Fused microneedle patch and method for producing same

Abstract

Microneedles for drug delivery comprising wax or other meltable material, and methods of making and using such microneedles are disclosed. The microneedle patch includes a backing layer and an array of microneedles extending from the backing layer, each of the microneedles including a distal tip portion comprising a drug, the microneedles configured to be inserted into mammalian tissue, and at least a portion of each of the microneedles configured to melt within the mammalian tissue. In some other cases, a melting material is used during the manufacture of the microneedles, but does not melt within the skin.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 314,835, filed February 28, 2022, the contents of which are incorporated herein by reference. [Background technology]

[0002] Microneedle patches have been developed as a minimally invasive means for delivering drugs through the skin using several approaches. Among the common approaches of skin delivery using microneedle patches, dissolving microneedle patches are of interest. Dissolving microneedle patches are made with dissolving excipients that tend to dissolve in interstitial fluid at the skin insertion site, thereby releasing drug payload. However, conventional microneedle-based technologies may have shortcomings that make microneedle patches unsuitable for use in certain situations.

[0003] For example, the poor water solubility of some active pharmaceutical ingredients can be an obstacle to expanding the use of conventional microneedle patches. The conventional approach to handle poorly water-soluble drugs is to use organic solvents in the microneedle casting process, which significantly complicates the manufacturing process with an additional long evaporation step that may ultimately destabilize the loaded bioactive substances.

[0004] Furthermore, the inherent instability of biomolecules is also a cause for concern and a major challenge for the commercialization of biopharmaceuticals. Because therapeutic proteins have greater conformational mobility in aqueous solutions, liquid formulations of proteins are more susceptible to degradation. As a result, water sequestration and removal, as well as embedding proteins in a rigid matrix, are good approaches to improve storage stability. Although dissolving microneedle patches have shown improved stability of incorporated biomolecules, such as proteins and vaccines, residual water content is unavoidable with the current drying techniques of existing microneedle patches.

[0005] Furthermore, some vaccines require at least one booster vaccination to induce sustained immunity. Long-term delivery of inactivated antigens allows antigens to be presented for a long period of time, thereby generating a stronger immune response to the same dose. A common approach for controlled release is to encapsulate the active ingredient in a biodegradable polymer, but this approach may not translate well to protein antigens. This is mainly due to the severe stresses experienced during the manufacture, sterilization, and release of biodegradable polymer matrices, which are known to damage sensitive proteins.

[0006] Thus, there is a need to provide microneedle compositions and patches that overcome or mitigate the aforementioned shortcomings of conventional microneedle patches, while also offering additional advantages over existing microneedle-based technologies. Summary of the Invention

[0007] In one aspect, a microneedle patch is provided that includes a backing layer and an array of microneedles extending from the backing layer, the microneedles each including a distal tip portion comprising a drug, the microneedles configured to be inserted into mammalian tissue, and at least a portion of each of the microneedles configured to melt within the mammalian tissue.

[0008] In another aspect, a method of making a microneedle is provided that includes preparing a first composition including a drug dispersed in a first excipient material that is heated to a temperature above the melting point of the first excipient material, casting the first composition at a temperature below 100°C in a mold having cavities defining one or more microneedles, and then cooling the first composition in the mold to a temperature below the melting point of the first excipient material to form one or more microneedles, or at least a distal tip portion of one or more microneedles, in the mold.

[0009] In yet another aspect, there is provided a microneedle patch comprising: a backing layer; and an array of microneedles extending from the backing layer, each microneedle including a portion comprising a drug, the microneedles being configured to be inserted into mammalian tissue, the microneedles being made of one or more materials that melt at a temperature between 60°C and 100°C.

[0010] In yet another aspect, a method of delivering a drug to a patient is provided, the method comprising inserting a microneedle containing the drug into the patient's skin and then melting the microneedle, or a distal tip portion thereof, into the patient's skin.

[0011] In a further aspect, a method is provided for isolating a drug within a distal tip portion of a microneedle of a microneedle patch from a backing layer of the microneedle patch, the method comprising interposing a hydrophobic material within a proximal portion of the microneedle between the backing layer and the distal tip portion, the distal tip portion and / or the proximal portion may be configured to dissolve or melt after insertion into the skin. [Brief description of the drawings]

[0012] The detailed description is described with reference to the accompanying drawings. The use of the same reference numbers may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those illustrated in the drawings, and some elements and / or components may or may not be present in various embodiments. Elements and / or components are not necessarily drawn to scale.

[0013] [Figure 1] FIG. 1 is a perspective view of an array of meltable microneedles according to one or more embodiments of the present disclosure. [Figure 2A] FIG. 2 is a micrograph showing a perspective view of an array of meltable microneedles according to one or more embodiments of the present disclosure. [Figure 2B] FIG. 1 is a micrograph showing a close-up of an array of two cast meltable microneedles, according to one or more embodiments of the present disclosure. [Diagram 3] 1 depicts a process for manufacturing an array of meltable microneedles in accordance with one or more embodiments of the present disclosure. [Figure 4A-4N] 1A-1D are schematic cross-sectional views of microneedles illustrating several different design approaches for incorporating meltable materials into the structure of the microneedles, in accordance with one or more embodiments of the present disclosure. [Diagram 5] 1 depicts the mechanism by which fused microneedles deliver drugs into tissue, according to one or more embodiments of the present disclosure. [Figures 6A-6D] 1A-1D are schematic cross-sectional views of different approaches for including a meltable portion in a detachable microneedle and illustrating its detachment after insertion into tissue, in accordance with one or more embodiments of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Microneedles, microneedle arrays, and microneedle patches have been developed that are (1) configured, e.g., have shape and mechanical properties, to be inserted into the skin (or other mammalian tissue), and (2) configured, e.g., have a suitable composition, to allow all or a portion of the microneedle to melt within the skin (or other mammalian tissue). Such microneedle compositions may advantageously reduce or eliminate some of the difficulties associated with conventional manufacturing of microneedle arrays, including maintaining the stability of drugs incorporated into the microneedles, (1) control the release of drugs from microneedle-based drug delivery systems, (2) facilitate separation of the microneedles from the microneedle patch as part of an administration method, and / or (3) beneficially provide alternative techniques for eliminating "sharps" after application of the microneedle-based drug delivery system to a patient.

[0015] In addition, the methods of making microneedle arrays described herein may advantageously, in some embodiments, allow for sequestering and protecting a drug from undesired exposure to water or other environmental components by including a suitable hydrophobic material in the construction of the microneedle patch. For example, a drug may be disposed in a microneedle patch at the distal tip portion of the microneedle, e.g., in a water-soluble first excipient, with a hydrophobic material interposed in the proximal portion of the microneedle between the backing layer of the patch and the distal tip portion of the microneedle.

[0016] As used herein, the terms "melt" and "melt" in relation to a microneedle patch refer to a phase change from solid to liquid of at least a portion of a composition, e.g., one excipient of a multi-excipient formulation, that forms a microneedle patch. This does not mean that all excipient components of the composition necessarily undergo this phase change. For example, there may be dispersed solid components that remain in solid form even though the microneedles lose their structural integrity when other components of the composition change to liquid. In another example, the drug remains solid and the microneedle matrix material is melted during manufacture, i.e., before / during the formation of the microneedles.

