Core shell microneedle patch and method

Abstract

A microneedle patch comprising a backing layer and an array of microneedles extending from the backing layer wherein the microneedles each comprise: a core portion comprising a drug; and a shell portion and a cover portion, wherein the core portion is encapsulated within the shell portion and the cover portion. The microneedles are configured to be inserted into mammalian tissue and then separated from the backing layer. The shell portion and / or the cap portion are biodegradable and delay release of the drug for an extended period of time.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 342,983, filed on May 17, 2022, which is incorporated herein by reference.

[0003] Statement Regarding Federally Funded Research

[0004] This invention was made with Government support under Grant 7200AA20CA00016 awarded by the U.S. Agency for International Development. The Government has certain rights in this invention. Background Art

[0005] Conventional microneedle patches typically deliver a single bolus of therapeutic or preventive agents into the skin after penetration and dissolution of the water-soluble microneedles or water-soluble microneedle coatings. This conventional microneedle-based delivery technology is therefore generally not suitable for long-term sustained release of drugs.

[0006] Although there are many conventional contraceptive methods, there is still a need for safe, effective and easily accessible and self-administered contraceptives. Non-hormonal contraceptive methods usually have a high failure rate due to poor patient acceptance and correct use compliance. Hormonal contraceptives, such as oral pills, transdermal patches, subcutaneous injections, implants and intrauterine contraceptive devices (IUDs), provide increased protection and improved patient compliance, but still have several disadvantages. For example, the effect of daily oral pills may be reduced due to improper use, but it is easy to obtain and self-administer. Long-acting products, such as injections, implants and IUDS, have improved effects, but require the expert administration and / or removal of a healthcare provider, and are therefore more difficult to obtain. At present, there is no long-acting (e.g., providing 6 months of protection) contraceptive that is both safe and effective and self-administered.

[0007] Therefore, it would be desirable to provide microneedles capable of long-term sustained drug release, particularly continuous, slow release, or zero-order release, for various drugs, including but not limited to hormones, such as long-acting contraceptives.

[0008] It would also be desirable to provide new and improved methods for making microneedle arrays and patches including such microneedle arrays capable of slow or sustained drug release. Summary of the invention

[0009] In one aspect, a microneedle patch is provided, comprising: a backing layer; and a microneedle array extending from the backing layer, each of the microneedles comprising: a core portion comprising a drug; and a shell portion and a cover portion, wherein the core portion is encapsulated within the shell portion and the cover portion. The microneedles are configured to be inserted into mammalian tissue and separated from the backing layer, and wherein the shell portion and / or the cover portion are biodegradable and delay the release of the drug for an extended period of time. The microneedles can be configured to release the drug via diffusion through only the shell portion, only through the cover portion, or through both the shell portion and the cover portion. In some embodiments, a microneedle patch for administering a contraceptive or other drug is provided, wherein the patch comprises: a backing layer comprising an array of bases; and an array of microneedles extending from each of the bases, each of the microneedles comprising: a core portion comprising a biodegradable polymer in which a contraceptive or other drug is dissolved or dispersed; and a water-insoluble shell portion and a cap portion, wherein the core portion is enclosed within the shell portion and the cap portion, wherein the microneedles are configured to be inserted into mammalian tissue, separated from the base, and then release an effective amount of the contraceptive or other drug via diffusion through only the shell portion, only the cap portion, or through both the shell portion and the cap portion over an extended period of at least 30 days.

[0010] On the other hand, a method for making a microneedle patch is provided, wherein the method includes: (i) forming a plurality of microneedles in a mold, wherein each microneedle has a core portion including a drug, and a shell portion and a cover portion completely surrounding the core portion; (ii) forming a backing layer connected to the bottom end of each of the plurality of microneedles; and then (iii) removing the backing layer and the microneedles from the mold, thereby producing a microneedle patch. In a specific embodiment, the method includes: (i) casting a first composition in a mold having a cavity defining a plurality of microneedles to form a shell portion in the mold; (ii) casting a second composition including a drug into an internal space defined by the shell portion in the mold to form a core portion; (iii) casting a third composition onto the core portion in the mold to form a cover portion; and (iv) casting a fourth composition onto the cover portion in the mold to form a backing layer, thereby producing a microneedle patch, the microneedle patch comprising a microneedle array extending from the backing layer, wherein each of the microneedles comprises a core portion, the core portion comprising a drug, enclosed within a shell portion and a cover portion. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The detailed description is set forth 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 shown 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.

