipient.EQUIVALENTS AND SCOPE

[0081] While several embodiments of the present disclosure have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the present disclosure. More generally, those skilled in the ail will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present disclosure is / are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the disclosure may be practiced otherwise than as specifically described and claimed. The present disclosure is directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the present disclosure.

[0082] In cases where the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control. If two or more documents incorporated by reference include conflicting and / or inconsistent disclosure with respect to each other, then the document having the later effective date shall control.

[0083] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0084] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

[0085] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elementslisted with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0086] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.”

[0087] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0088] When the word “about” is used herein in reference to a number, it should be understood that still another embodiment of the disclosure includes that number not modified by the presence of the word “about.”

[0089] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0090] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.What is claimed is:

Claims

CLAIMS1. A device, comprising: a microneedle array comprising a plurality of microneedles having a first end and a second end; and a backing layer in contact with the second end of the microneedles of the microneedle array, wherein at least some of the microneedles comprises a peptide, the peptide present at a concentration of between 15% and 85% (w / v).

2. The device of claim 1, wherein the backing layer comprises less than 10% (w / v) of the peptide loaded into the microneedle device.

3. The device of claim 1 or 2, wherein the plurality of microneedles comprises the peptide at a concentration of between 80% and 90% (w / v).

4. The device of any one of claims 1-3, wherein the peptide is tirzepatide.

5. The device of any one of claims 1-4, wherein at least some of the microneedles further comprises one or more excipients.

6. The device of claim 5, wherein the one or more excipients comprises glycerol.

7. The device of claim 6, wherein the glycerol is present at a concentration of between 1% and 3% (w / v).

8. The device of any one of claims 5-7, wherein the one or more excipients comprises PVPK30.

9. The device of claim 8, wherein the PVPK30 is present at a concentration of between 8% and 40% (w / v).

10. The device of any one of claims 5-9, wherein the one or more excipients comprises trehalose.

11. The device of claim 10, wherein the trehalose is present at a concentration of between 2% and 10% (w / v).

12. The device of any one of claims 5-11, wherein the one or more excipients comprises glycerol, PVPK30, and trehalose.

13. The device of claim 12, glycerol is present at a concentration of between 1% and 3% (w / v), PVPK30 is present at a concentration of between 8% and 40% (w / v), and trehalose is present at a concentration of between 2% and 10% (w / v).

14. The device of any one of claims 1-13, wherein at least some microneedles in the plurality of microneedles are dissolvable when placed onto skin.

15. A device, comprising : a microneedle array comprising a plurality of microneedles having a first end and a second end; and a backing layer in contact with the second end of the microneedles of the microneedle array, wherein at least some of the microneedles comprises a peptide having a pl value, wherein the backing layer has a pH lower than the peptide pl value and the microneedle array has a pH higher than the peptide pl value.

16. A device, comprising: a microneedle array comprising a plurality of microneedles having a first end and a second end, wherein at least some of the microneedles comprise tirzepatide at a concentration of between 15% and 85% (w / v).

17. The device of claim 16, wherein the device further comprises a backing layer in contact with the second end of the micronccdlcs.

18. The device of claim 17, wherein the backing layer comprises less than X% (w / v) tirzepatide.

19. A method, comprising: creating a negative mold of a microneedle array, the negative mold comprising a plurality of cavities; adding a first solution at a first pH to the plurality of cavities of the negative mold, wherein the first solution comprises a peptide; allowing the first solution to at least partially dry within the plurality of cavities of the negative mold to form a plurality of microneedles; adding a second solution at a second pH comprising an excipient to the negative mold, and allowing the second solution to dry within the negative mold to form a backing layer, wherein the difference in the pH of the first and second solutions inhibits diffusion of the peptide from the first solution into the second solution.

20. The method of claim 19, wherein the pH of the first solution is between 8-9.

21. The method of claim 19 or 20, wherein the first solution further comprises one or more excipients.

22. The method of any one of claims 19-21, wherein the peptide is present in the first solution at a concentration of between 15% and 85% (w / v).

23. The method of any one of claims 19-22, wherein the peptide is tirzepatide.

24. The method of any one of claims 19-23, wherein the peptide is soluble in the first solution.

25. The method of any one of claims 19-24, wherein the peptide is at least partially insoluble in the second solution.

26. The method of claim 19, wherein the second pH is between 4 and 6.

27. The method of claim 19 or 26, wherein the excipient is PVP90K.

28. The method of claim 27, wherein the PVP90K present in the second solution at a concentration of between 8-40% (w / v).

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