[0017] Microneedle patch An example of a microneedle patch having an array of microneedles is depicted in FIG. 1. The microneedle patch 100 includes a base substrate 110 from which extend microneedles 120 in a 10×10 array. The phrases "base substrate" and the terms "substrate" or "backing" are used interchangeably herein. Each microneedle 120 has a proximal end 122 that is directly attached to the base substrate 110 or indirectly attached via one or more proximal portions 124, and a distal tip 126 that is sharp and effective for penetrating biological tissue. The microneedles 120 have tapered sidewalls 128 between the proximal and distal ends 122 and 126 of the microneedles 120. Other geometries are possible. As described in more detail below, at least a portion of the microneedles 120, the proximal portions 124, and / or the substrate 110 comprise a meltable material. The substrate 110 may remain intact or some or all of it may melt along with all or some of the microneedles 120. Exemplary photographs of microneedle arrays including meltable portions as disclosed herein are shown in Figures 2A-2B.

[0018] The microneedles of the microneedle patch are designed to be inserted into the skin or another biological tissue, and then melt all or part of the microneedles in response to heating by (i) heat transfer from mammalian tissue, and / or (ii) application of heat from an external heat source applied to the inserted microneedles. Essentially, any suitable heat source can be used, for example, applied to the back of the microneedle patch. Examples include heating pads and hand warmers known in the art. In some embodiments, the heat source can be incorporated into the backing of the microneedle patch, so that heating can be triggered by pressing the back of the patch during insertion into the skin to initiate the process of warming and melting the electronic mail.

[0019] In some embodiments, the length of the microneedles may be from about 50 μm to 2 mm, from about 100 μm to about 2000 μm, from about 100 μm to about 1500 μm, from about 200 μm to 1000 μm, or ideally from about 500 μm to 1000 μm. In some embodiments, the array of microneedles comprises 10 to 1000 microneedles, 10 to 500 microneedles, 10 to 250 microneedles, 50 to 250 microneedles, or 100 microneedles (e.g., a 10×10 array of microneedles).

[0020] In some embodiments, the microneedles comprise a wax, such as a glycerol ester of a fatty acid as found in Witespol, or a fatty acid such as stearic acid, lauric acid, etc. In some preferred embodiments, the wax is designed to melt after the microneedle is inserted into human skin and reaches or exceeds the temperature of the human skin, causing the microneedle to lose its structure and, in at least some cases, separate from the base. For example, the wax may comprise mono-, di-, and triglycerides of C8 to C20 fatty acids such as capric acid (C10), pelargonic acid (C9), undecylic acid (C11), lauric acid (C12), tridecylic acid (C13), myristic acid (C14), pentadecylic acid (C15), palmitic acid (C16), palmitoleic acid (C16:1), margaric acid (C17), stearic acid (C18), oleic acid (C18:1), linoleic acid (C18:2), nonadecylic acid (C19), and / or arachidic acid (C20), and / or vegetable oils such as coconut oil, palm kernel oil, palm oil, and / or palm stearin consisting of mixtures of fatty acids.

[0021] In some preferred embodiments, the microneedle comprises a hydrophobic matrix material in which the drug is dissolved or dispersed, the matrix material being designed to melt after insertion of the microneedle into human skin. When the matrix material reaches or exceeds the human skin temperature, which may be about 30°C to 38°C, it then becomes liquid, causing the microneedle to lose its structure and, in at least some cases, to separate from the base. The drug is then released from the matrix material into tissue at the insertion site. For example, the drug may partition into the surrounding interstitial fluid during and / or after the hydrophobic matrix is ​​melted by the skin. The extent to which the drug partitions into the interstitial fluid may depend on the inherent aqueous solubility of the drug. For example, a highly water-soluble drug may partition into the interstitial fluid at a faster rate than a less water-soluble drug. This system is particularly advantageous for delivering poorly water-soluble or water-insoluble drugs that are typically difficult to administer using existing microneedle technology.

[0022] In some embodiments, the hydrophobic matrix comprises a so-called fatty suppository base. Fatty suppository bases are known in the art to be safe for rectal insertion for drug administration to the human body and may provide additional localized benefits such as skin moisturization. A wide selection of suppository bases can be used individually or in combination with other bases to obtain optimal drug release profiles for different applications as described herein. Examples of suitable fatty suppository bases include carnuba wax, beeswax, Koriwax CA (BASF), Novata BCF PH, BC PH, or B PH (BASF), Wecobee M or FS (Stephan), Witepsol H 15 (Fagron), Witepsol W32, W45, S55, E75, E76, E85, or S58 (IOI Oleo GmbH), HydroKote 112 or M (Abitec), or Suppocire NA15, AML, D, BM, AS2, or A (Gattefose). In a preferred embodiment, the fatty suppository base is Witepsol S55 (IOI Oleo GmbH). The terms and phrases "medication" and "substance of interest" (referred to as "SOI") are used interchangeably herein unless otherwise specified. The drug may be completely or partially soluble or insoluble within the matrix material forming the microneedles. In some embodiments, the drug is solubilized with the fatty suppository base by heating the base above its melting point and adding the drug to the molten material. In some other embodiments, the insoluble drug is dispersed in the molten fatty suppository base without the use of organic solvents or other additives to improve solubility.

[0023] In some embodiments, the SOI is a cosmetic agent, cosmeceutical, diagnostic agent, marker, or other material desired for introduction into living tissue. In some embodiments, the agent is a prophylactic or therapeutic agent, which may be referred to herein as an active pharmaceutical ingredient (API). The API may be selected from suitable proteins, peptides, and fragments thereof, which may be naturally occurring, synthetic, or recombinantly produced.

[0024] In some embodiments, the drug is a hormone or a steroid. The hormone can be a contraceptive hormone known in the art. In one example, the drug includes levonorgestrel.

[0025] In some embodiments, the medicament comprises a vaccine. Examples of vaccines include vaccines for infectious diseases, cancer, neurological disorders, allergies, and therapeutic vaccines for smoking cessation or other addictions.

[0026] In some other embodiments, the agent comprises a therapeutic agent, which may be selected from small molecules and larger biotechnologically produced or purified molecules (e.g., peptides, proteins, DNA, RNA, aptamers).

[0027] In yet another embodiment, the SOI is a vitamin, herb, or dietary supplement known in the art.

[0028] In some embodiments, the microneedles in a given array of microneedles all contain the same drug and excipients. In other embodiments, the microneedles in a given array of microneedles may contain different drugs and / or excipients. For example, the drug and / or excipients may be different in each microneedle, in different rows of microneedles, or in sections / regions of the microneedle array. Possible reasons for designing microneedles with such isolation are i) different drugs are incompatible with each other, ii) different drugs require different stabilizing excipients, and iii) different release profiles (e.g., a combination of a rapid bolus followed by a sustained release) are desired for a single drug or different drugs.