[0012] Figure 1 is a perspective view of a core-shell microneedle array according to one or more embodiments of the present disclosure.

[0013] Figure 2 is a schematic cross-sectional view of a core-shell microneedle array according to one or more embodiments of the present disclosure.

[0014] Figure 3 Depicted are methods for fabricating core-shell microneedle arrays according to one or more embodiments of the present disclosure.

[0015] Figure 4A Depicted is a core-shell microneedle array prior to insertion into the skin according to one or more embodiments of the present disclosure.

[0016] Figure 4B A core-shell microneedle array is depicted after insertion into the skin and prior to separation from a backing according to one or more embodiments of the present disclosure.

[0017] Figure 4C Depicted is a core-shell microneedle array embedded into the skin after being separated from a backing according to one or more embodiments of the present disclosure.

[0018] Figure 4D Depicted is drug diffusion from the core of a core-shell microneedle through the shell of a core-shell microneedle according to one or more embodiments of the present disclosure.

[0019] Figure 4E Depicted is drug diffusion from the core of a core-shell microneedle through the cap of a core-shell microneedle according to one or more embodiments of the present disclosure.

[0020] Figure 4F Depicted is drug diffusion from the core of a core-shell microneedle through the shell and cap of a core-shell microneedle according to one or more embodiments of the present disclosure.

[0021] Figure 5A is a micrograph showing a perspective view of a core-shell microneedle array according to one or more embodiments of the present disclosure.

[0022] Figure 5B is a micrograph showing a close-up of a core-shell microneedle according to one or more embodiments of the present disclosure.

[0023] Figure 5C is a micrograph showing a close-up of a detached core-shell microneedle, with a magnified view of the cap detached from the base, according to one or more embodiments of the present disclosure.

[0024] Fig. 6A is a graph comparing cumulative levonorgestrel (LGN) release over time from a core-shell microneedle patch and a conventional microneedle patch according to one embodiment of the present disclosure.

[0025] Figure 6B Depicted are exemplary core-shell microneedles according to one or more embodiments of the present disclosure.

[0026] Figure 6C Depicted is an exemplary conventional (core-only) microneedle according to one or more embodiments of the present disclosure. DETAILED DESCRIPTION

[0027] Microneedles, microneedle arrays, and microneedle patches have been developed in which the microneedles have a drug-containing core that is then inserted in vivo and separated from the microneedle patch, kept isolated (enclosed) within a shell and lid structure so that the drug from the core of the isolated microneedle is slowly released into the patient's tissue over an extended period of time. In particular, the shell (and optional lid) acts as a diffusion membrane that controls drug release. The shell and lid structure can be formed, for example, of one or more hydrophobic or water-insoluble polymers, which can be biodegradable.

[0028] The microneedles are also configured, for example, with geometry, composition, and mechanical properties to be inserted into the skin or other biological tissue, and then separated from the backing layer of the microneedle patch as part of the administration method.

[0029] In some embodiments, the microneedles are advantageously capable of controlling the release of the drug for an extended period of time, which may be 30 days to 1 year, for example at least 2 months, 3 months, 4 months, 5 months or 6 months. The drug release may occur continuously over an extended period of time, or it may be delayed until the extended period of time has passed, which may be particularly useful as a vaccine booster.

[0030] In addition, methods for making such microneedle arrays and patches have been developed. In a preferred embodiment, the method comprises forming all structural components of the microneedles and backing using a single mold, which is simpler than conventional methods for making microneedles with drug cores and is most cost-effective for large-scale production.

[0031] Microneedle patch

[0032] In some embodiments, the microneedle patch comprises a backing layer; and a microneedle array extending from the backing layer, wherein the microneedle has a core portion, a shell portion and a cap portion including a drug, wherein the core portion is enclosed (or encapsulated) within the shell portion and the cap portion. The microneedle is configured to be inserted into a mammalian tissue. In some preferred embodiments, the microneedle is configured to be separated from the backing layer to remain embedded in the tissue. In a preferred embodiment, the shell portion and / or the cap portion are biodegradable and delay the release of the drug for an extended period of time.