[0029] The drug is desirably provided in a stable formulation or composition (i.e., one in which the biologically active material therein essentially retains its physical and / or chemical stability and / or biological activity upon storage). Stability may be measured at a selected temperature for a selected period of time. Trend analysis may be used to estimate the expected shelf life before the material is actually stored for that period of time. The fused microneedle patch disclosed herein may have improved stability and allow for extended storage outside of the cold chain because water is removed from at least a portion of the casting process. Furthermore, formulating the drug into fused microneedles may effectively extend the release of the drug without the need for harsh encapsulation conditions that would otherwise be required to delay the release of the drug upon dissolution of the microneedles, for example.

[0030] The microneedle patch may further include other structural elements (not shown in FIG. 1) that enhance storage and usability of the microneedles. For example, the patch may include other layers, such as a housing and / or handle layer, on the side of the base substrate opposite the microneedles. Examples of such additional structural components are described in U.S. Patent No. 10,265,511 to McAllister et al., which is incorporated herein by reference.

[0031] Method for producing a microneedle array The array of microneedles described herein can be made by any suitable process. In a preferred embodiment, the array of microneedles is made using a molding process that is advantageously highly scalable. The filling and molding steps described herein can be referred to herein as "casting". In some embodiments, the casting method, mold, and other equipment can be adapted from those known in the art, such as those described in U.S. Pat. No. 10,828,478 to McAllister et al., which is incorporated herein by reference. The method for making microneedles is preferably carried out under a minimum ISO 7 (Class 10,000) process or ISO 5 (Class 100) process.

[0032] The process may include preparing a composition having a drug dispersed or dissolved in an excipient such as a fatty suppository base, heating the composition to a temperature above the melting point of the excipient, filling a mold having a cavity defining one or more microneedles, and cooling the composition in the mold below the melting point of the excipient to form one or more microneedles. Centrifugation and / or vacuum may be used to aid in this process, particularly in that centrifugation and / or vacuum may help maintain the microneedle shape as defined by the mold when the drug-excipient composition solidifies. This process based on melting and solidification advantageously eliminates the need for an extensive drying step, which may significantly reduce the duration of the manufacturing process.

[0033] In some embodiments, a two-cast or three-cast process is used. In these embodiments, the first cast of drug and excipients forms only the distal tip portion of the microneedle. Subsequent casts may involve filling the remaining space of the mold above the distal tip portion of the microneedle to form the proximal portion of the microneedle. In some embodiments, a second cast is applied to the microneedle mold before removing the microneedle from the mold. In some embodiments, the second cast is of a different composition than the first cast. For example, the second cast may be aqueous so that it may dissolve in vivo simultaneously with the melting of the first cast composition. For example, an aqueous cast may be made from a mixture of a polymer, such as polyvinyl alcohol (PVA) or polyvinylpyrrolidone (PVP), and a sugar, such as sucrose. In some preferred embodiments, the second cast is equal parts of 18% PVP (360 / 55) and sucrose.

[0034] In a preferred embodiment, as shown in FIG. 3, the manufacture of solid fused microneedles (300) includes at least four steps: (1) forming a first cast composition 310, (2) first cast fill 320, (3) second cast fill 330, and (4) cooling / drying 340.

[0035] Forming the first cast composition includes (i) melting the excipient to a temperature above its melting point, and (ii) dissolving or dispersing the drug in the molten excipient to form the first cast composition. While the drug is mixed with the excipient, the temperature remains above the melting point of the excipient to avoid premature solidification or hardening of the composition. In some embodiments, the melting point of the excipient is between 30°C and 40°C, such that the excipient can be heated to at least 40°C, or preferably to 50°C, but still melt upon insertion into the skin and / or application of an external heat source. In other embodiments, the melting point of the excipient is much higher, such as between 50°C and 100°C, where the excipient melts during the manufacturing process but does not melt when the microneedle is inserted into the skin.

[0036] After the first cast composition is formed, it is transferred to a negative mold of one or more microneedles, typically an array of 10 to 1000 microneedles. This may be referred to as the "first cast". The mold may then be centrifuged and / or evacuated to facilitate displacement of any air bubbles and movement of the composition to the microneedle tips of the mold. The mold may be centrifuged at a temperature above the melting point of the excipient. In some embodiments, the temperature is less than 50°C, preferably between 40°C and 25°C. Temperatures for casting high melting point waxes (i.e., waxes that do not melt on the skin) may range from about 60°C to about 80°C. During the first cast of the multicast process, the composition may at least partially solidify or harden, but it is not necessary for the first cast to be completely solidified at this point.

[0037] The mold is then filled with a backing substrate and, optionally, a second composition suitable for forming the proximal end portion of the microneedle. In some embodiments, this second casting material may be or may include one or more water-soluble materials. In some other embodiments, this second casting material may be or may include a meltable material. In some embodiments, this second casting material does not include a drug, i.e., contains only one or more excipients. In some embodiments, this second casting material for the proximal portion of the microneedle may include a drug that is the same as or different from the drug in the first casting composition. After being filled, the mold may be centrifuged and / or evacuated to facilitate and speed up the casting process.

[0038] The filled mold can be allowed to solidify and / or dry as necessary. The filled mold can optionally be dried in a desiccant chamber to facilitate removing excess water or moisture from the patch. After the cast is substantially solidified and / or dried, the fused microneedle patch can be removed from the mold.

[0039] In some embodiments, the microneedle patch is manufactured using a three-cast process, where the first cast is a drug matrix composition that forms the distal tip portion of the microneedle, the second cast is an excipient that forms the proximal end portion of the microneedle and / or the connector / funnel portion between the microneedle and the base substrate, and the third cast is a composition suitable for forming the base substrate. In these embodiments, the second cast excipient may melt upon insertion and serve as a separating layer between the distal tip portion (which may or may not melt in the skin, or may or may not dissolve in the skin) and the backing substrate (which may or may not melt in or on the skin, or may or may not dissolve in or on the skin). In some embodiments, it may be preferable to prevent the drug matrix composition and the base composition from contacting each other, i.e., mixing. An intermediate second cast can serve to prevent this interaction. For example, molten wax can be used as the intermediate second cast in the three-cast microneedle patch manufacturing process. The wax may act as a hydrophobic barrier between the drug in the microneedle and the backing, preventing the drug from being wetted by water present in the backing during and / or after manufacture, which may affect drug stability.

[0040] 4A-4N illustrate different casting arrangement embodiments. In FIG. 4A-4B, the meltable microneedle patch is formed from only two casts. In these embodiments, a first cast is formed of a meltable drug-excipient composition 430, while a second cast is formed of a different water-soluble material 432. As shown in FIG. 4A, a first cast formed of the drug-excipient composition 430 may form the distal tip portion 426 of the microneedle 420, and a second cast of a water-soluble base 432 may form the proximal end portion 422 of the microneedle 420 and the substrate 410 from which the microneedle 420 extends. As shown in FIG. 4B, the microneedle 420 may include a base portion 424 at the proximal end 422 of the microneedle 420. This proximal base 424 may be formed of the second cast 432, along with the substrate 410 to which the proximal portion is attached. In Figure 4A, the microneedle has a continuous taper, and in Figure 4B, the microneedle has a discontinuous taper that forms a funnel. The materials and fabrication processes can be the same for both geometries.

[0041] 4C-D, the microneedle 420 is formed from a single cast of the drug-excipient composition 430. In some embodiments, as shown in FIG. 4C, the microneedle 420 is cast from the drug-excipient composition 430 and extends from a substrate 410 formed from a cast of a water-soluble base 432. In FIG. 4D, the microneedle 420 and substrate 410 (from which the microneedle 420 extends) may be formed from the drug-excipient composition 430.

[0042] In Figures 4E-4H, the fused microneedle 420 is formed from two or more casts. In these embodiments, the first cast is a drug-excipient composition 430 and the second cast is an excipient 434. The first drug-excipient composition cast 430 forms the distal tip portion 426 of the microneedle 420, while the second excipient cast 434 forms at least a portion of the microneedle 420 between the distal tip portion 426 and the proximal end portion 422 of the microneedle. In Figures 4E-4F, the microneedle patch includes a third cast formed of a water-soluble base 432, the third cast of the base forms the proximal end portion 422 of the microneedle 420 and the substrate 410 from which the microneedle 420 extends. In other embodiments, as shown in Figure 4G, the second excipient cast 434 also forms the proximal end portion 422 of the microneedle 420. In a further embodiment, as shown in FIG. 4H, a second excipient cast 434 forms the proximal end portion 422 of the microneedle 420 and the substrate 410 from which the microneedle 420 extends.

[0043] In Figures 4I-4L, the fused microneedles are also formed from two or more casts. In these embodiments, at least two casts form the microneedle 420 such that one or more casts form a coating or shell around the cast of the drug-excipient composition 430. In Figures 4I-4J, a first cast of excipient forms a coating around a second cast of the drug-excipient composition 430. In Figure 4I, a third excipient 434 cast caps the excipient 434 coating and the drug-excipient 430 core such that the excipient 434 casts together form a shell around the drug-excipient composition 430. The substrate 410 (from which the microneedle 420 extends) is then formed of a water-soluble base 432 as a fourth cast. Similar to Figure 4I, Figure 4J depicts a first excipient 434 cast forming a coating around a second cast of the drug-excipient composition. However, the substrate 410 formed with a third cast of water-soluble base 432 is formed directly on top of the excipient 434 coating and drug-excipient 430 core (i.e., the coating and core are not capped with another excipient 434 cast).

[0044] In Figures 4K-4L, a first cast of excipient 434 forms a coating around the second cast of drug-excipient composition 430. In Figure 4K, a third excipient 434 cast forms a cap on the proximal end portion 422 of the microneedle, such that the first and third excipient 434 cases together form a shell around the drug-excipient 430 core of the microneedle 420. The substrate 410 (from which the microneedle 420 extends) is formed with a fourth cast of water-soluble base 432. In Figure 4L, the substrate 410 (from which the microneedle 420 extends), formed of water-soluble base 432, is cast directly on top of the excipient 434 coating and drug-excipient 430 core. In Figures 4I-4J, the SOI is in the core and not in the shell / coating, whereas in Figures 4K-4L, the SOI is in the shell / coating but not in the core.

[0045] In Figures 4M-N, the distal tip portion 426 of the microneedle is formed with three casts, with the first cast forming a coating around the second cast, which is capped using the third cast. In Figure 4M, the first and third cases of drug-excipient composition 430 form a coating around the second excipient 434 cast. In Figure 4N, the first and third excipient 434 casts 434 form a shell around the second SOI composition cast 430. In each of these embodiments, a fourth cast of water-soluble base 432 is used to form the proximal portion 424 of the microneedle and the substrate 410 from which the microneedle extends.

[0046] How to use The microneedle arrays described herein can be used to administer various substances to tissue sites in humans or other mammals, typically by applying a microneedle patch comprising an array of meltable microneedles to a skin surface such that the microneedles penetrate the stratum corneum and enter the viable epidermis and, in some cases, the dermis.

[0047] As used herein, the phrase "penetrating a tissue surface" includes penetrating a biological tissue surface with at least the distal tip of the microneedle. Upon separation of the microneedle from the substrate, the proximal end of the microneedle may be above the tissue surface, substantially level with the tissue surface, or below the tissue surface.

[0048] As used herein, the phrase "biological tissue" generally includes any human or mammalian tissue. The biological tissue may be skin or mucosal tissue of a human or other mammal in need of treatment or prophylaxis. It is contemplated that the devices and methods of the present invention may also be adapted to other biological tissues and other animals.

[0049] Microneedle patches can be self-administered or can be administered by another individual (e.g., a parent, guardian, healthcare professional).

[0050] The method described herein further includes a simple and effective method of administering SOI to a patient using a microneedle patch. The method may include identifying an application site and preferably disinfecting the area (e.g., using an alcohol wipe) before applying the microneedle patch. The microneedle patch is then applied to the patient's skin / tissue and pressed into the patient's skin / tissue manually (e.g., using a thumb or finger) or using a device to facilitate application of the patch so that the microneedles penetrate the tissue surface.

[0051] After administration, the substrate (and the remaining microneedle patch structure) may be removed from the patient's skin / tissue, at least in embodiments where the substrate remains intact.

[0052] In some embodiments, the microneedle patch described herein is used to deliver one or more SOIs into the skin. In one embodiment, the microneedle patch is used to deliver the SOI into the skin by inserting the microneedle across the stratum corneum (the outer 10-20 micrometers of skin that is a barrier to transdermal transport) and into the viable epidermis and possibly the dermis. The small size of the microneedle allows for targeting of the intradermal space while causing little or no pain. The intradermal space is highly vascularized in the dermis and rich in immune cells in the dermis and epidermis, providing an attractive passageway for administering both vaccines and therapeutic agents. The microneedle may melt once in the intradermal space to release the SOI into the interstitial fluid and into the skin.

[0053] FIG. 5 illustrates one method (500) for administering an SOI to a patient. The method includes providing a microneedle patch 100 as described herein, aligning the microneedle patch with a target site on the skin surface (step 510), and inserting the microneedles of the microneedle patch into the skin (step 520) to push the microneedles through at least the stratum corneum and into the viable epidermis and possibly the dermis layer of the skin. The microneedles are then shown to separate from the base (step 530), and the microneedles begin to melt (step 540). Separation can occur quickly after insertion, for example if the substrate and / or the proximal end of the microneedle are formed of a water-soluble material, allowing the base to be removed within seconds or minutes after microneedle insertion (and prior to completion of melting and drug release). Melting and dissipation of the microneedle composition continues (steps 550 and 560).

[0054] Although the microneedles have been shown to separate from the base before the microneedles melt, this is not required, for example, the microneedles can melt before and / or during their separation from the base, or the microneedles can not separate from the base at all.