[0033] In some preferred embodiments, the microneedle is configured to release the drug via diffusion through only the shell portion, only the cover portion, or through both the shell portion and the cover portion. Even if the shell or cover biodegrades during the drug release process, the drug is considered to be released from the core by diffusion (i.e., through the biodegradable polymer shell and / or cover).

[0034] The shell portion and the cover portion may be formed from essentially any suitable substantially water-insoluble biocompatible material such that it is capable of sequestering the core portion in vivo for an extended period of time and preferably biodegrades while and / or after performing this function.

[0035] In some preferred embodiments, the shell and lid portions are formed of one or more biodegradable polymers. In some embodiments, the shell and lid portions may be formed of poly(L-lactide) (PLLA, also known as poly(L-lactic acid)) and / or polylactide (PLA, also known as poly(lactic acid) or poly(D,L-lactic acid)). Other suitable biodegradable polymers known in the art may also be used.

[0036] In some preferred embodiments, the backing layer comprises one or more water-soluble materials, which facilitate the insertion of microneedles in vivo and the separation of the microneedles from the backing layer after the backing layer is exposed to interstitial fluid or other aqueous fluids. In some embodiments, the backing layer comprises polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), one or more sugars, such as sucrose or a combination thereof. In some embodiments, the backing layer comprises an effervescent material, which will react and effervesce after the backing layer is exposed to interstitial fluid or other aqueous fluids, which can accelerate the separation of the microneedles from the backing layer. For example, the backing layer may comprise sodium bicarbonate, citric acid, or another effervescent material, such as described in U.S. Publication 2020 / 0238065 of Prausnitz et al.

[0037] In other embodiments, the interface of the backing layer and the cover portion includes a mechanical weakness so that the microneedle can "break apart" from the backing. For example, the mechanical weakness can be in the form of a cavity or bubble that reduces the strength of the backing cover interface. The microneedle patch can include a base formed at the interface of the backing layer and each of the cover portions of the microneedles. The base can be part of the backing layer, such as being integrally formed (e.g., molded) with the backing layer.

[0038] The core part can be made up of one or more medicines, or more generally comprises one or more medicines dispersed in a suitable matrix material. The matrix material of core can further control the release of medicine, for example, serves as the rate limiting barrier of diffusion. In certain embodiments, the matrix material of core comprises a biodegradable polymer wherein dissolved or dispersed with medicine. In certain embodiments, the biodegradable polymer of core comprises poly (lactide-co-glycolide) (PLGA).

[0039] As mentioned above, the microneedle can be configured to separate from the backing layer. This separation can be triggered by the process of aqueous dissolution of at least part of the material forming the backing layer, also as described above. Alternatively or in addition, mechanical shear force or axial force can be applied to the backing layer after the microneedle is inserted, which, for example, causes a mechanical fracture between the microneedle and the backing layer at the interface of the cover portion and the backing layer. In some embodiments, the microneedle is configured to separate within a time period of 1 minute after the microneedle is inserted into the skin or other mammalian tissue. In some other embodiments, the microneedle is configured to separate within a time period between 1 minute and 10 minutes, for example, between 2 minutes and 9 minutes, 3 minutes to 8 minutes, 4 minutes to 6 minutes or preferably 5 minutes. In some other embodiments, the microneedle is configured to separate in less than 1 minute, for example 45 seconds, 30 seconds, 15 seconds, 10 seconds or preferably 5 seconds.

[0040] Based on the selected drug, the selected materials for other structural components of the microneedle, and the thickness of the shell and cover portions, the release of the drug from the separated microneedle can be continuous over a period of 1 month to 1 year. As used herein, "continuous release" refers to any mechanism of drug release that occurs during a predetermined time period. For example, the continuous release can be a constant release curve, in which there is an initial release peak, an inactive period, and then a release curve of constant release thereafter, or a variable release curve with a shorter periodic release burst throughout the predetermined time period. In some embodiments, the microneedle is configured to continuously release the drug from the separated microneedle over a period of 2 months to 6 months. In some embodiments, the drug includes a steroid. In some embodiments, the drug includes a hormone, such as levonorgestrel or another contraceptive hormone.

[0041] The drug may be a drug intended for systemic administration or action, or it may be a drug targeted to a tissue at the site of delivery. For example, the drug may be a drug effective for treating a skin disease, i.e., administering the drug into the skin to treat or prevent a skin disease, such as eczema, psoriasis, rosacea, acne, etc.