[0055] 6A-6D illustrate some embodiments of the method of use. In FIG. 6A, the distal tip portion 626 of the microneedle 620 is formed of a drug-hydrophobic matrix composition 630, while the proximal tip portion 622 of the microneedle 620 and the substrate 610 (from which the microneedle extends) are formed of a water-soluble composition 632 or aqueous cast base. When the microneedle 620 is inserted into the skin of a patient, the entire distal tip portion 626 is preferably inserted into the skin. While the distal tip portion 626 formed of the drug-hydrophobic matrix composition 630 is in the skin, the distal tip portion 626, and only this portion of the microneedle, melts when warmed by the patient's body temperature. The proximal tip portion 622 is also partially inserted into the skin and can be solubilized by contact with interstitial fluid from the skin.

[0056] In Figure 6B, the entire microneedle 622 is formed of the drug-hydrophobic matrix composition 630, and the base substrate 610 (from which the microneedle 620 extends) is formed of the water-soluble composition 632. When the microneedle 420 is inserted into the skin, at least a distal tip portion 626 of the microneedle 622 formed of the composition penetrates the epidermis layer, and possibly the dermis layer, of the skin. However, at least some of the proximal end 622 of the microneedle 620 may remain outside the skin. While inserted into the skin, at least a portion of the microneedle 620 melts when warmed by the patient's skin such that at least a portion of the drug-hydrophobic matrix composition 430 may be released into the skin.

[0057] In Figure 6C, the distal tip portion of the microneedle is formed of a drug-hydrophobic matrix composition 630, followed by a layer of an excipient composition 634, such as a fatty suppository base, followed by a base 632 that forms the proximal end portion 622 of the microneedle 620 and the substrate 610 from which the microneedle 620 extends. During insertion, the excipient 634 layer melts when heated by the patient's skin temperature, releasing the distal tip portion 626 into the skin. The drug-hydrophobic matrix composition 630 may or may not melt, or may or may not dissolve, as part of releasing the drug into the skin.

[0058] In FIG. 6D, the distal tip portion 626 of the microneedle 620 is formed of a drug-hydrophobic matrix composition 630 and two excipients 634 cast as described with respect to FIG. 4I, with the excipients 434 cast forming a shell around the drug-hydrophobic matrix composition cast 630. The microneedle 620 also has a proximal base portion 624 formed of a water-soluble base 632, which also forms the substrate 610 from which the microneedle 620 extends. As with the embodiment of FIG. 6C, encasing the drug-hydrophobic matrix composition 630 in a shell of excipients 634 may be effective to delay release of the SOI or limit the amount of SOI administered to a patient. The excipients 434 may also be effective as a hydrophobic barrier to protect the SOI composition 430 from contact with moisture, which may affect the stability of the SOI composition 430.

[0059] In some embodiments, microneedles that do not melt into the skin can be formed with meltable excipients and / or drug matrices. The use of meltable excipients to form microneedles can be beneficial when the active substance is not soluble, unstable, or at risk of being damaged at high temperatures. Forming microneedles from meltable excipients reduces the temperature to which the drug-excipient matrix must be heated (i.e., up to about 100°C), which does not damage biomolecules such as certain proteins, vaccines, or DNA molecules. In some embodiments, meltable excipients can be used to reduce the manufacturing cost of microneedles by reducing the drying time of the microneedle patch.

[0060] For microneedles that do not melt in the skin, the active agent may be released according to several mechanisms, such as diffusion, dissolution, and / or decomposition. In embodiments, the microneedles may be manufactured such that the active agent is released through the intact microneedle. In other embodiments, the microneedles may be formed with excipients configured to dissolve in the skin such that the active agent is released into the skin as the microneedle dissolves. In further embodiments, the microneedles may be formed with excipients configured to degrade, for example, via hydrolysis, enzymatic activity, or other similar mechanisms. This allows the drug to be released at a rate consistent with the rate of degradation. According to preferred embodiments, the microneedles dissolve or decompose such that they are eventually eliminated within the patient's skin.

[0061] In other embodiments, the active agent remains in a solid state (e.g., within the core of the microneedle or within the drug-excipient matrix), so that only the excipient melts within the skin. For example, certain active agents (e.g., proteins, vaccines, DNA, etc.) are not soluble and therefore do not dissolve within the molten excipient during the casting process. Therefore, when the microneedle patch is applied to the skin, the excipient melts around the active agent so that it can be delivered into the skin.

[0062] The present invention can be further understood with reference to the following non-limiting examples.

[0063] Example 1: Screening of fatty bases as materials for forming microneedles Several fatty base materials commonly used in the formulation of suppositories for rectal administration of drugs were tested to determine their suitability for manufacturing microneedles and microneedle arrays (and thus as microneedle patches). The bases tested were Witepsol H15 (Fagron), 1% polyvinylpyrrolidone (PVP) 360 kDa in Witepsol H15, 2% PVP 360 kDa in Witepsol H15, 1% poly(methyl methacrylate) (PMMA) 35 kDa in Witepsol H15, 1% polymethylvinylether-alt-maleic anhydride (PMVE / MA) 216 kDa in Witepsol H15, 3% PMVE / MA 216 kDa in Witepsol H15, and 6% polycaprolactone (PCL) in Witepsol H15. The selection criteria for the optimal fatty base were the integrity and hardness of the resulting microneedle upon insertion into the skin. All fat-based materials were tested with a second cast of 18% PVP (360 / 55) / 18% sucrose. Specifically, 10 μL of each fat-based material was cast into a microneedle mold at 50° C., and the mold was centrifuged at a relative centrifugal force of 3234×g and a temperature of 40° C. for 1 hour.

[0064] Of the lipid-based materials tested, Witepsol H15 demonstrated optimal properties for the first cast material (forming the distal tip portion of the microneedle). After further optimization, Witepsol S55 (IOI Oleo GmbH) was subsequently determined to be more suitable as it has the highest range of OH values ​​(approximately 50-65) among the waxes tested.

[0065] Example 2: Screening of non-dissolving or water-soluble backings as a second cast Various polymer-based aqueous formulations were tested for suitability as a second cast material (to form the proximal portion and / or base from which the microneedle extends) based at least in part on their compatibility with the lipid-based microneedle (or its distal tip portion). All polymer-based aqueous formulations were tested using Witespol H15 as the first cast to form the microneedle, as described in Example 1.

[0066] The polymer-based aqueous formulations tested for the second cast formulation included Witespol H15, 13% PVA / 13% sucrose, 13% PVP 55 kDa, 13% PVP 360 kDa, and 13% PVP (360 / 55) / 13% sucrose, as well as 18% PVP (360 / 55) / 18% sucrose, and 20% polystyrene in molten dioxane and polycaprolactone. Specifically, 400 μL of each polymer-based formulation was cast into the microneedle mold at 25° C., except for Witespol H15, which was cast at 50° C., and polycaprolactone, which was cast at 60° C. After filling, the mold was placed on a vacuum chuck at 54° C. for 2 hours, followed by an additional 2 hours at 25° C. The mold was then removed from the vacuum chuck and allowed to dry before releasing the microneedle patch.

[0067] Of all the materials tested, it was determined that 13% PVP (360 / 55) / 13% sucrose and 18% PVP (360 / 55) / 18% sucrose, but preferably 18% PVP (360 / 55) / 18% sucrose, exhibited optimal properties for the second cast material.

[0068] Example 3: Microneedle insertion into the skin Pig skin was obtained from a slaughterhouse and a dermatome was used to remove the subcutaneous fat layer. The sections were thoroughly washed with alcohol wipes, blotted dry with Kimwipes, secured to a wooden block to support insertion, and placed in an oven set at 32°C for 30 minutes to obtain ambient temperature. The wooden block was then briefly removed from the oven and a microneedle patch was inserted into the skin. The skin, with the patch applied, was then placed back into the oven at 32°C for up to 15 minutes. The microneedle patch was then removed and the skin was imaged microscopically for signs of melting and separation of the microneedle from the base. The skin was also imaged using bright field and fluorescence optics for the same purpose.

[0069] Example 4: Levonorgestrel-loaded microneedle patch Levonorgestrel-loaded melt-microneedle patches were prepared with a drug loading of 60% and characterized for in vitro release.

[0070] The levonorgestrel microneedle patch was placed in a nylon mesh bag (nylon monofilament mesh, Midwest Filter, St. Charles, IL) and then incubated in 1950 mL of 0.02% Tween 20 in phosphate buffered saline (PBS) containing 25% ethanol as the release medium. The release experiment was carried out at 37°C and stirred at 80 rpm for 7 days. The 0.02% Tween 20 in PBS medium was first adjusted to pH 7.4 and then mixed with 25% ethanol for the release medium. The nylon mesh bag with 1 μm pore size was used to better separate the released free drug from the molten microneedle matrix and undissolved levonorgestrel crystals. At predetermined time intervals, 0.5 mL aliquots were withdrawn from the release medium and replaced with the same volume of fresh medium.

[0071] The amount of levonorgestrel released over time from each microneedle patch was quantitatively analyzed by ultra-performance liquid chromatography (UPLC, Waters, Milford, MA) with a tunable ultraviolet (UV) detector. Levonorgestrel was separated on an Acquity UPLC ethylene bridged hybrid (BEH) C18 column (100 mm x 2.1 mm inner diameter, 1.7 μm particle size) at 50 °C. The mobile phase was a mixture of acetonitrile containing 0.1% formic acid and water containing 0.1% formic acid in a ratio of 55 / 45 (v / v) at a flow rate of 0.3 mL / min. The injection volume was 10 microliters. The UV absorbance of the LNG was measured at 345 nm. The cumulative levonorgestrel release (%) was calculated based on the amount of levonorgestrel loaded in the microneedles and then normalized based on the average amount released at the end of the experiment.

[0072] The cumulative release of levonorgestrel from the molten microneedle patch showed a biphasic release pattern with an initial zero-order burst followed by a near zero-order sustained release for up to 7 days in 0.02% Tween 20 in PBS release medium containing 25% (v / v) ethanol. The levonorgestrel molten microneedle patch achieved 100% cumulative release within this 7-day time frame.

[0073] Example 5: Measles and rubella vaccine-loaded microneedle patch A higher melting point wax, specifically Witepsol E85, was used as a second intermediate cast between the first aqueous cast of concentrated measles and rubella vaccine and the third aqueous cast of PVA / sucrose composition to form a microneedle patch. The microneedle patch was then coated with TCID 50 The assay was used to characterize vaccine activity when dry and stability upon storage at 40°C.

[0074] Monolayers of Vero cells (ATCC, CCL-81) for measles and RK13 cells (ATCC, CCL-37) for rubella were cultured at 2.5 × 10 4Cells were seeded in 96-well plates at a density of 1000 cells / well and then inoculated with serial dilutions of the reconstituted microneedle patches in Dulbecco's Modified Eagle Medium (DMEM). After 5 days of incubation at 37°C and 5% CO2, the measles plates were stained with crystal violet solution for evidence of viral cytotoxicity effects. For rubella plates, cells were fixed with methanol and immunostaining was used to visualize the site of infection. 50% tissue culture infectious dose (TCID 50 Titers, expressed as percentile %, were calculated using the Spearman and Karber algorithm.

[0075] Some embodiments of the present disclosure can be described in consideration of one or more of the following.

[0076] Embodiment 1. A microneedle patch comprising a backing layer and an array of microneedles extending from the backing layer, each of the microneedles including a distal tip portion comprising a drug (or SOI), the microneedles configured to be inserted into mammalian tissue, and at least a portion of each of the microneedles configured to melt within the mammalian tissue.

[0077] Embodiment 2. The microneedle patch of embodiment 1, wherein the mammalian tissue is human skin.

[0078] Embodiment 3. A microneedle patch as described in either embodiment 1 or 2, wherein the microneedles contain a drug dissolved or dispersed in a wax, such as a glycerol ester of a fatty acid, such as Witespol, or a fatty acid, such as stearic acid, lauric acid, and the like.

[0079] Embodiment 4. A microneedle patch according to any one of embodiments 1 to 3, wherein the microneedles are configured to separate from the backing layer after insertion into mammalian tissue.

[0080] Embodiment 5. A microneedle patch according to any one of embodiments 1 to 4, wherein the drug is hydrophobic or hydrophilic.

[0081] Embodiment 6. A microneedle patch according to any one of embodiments 1 to 5, wherein the drug comprises a vaccine.

[0082] Embodiment 7. A microneedle patch according to any one of embodiments 1 to 6, wherein the drug comprises a protein, a peptide, RNA, or DNA.

[0083] Embodiment 8. A microneedle patch according to any one of embodiments 1 to 5, wherein the drug comprises a hormone such as a steroid or levonorgestrel.

[0084] Embodiment 9. A microneedle patch described in any one of embodiments 1 to 8, wherein the microneedles further comprise a drug-free proximal portion between the backing layer and each of the distal tip portions.

[0085] Embodiment 10. A microneedle patch as described in embodiment 9, wherein the drug-free proximal portion and / or backing layer comprises one or more water-soluble materials, such as polyvinylpyrrolidone, polyvinyl alcohol, disaccharides such as sucrose, or combinations thereof.

[0086] Embodiment 11. A microneedle patch as described in embodiment 10, wherein the drug-free proximal portion comprises wax.

[0087] Embodiment 12. A method of making a microneedle comprising preparing a first composition comprising a drug (or SOI) dispersed in a first excipient material, such as a wax, heated to a temperature above its melting point; casting the first composition at a temperature below 100°C (e.g., below 90°C, 80°C, 70°C, 60°C, 50°C, or 40°C) in a mold having cavities defining one or more microneedles; and cooling the first composition in the mold below the melting point of the first excipient material to form one or more microneedles, or at least a distal tip portion thereof, in the microneedle mold.

[0088] Embodiment 13. The method of embodiment 12, further comprising casting the second composition onto a distal tip portion of the one or more microneedles to form a proximal portion of the one or more microneedles.

[0089] Embodiment 14. The method of embodiment 13, wherein the second composition comprises a solution comprising an aqueous solvent and a solute material, such as polyvinylpyrrolidone, polyvinyl alcohol, a disaccharide such as sucrose, or a combination thereof.