[0042] In some embodiments, the drug is a vaccine, for example, for preventing infectious diseases such as influenza, measles, COVID, etc.

[0043] In some preferred embodiments, the shell portion and the cap portion are not formed by a composition containing a drug, so that the entire drug payload is located in the core portion when manufactured. In some cases, even when manufactured, a small amount of drug may be present in the shell and the cap, but the target in those cases (even after storage) is that the fraction of the drug described in the shell and the cap will be less than 10%, less than 5% or less than 2% by weight. In some other embodiments, the shell portion and / or the cap portion also intentionally include a drug. The drug may be the same or different from the drug in the core portion.

[0044] Figure 1 100 is a microneedle patch with a microneedle array. The microneedle patch 100 includes a backing layer 110, and microneedles 120 in a 10x 10 array extend from the backing layer. The phrase "backing layer" and the term "base substrate" or "substrate" are used interchangeably herein. Each microneedle 120 has a proximal end 122, or a base 124, attached directly or indirectly to the backing layer 110 via one or more proximal portions, and a distal tip 126 that is sharp and can effectively penetrate biological tissue. The microneedle 120 has a tapered sidewall 128 between the proximal end 122 and the distal end 126 of the microneedle 120. Other geometric shapes are possible.

[0045] The microneedles of the microneedle patch are designed to be inserted into the skin or another biological tissue and separated from the backing layer shortly after insertion. In some embodiments, the microneedles 120 and / or the backing layer 110, preferably the base 124, contain features that facilitate the separation of the microneedles 120 from the backing 110, such as pre-fracture regions, porosity, bubble structures, effervescent materials, and / or water-soluble materials. As used herein with respect to microneedle separation, the terms "facilitate," "facilitating," and the like refer to features that: (i) reduce the minimum force (e.g., axial or shear force) necessary to achieve microneedle separation; (ii) reduce the amount of backing material that must be dissolved in order to achieve microneedle separation (e.g., bubble structures can produce thinner walls in microneedles); (iii) increase the dissolution rate of the backing layer to which the microneedles are attached; or (iv) a combination thereof.

[0046] After separation, the microneedle can be embedded in biological tissue, such as the patient's skin. A microneedle is "embedded" in biological tissue when all or a portion of the structure of the microneedle is below the surface of the biological tissue. In some embodiments, the entirety of the structure of the embedded microneedle is below the surface of the tissue.

[0047] In some embodiments, the backing layer 110, or more preferably the base 124, comprises an effervescent material to facilitate the separation of the microneedles from the backing. As used herein, the phrase "effervescent material" refers to a material or material combination that generates gas when in contact with an aqueous liquid. When the microneedle patch comprises an effervescent material, the effervescent material may react when in contact with an aqueous liquid, such as a biological fluid (e.g., interstitial fluid) on, in, or below a biological tissue, thereby generating gas to accelerate the dissolution of the backing. In some preferred embodiments, the backing layer 110 comprises polyvinyl pyrrolidone (PVP), sodium bicarbonate, and citric acid with ethanol to generate effervescence to facilitate the separation of the microneedles from the backing.

[0048] In some embodiments, the backing layer 110 comprises a water-soluble material that can effectively promote the separation of the microneedles from the backing. As used herein, the phrase "water-soluble material", "hydrophilic material" or the like refers to a material or material combination that dissolves or substantially dissolves when in contact with an aqueous liquid. When the microneedle patch comprises a water-soluble material, the water-soluble material can contact an aqueous liquid, such as a biological fluid (e.g., interstitial fluid) on, in or below a biological tissue, thereby partially or completely dissolving at least a portion of the backing. In some preferred embodiments, the backing layer 110 comprises PVA and sucrose.

[0049] In some other embodiments, the interface of the backing layer and the cover portion includes a mechanical weakness so that the microneedles can "break apart" from the backing. For example, the mechanical weakness can be in the form of a cavity or bubble that reduces the strength of the backing-cover interface.