[0090] Embodiment 15. The method of embodiment 13, wherein the second composition is solvent-free and comprises a second excipient material, such as a wax, heated to a temperature above its melting point.

[0091] Embodiment 16. The method of any one of embodiments 12-15, wherein the first excipient and / or the second excipient comprises a glycerol ester of a fatty acid, such as Witespol, or a fatty acid, such as stearic acid, lauric acid, and the like.

[0092] Embodiment 17. The method of any one of embodiments 12 to 16, further comprising casting a backing layer onto the base of the one or more microneedles.

[0093] Embodiment 18. The method of any one of embodiments 12 to 17, wherein the agent is hydrophobic or the agent is hydrophilic.

[0094] Embodiment 19. The method of any one of embodiments 12 to 17, wherein the medicament comprises a vaccine.

[0095] Embodiment 20. The method of any one of embodiments 12 to 17, wherein the agent comprises a protein, a peptide, RNA, or DNA.

[0096] Embodiment 21. The method of any one of embodiments 12-17, wherein the agent comprises a hormone, such as a steroid or levonorgestrel.

[0097] Embodiment 22. A microneedle patch according to any one of embodiments 1 to 11 or a method according to any one of embodiments 12 to 21, wherein the microneedles are made of one or more materials that melt at a temperature of 20°C to 50°C, or 30°C to 37°C, for example 32°C to 35°C.

[0098] Embodiment 23. A microneedle patch according to any one of embodiments 1 to 11, or a method according to any one of embodiments 12 to 21, wherein the microneedles are made of one or more materials that melt at a temperature of 38°C to 100°C, for example 40°C to 90°C, 40°C to 60°C, or 40°C to 50°C.

[0099] Embodiment 24. A microneedle patch described in any one of embodiments 1 to 11, 22, and 23, wherein each portion of the microneedle that is configured to melt within mammalian tissue includes or consists of a distal tip portion.

[0100] Embodiment 25. A microneedle patch described in any one of embodiments 1 to 11, 22, and 23, wherein each portion of the microneedle configured to melt in mammalian tissue comprises or consists of a proximal portion that does not contain a (or the above) drug.

[0101] Embodiment 26. A microneedle patch described in any one of embodiments 1 to 11 and 22 to 25, wherein the backing layer is configured to melt upon contact with mammalian tissue.

[0102] Embodiment 27. A microneedle patch described in any one of embodiments 1 to 11 and 22 to 26, wherein a proximal portion of each of the microneedles that does not contain a certain (or the above) drug is formed of one or more hydrophobic materials having a melting point of 38°C to 60°C, for example 40°C to 50°C.

[0103] Embodiment 28. A microneedle patch as described in embodiment 27, wherein the distal tip portion of each of the microneedles and / or the backing layer are formed of one or more hydrophilic materials.

[0104] Embodiment 29. The method of any one of embodiments 12-21, wherein the agent is in a solid state and is non-homogeneously mixed with the first excipient material.

[0105] Embodiment 30. A method of delivering a drug to a patient comprising inserting one or more microneedles containing a drug into the patient's skin and then melting the one or more microneedles, or at least a portion thereof, to (i) release the drug into the patient's skin and / or (ii) separate at least a portion of the one or more microneedles from a base or backing layer of a microneedle patch.

[0106] Embodiment 31A. The method of embodiment 30, wherein melting occurs when the inserted microneedle or microneedles reach the patient's body temperature (e.g., 30°C to 37°C).

[0107] Embodiment 31B. The method of embodiment 30, wherein melting comprises applying heat from a source external to the patient to one or more inserted microneedles, wherein the applied heat is delivered in an amount / rate effective to melt at least a portion of the microneedles.

[0108] Embodiment 32. The method of any one of embodiments 29 to 31, wherein the one or more microneedles are part of a microneedle patch comprising an array of microneedles extending from a backing layer.

[0109] Embodiment 33. The method of embodiment 32, further comprising separating the microneedles from the backing layer after insertion.

[0110] Embodiment 34. The method of any one of embodiments 29 to 33, wherein the melted microneedles within the skin form hydrophobic liquid depots from which the drug is released over an extended period of time.

[0111] Embodiment 35. The method of embodiment 34, wherein the extended period is at least 1 day, such as 2 days, 3 days, 4 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or 1 month.

[0112] Embodiment 36. A method of isolating a drug within a distal tip portion of a microneedle of a microneedle patch from a backing layer of the microneedle patch by interposing a hydrophobic material, such as wax, within the proximal portion of the microneedle between the backing layer and the distal tip portion.

[0113] Embodiment 37. The method of embodiment 36, wherein the agent is a vaccine or other biomolecule and / or is susceptible to degradation by exposure to moisture.

[0114] Embodiment 38. The method of any of embodiments 36 or 37, wherein the distal tip portion is configured to dissolve or melt after insertion into tissue (e.g., mammalian skin or other biological tissue).

[0115] Embodiment 39. The method of any one of embodiments 36 to 38, wherein the proximal portion is configured to melt after insertion into tissue (e.g., mammalian skin or other biological tissue).

[0116] Embodiment 40. The method of any one of embodiments 29 to 39, wherein the proximal portion is formed of one or more materials, such as wax, having a melting point of 38°C to 100°C, e.g., 50°C to 100°C.

[0117] Embodiment 41. The method of any one of embodiments 29 to 40, wherein the distal tip portion is formed of one or more materials having a melting point of 20°C to 50°C.

[0118] Embodiment 42. A microneedle patch comprising a backing layer and an array of microneedles extending from the backing layer, each microneedle including a portion containing a drug, the microneedles being configured to be inserted into mammalian tissue, the microneedles being made of one or more materials that melt at a temperature between 60°C and 100°C (e.g., between 70°C and 100°C).

[0119] Embodiment 43. A microneedle patch as described in embodiment 42, wherein the microneedles are configured to dissolve or biodegrade within mammalian skin.

[0120] Embodiment 44. A method of delivering a drug to a patient, comprising inserting a microneedle containing the drug into the patient's skin and then melting the microneedle, or a distal tip portion thereof, into the patient's skin.

[0121] Embodiment 45. The method of embodiment 44, wherein melting occurs when the inserted microneedles reach the patient's skin temperature.

[0122] Embodiment 46 The method of embodiment 44, wherein melting comprises applying heat from a source external to the patient to the inserted microneedle.

[0123] Embodiment 47. The method of any one of embodiments 44 to 46, wherein the microneedle is part of a microneedle patch comprising an array of microneedles extending from a backing layer.

[0124] Embodiment 48. The method of any one of embodiments 44 to 47, further comprising separating the microneedles from the backing layer after insertion.

[0125] Embodiment 49. The method of any one of embodiments 44 to 48, wherein the melted microneedles in the skin form a hydrophobic liquid depot from which the drug is released over an extended period of at least one day.

[0126] Embodiment 50. The method of embodiment 49, wherein the extended period is between 2 days and 30 days.