[0050] like Figure 2 As shown, the microneedle patch 110 includes microneedles 120, each of which includes a shell portion 130, a core portion 132, and a cover portion 134 adjacent to the backing layer 110. The shell portion 130 may surround the core portion 132 on most sides, and the cover portion 134 covers the core 132 that is not covered by the shell 130, so that the shell 130 and the cover 134 surround the core region 132 together. In some preferred embodiments, the core 132 may be in the shape of a cone, so that the shell 130 is in the shape of a hollow cone, and the cover 134 is in the shape of a truncated cone. Although it is preferred that the shell 130 and the cover 134 completely surround the core 132, it will be understood that the shell 130 and / or the cover 134 may have gaps, cracks or other defects, so that the shell 130 and the cover 134 do not completely cover the core 132.

[0051] In some embodiments, the length of the microneedle may be between about 50 μm and 2000 μm, about 100 μm to about 2000 μm, about 100 μm to about 1500 μm, about 200 μm to about 1000 μm, or ideally between about 500 μm and 1000 μm. In some embodiments, the microneedle array comprises 10 to 1000 microneedles, 10 to 500 microneedles, 10 to 250 microneedles, 50 to 250 microneedles, or 100 microneedles (e.g., 10x10 microneedle array).

[0052] In some embodiments, the length of pedestal 124 may be between about 50 μm and 1000 μm, about 100 μm to about 750 μm, about 100 μm to about 500 μm, about 200 μm to about 400 μm, or about 500 μm and 1000 μm.

[0053] In some embodiments, shell 130 and lid 134 comprise biocompatible polymers with an expected degradation time longer than six months. In some embodiments, biocompatible polymers are hydrophobic and / or water-insoluble. For example, biocompatible polymers can be polylactide (PLA), poly-l-lactic acid (PLLA), poly(lactide-co-glycolide) (PLGA) and other biodegradable polymers and copolymers. As used herein, the term "water-insoluble" refers to a material that does not substantially dissolve or lose structural integrity when in contact with an aqueous liquid unless it is subsequently biodegraded to produce a water-soluble degradation product. In some preferred embodiments, shell 130 and lid 134 comprise different biocompatible polymers. For example, shell 130 comprises PLLA and lid 134 comprises PLA.

[0054] In some embodiments, the core portion 132 comprises a drug and a biodegradable polymer with an expected degradation time of less than six months. In some embodiments, the biocompatible polymer is a hydrophobic polymer such as poly(lactide-co-glycolide) (PLGA), polylactide (PLA), poly-l-lactic acid (PLLA), and other biodegradable polymers and copolymers.

[0055] The core-shell microneedle patch disclosed herein can be used to formulate a wide range of drugs for delivery to biological tissues. As used herein, the term "drug" refers to preventive, therapeutic or diagnostic agents for medical applications, as well as the beauty, cosmeceuticals, tattoos and other non-medical applications used. It can be any suitable active pharmaceutical ingredient or allergen. In some embodiments, the drug can be selected from small molecules and larger biotechnologies that produce or purify molecules (e.g., peptides, proteins, DNA, RNA, aptamers). In some preferred embodiments, the drug is a hormone or steroid. The hormone can include contraceptive hormones such as levonorgestrel, etonogestrel, norgestrel acetate and other progestogens, as well as estrogens, estradiol and other estrogens. In some embodiments, the drug has a skin indication. In some embodiments, the drug includes a vaccine. Examples of vaccines include vaccines for infectious diseases, therapeutic vaccines for cancer, neurological disorders, allergies and smoking cessation or other addictions.

[0056] In some embodiments, the microneedles within a given microneedle array all contain the same drug. In some other embodiments, the microneedles within a given microneedle array may contain different drugs. For example, the drug may be different in each microneedle, in different rows of microneedles, or in portions / regions of a microneedle array. For example, the drug may be different in the core, shell, and / or cap of a microneedle.

[0057] In some preferred embodiments, the core portion 132 is designed to continuously release the drug from the microneedle over an extended period of time via diffusion through the shell portion 130 and / or the cover portion 134 at a controlled rate. In some embodiments, the extended period of time is one month, 2 months, 3 months, 4 months, 5 months, 6 months, one year or longer. In some embodiments, the release rate is substantially zero order, which is achieved by diffusion across the rate-controlling membrane provided by the shell portion and / or the cover portion of the microneedle. In some other embodiments, the release rate is substantially first order. In other embodiments, the release is pulsed over the duration of the release period (e.g., a single bolus is administered daily during an extended treatment period).

[0058] The microneedle patch may further include other structural elements that enhance the storage and availability of the microneedles ( Figure 1 For example, the patch may include a housing and / or other layers, such as a treatment layer, located on the side of the backing layer opposite the microneedles. Examples of such other additional structural components are described in U.S. Pat. No. 10,265,511 to McAllister et al., which is incorporated herein by reference.

[0059] Method for making microneedle array and microneedle patch

[0060] The microneedle described herein can be made by any suitable process. However, in some preferred embodiments, the microneedle array is made using a molding process, which is advantageously highly scalable. In a particularly preferred embodiment, the manufacturing process includes a series of solution casting steps performed in the same mold, which is suitable for low-cost mass production. This is in contrast to other efforts to make core-shell microneedles, in which shells, cores, lids, and patch backing layers are each individually made using separate molds and processes, and then assembled into a complete microneedle patch using a process that requires more steps.

[0061] The filling and molding steps described herein may be referred to as "casting". In some embodiments, the casting methods, molds, and other equipment may be adapted according to casting methods, molds, and equipment known in the art, such as 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 performed at a minimum ISO 7 (10,000 grade) process or an ISO 5 (100 grade) process.

[0062] In a particular embodiment, a method for making a microneedle patch includes: (i) forming a plurality of microneedles in a mold, wherein each microneedle has a core portion including a drug, and a shell portion and a cap portion surrounding the core portion; (ii) forming a backing layer connected to the bottom end of each of the plurality of microneedles; and then (iii) removing the backing layer and the microneedles from the mold, thereby producing a microneedle patch. The method may further include forming an array of bases for each of the microneedles. For example, the mold may include a funnel-shaped portion proximal to the opening, such that the base (i.e., the funnel-shaped portion) is formed simultaneously with the formation of the backing layer. In this manner, the backing layer includes an array of bases, each of which is connected to the bottom end of one of the plurality of microneedles.

[0063] In a specific embodiment, a method for making a microneedle comprises: (i) casting a first composition in a mold having a cavity defining a plurality of microneedles to form a shell portion in the mold; (ii) casting a second composition comprising a drug into an interior space defined by the shell portion in the mold to form a core portion; (iii) casting a third composition onto the core portion in the mold to form a cover portion; and (iv) casting a fourth composition onto the cover portion in the mold to form a backing layer, thereby producing a microneedle patch comprising an array of microneedles extending from the backing layer, wherein each of the microneedles comprises a core portion, the core portion comprising a drug, enclosed within a shell portion and a cover portion. In some preferred embodiments, the first, second, third, and fourth compositions each comprise a fluid comprising a polymer structural material dissolved in a solvent, wherein the solvent of each of the second, third, and fourth compositions is substantially a non-solvent for the polymer structural material of the first, second, and third compositions, respectively. For example, the polymer structural materials of the first, second and third compositions may each be a different biodegradable polymer, and the polymer structural material of the fourth composition may be a water-soluble polymer, so that a different solvent may be selected for each polymer that does not dissolve or degrade the polymer structural portion of the microneedle formed in the previous step. The solvent in the composition may be substantially a non-solvent for the drug present in the second composition.

[0064] Centrifugation, drying and / or vacuum can be used to help form each of the steps in the portion of the microneedle patch. For example, centrifugation and / or vacuum can help evenly disperse the first composition within the mold to form a shell and / or remove any excess third composition so that the microneedles are uniformly capped.

[0065] Figure 3An example of a manufacturing process 300 for making the core-shell microneedles described herein is shown in FIG. It includes at least five steps: (1) a first casting fill (310) to form the shell portion; (2) a second casting fill (320) to form the core portion; (3) a third casting fill (330) to form the cap portion; (4) a fourth casting fill (340) to form the backing layer; and (5) demolding the resulting microneedle patch (350). The mold is a negative mold of at least part of the microneedles and the backing layer. Suitable microneedle molds typically include an array of between 10 and 1000 microneedles and can be made of silicone or other elastic materials, as known in the art.

[0066] In order to form the shell portion of the microneedle, a first casting composition is prepared and then transferred to the mold (310). This may be referred to as the first casting. In some embodiments, the first casting is formed by dissolving or dispersing a suitable structural material for the shell in a suitable solvent to form a castable fluid. For example, the structural material is preferably a biodegradable polymer and the solvent may be an organic solvent. In one embodiment, the biodegradable polymer is PLLA (L-lactide, ester-terminated) and the solvent is dioxane, or another suitable solvent that can expand into the mold to form the "skin" of the first casting on the mold cavity wall. The mold with the first casting is then centrifuged to evenly distribute and coat the mold with the first casting to form a film (315) that is a uniform shell portion. The mold and film are typically dried (e.g., with heat and vacuum) to remove the solvent and convert the film into a solid shell.