[0127] The term "about," as used herein, denotes a given quantity value and can include an amount within a range of within 10% of the indicated value, or optionally, within 5% of that value, or in some embodiments, within 1% of that value.

[0128] While the present disclosure has been described with reference to certain exemplary embodiments, it will be understood by those skilled in the art that the present disclosure is not limited to such disclosed embodiments. Rather, the disclosed embodiments can be modified to incorporate any number of variations, alterations, substitutions, or equivalent arrangements not described herein, but which are consistent with the spirit and scope of the present disclosure.

Claims

1. A microneedle patch, A backing layer; an array of microneedles extending from the backing layer, the microneedles each including a distal tip portion comprising a drug; A microneedle patch, wherein the microneedles are configured to be inserted into mammalian tissue and at least a portion of each of the microneedles is configured to melt within the mammalian tissue.

2. The microneedle patch of claim 1 , wherein the mammalian tissue is human skin.

3. The microneedle patch of claim 1 , wherein the microneedles contain the drug dissolved or dispersed in a wax.

4. The microneedle patch of claim 3 , wherein the wax comprises a fatty acid or a glycerol ester of a fatty acid.

5. The microneedle patch of claim 3 , wherein the wax comprises stearic acid, lauric acid, or another fatty acid.

6. The microneedle patch of claim 1 , wherein the microneedle, or at least a portion of the distal tip portion thereof, is configured to separate from the backing layer after insertion into the mammalian tissue.

7. The microneedle patch of claim 1 , wherein the portion of each of the microneedles configured to melt within the mammalian tissue includes at least a portion of the distal tip portion.

8. The microneedle patch of claim 1 , wherein the portion of each of the microneedles configured to melt within the mammalian tissue includes a proximal portion that does not contain a drug.

9. The microneedle patch of claim 1 , wherein the backing layer is configured to melt upon contact with the mammalian tissue.

10. The microneedle patch of claim 1 , wherein the drug is hydrophobic.

11. The microneedle array of claim 1 , wherein the drug comprises a vaccine.

12. The microneedle patch of claim 1 , wherein the drug comprises levonorgestrel or another steroid or hormone.

13. The microneedle patch of claim 1 , wherein the drug comprises a protein, a peptide, RNA, or DNA.

14. The microneedle patch of claim 1 , wherein the microneedles further comprise a drug-free proximal portion between the backing layer and each of the distal tip portions.

15. The microneedle patch of claim 14 , wherein the drug-free proximal portion and / or the backing layer comprises one or more water-soluble materials.

16. The microneedle patch of claim 14 , wherein the drug-free proximal portion comprises wax.

17. The microneedle patch of claim 14, wherein the drug-free proximal portion of each of the microneedles is formed from one or more hydrophobic materials having a melting point of between 20°C and 50°C.

18. The microneedle patch of claim 17 , wherein the distal tip portion of each of the microneedles and / or the backing layer are formed from one or more hydrophilic materials.

19. 1. A method of making a microneedle, comprising: preparing a first composition comprising a drug dispersed in a first excipient material heated to a temperature above the melting point of said first excipient material; casting the first composition in a mold having cavities defining one or more microneedles at a temperature less than 100°C; and cooling the first composition in the mold to a temperature that is below the melting point of the first excipient material to form one or more microneedles, or at least a distal tip portion of one or more microneedles, in the mold.

20. 20. The method of claim 19, further comprising casting a second composition onto the distal tip portion of the one or more microneedles to form a proximal portion of the one or more microneedles.

21. 21. The method of claim 20, wherein the second composition comprises a solution comprising an aqueous solvent and a solute material.

22. 21. The method of claim 20, wherein the second composition is solvent-free and comprises a second excipient material heated to a temperature above the melting point of the second excipient material.

23. 23. The method of claim 22, wherein the first excipient and / or the second excipient comprises a fatty acid or a glycerol ester of a fatty acid.

24. 20. The method of claim 19, further comprising casting a backing layer onto the base of the one or more microneedles.

25. 20. The method of claim 19, wherein the agent is hydrophobic.

26. 20. The method of claim 19, wherein the agent comprises a vaccine.

27. 20. The method of claim 19, wherein the agent comprises a protein, a peptide, RNA, or DNA.

28. 20. The method of claim 19, wherein the agent comprises levonorgestrel or another hormone.

29. 20. The method of claim 19, wherein the drug is in a solid state and non-homogeneously mixed with the first excipient material.

30. A microneedle patch according to any one of claims 1 to 18 or a method according to any one of claims 19 to 29, wherein the microneedles are made of one or more materials that melt at a temperature between 20°C and 50°C.

31. The microneedle patch of claim 30, wherein the microneedles are made of one or more materials that melt at a temperature between 20°C and 38°C, such that the microneedles melt when applied to a patient's skin.

32. The microneedle patch of claim 30, wherein the microneedles are made of one or more materials that melt at a temperature between 40°C and 50°C, such that the microneedles melt upon application of heat from an external heat source.

33. A microneedle patch, A backing layer; an array of microneedles extending from the backing layer, each of the microneedles including a portion including a drug; the microneedle is configured to be inserted into mammalian tissue; A microneedle patch, wherein the microneedles are made of one or more materials that melt at a temperature between 60°C and 100°C.

34. 34. The microneedle patch of claim 33, wherein the microneedles are configured to dissolve or biodegrade within the skin of the mammal.

35. 1. A method of delivering a drug to a patient, comprising: inserting a microneedle containing a drug into the skin of the patient; and and melting the microneedle, or a distal tip portion thereof, into the skin of the patient.

36. 36. The method of claim 35, wherein the melting occurs when the inserted microneedles reach the patient's skin temperature.

37. 36. The method of claim 35, wherein the melting comprises applying heat from a source external to the patient to the inserted microneedle.

38. 36. The method of claim 35, wherein the microneedle is part of a microneedle patch comprising an array of microneedles extending from a backing layer.

39. 36. The method of claim 35, further comprising separating the microneedles from the backing layer after the insertion.

40. 36. The method of claim 35, wherein the melted microneedles within the skin form a hydrophobic liquid depot from which the agent is released over an extended period of at least one day.

41. 41. The method of claim 40, wherein the extended period is between 2 days and 30 days.

42. A method for isolating a drug within a distal tip portion of a microneedle of a microneedle patch from a backing layer of the microneedle patch, the method comprising interposing a hydrophobic material within a proximal portion of the microneedle between the backing layer and the distal tip portion.

43. 43. The method of claim 42, wherein the agent is a vaccine or other biological molecule and / or is susceptible to degradation by exposure to moisture.

44. 43. The method of claim 42, wherein the distal tip portion is configured to dissolve or melt after insertion into the skin or other biological tissue.

45. 43. The method of claim 42, wherein the proximal portion is configured to melt after insertion into the skin or another biological tissue.

46. The method of any one of claims 42 to 45, wherein the proximal portion is formed from one or more materials having a melting point between 38°C and 100°C.

47. The method of any one of claims 42 to 46, wherein the distal tip portion is formed from one or more materials having a melting point between 20°C and 50°C.

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