[0067] Next, to form the core portion of the microneedle, a second casting composition is prepared and then transferred to the mold (320). This may be referred to as a second casting. In some embodiments, the second casting is formed by dissolving or dispersing the drug for the core and a suitable structural material in a suitable solvent to form a castable fluid. For example, the structural material may be a biodegradable polymer and the solvent may be an organic solvent or an aqueous organic solvent mixture. In one embodiment, the biodegradable polymer is 85 / 15 lactide / glycolide molar ratio, ester-terminated) and the solvent is diethylene glycol dimethyl ether / water (95% / 5%, v / v). The mold with the second casting is then centrifuged to pull the casting material into the mold and into the interior of the shell (325). The mold and film are typically dried (e.g., with heat and vacuum) to remove the solvent and solidify the core portion. In this case, the second casting solvent (diethylene glycol dimethyl ether / water) is generally a non-solvent for the PLLA shell produced by the first casting.

[0068] Next, to form the cap portion of the microneedle, a third casting composition is prepared and then transferred to the mold (330). This may be referred to as the third casting. In some embodiments, the third casting is formed by dissolving or dispersing a suitable structural material for the cap in a suitable solvent to form a castable fluid. For example, the structural material may be a biodegradable polymer and the solvent may be an organic solvent. In one embodiment, the biodegradable polymer is PLA (DL-lactide, ester-terminated) and the solvent is dimethylacetamide. The mold with the third casting is then centrifuged to pull the casting material into the mold and remove any excess third casting so that the microneedles are uniformly capped (335). The mold and film are typically dried (e.g., with heat and vacuum) to remove the solvent and solidify the cap portion. In this case, the third casting solvent (dimethylacetamide) is generally a non-solvent for the PLLA shell formed by the first casting.

[0069] Then, in order to form a backing layer for the microneedle patch, a fourth casting composition is prepared and then transferred to the mold (340). This may be referred to as the fourth casting. In some embodiments, the fourth casting is formed by dissolving or dispersing a suitable structural material for the backing layer in a suitable solvent to form a castable fluid. For example, the structural material may include one or more water-soluble materials and the solvent may be an aqueous solvent or a solvent mixture. In one embodiment, the structural material is a combination of PVA and sucrose to produce a desired combination of mechanical strength and water solubility. In another embodiment, polyvinyl pyrrolidone (PVP) may be formulated with sodium bicarbonate and citric acid in ethanol, which produces effervescence, which accelerates the separation of microneedles from the backing layer when contacting the aqueous interstitial fluid in the skin. Anhydrous ethanol is a suitable solvent because it dissolves citric acid and supports a suspension of sodium bicarbonate, but does not allow its water-based effervescent reaction to occur during manufacturing. PVP can serve as a suitable matrix material for the backing layer because it can be dissolved in ethanol during manufacturing and can be dissolved in water during the application of the microneedle patch to the skin.

[0070] The mold with the fourth casting is then dried (e.g., with water and vacuum) to remove the solvent and cure the backing layer. In this case, the fourth casting solvent (water or ethanol) is generally a non-solvent for all three polymers used in the microneedles, i.e., PLA is found in the third casting, PLGA is found in the second casting, and PLLA is found in the first casting.

[0071] After the final casting is substantially dried, the core-shell microneedle patch is removed from the mold, ie, demolded ( 350 ).

[0072] As mentioned above, each of the castings may include solvents having different solubility properties in order to prevent the previous casting composition from dissolving during the manufacture of the microneedle patch. In some embodiments, the solvents of the second, third, and fourth castings do not have to dissolve the polymer of the first casting. In some embodiments, the first casting solvent must be different from at least the second casting solvent, the second casting solvent must be different from at least the first and third casting solvents, the third casting solvent must be different from at least the second and fourth casting solvents, and the fourth casting solvent must be different from at least the third casting solvent. In some other embodiments, each casting includes a different solvent. In general, it is not important whether the fourth casting dissolves the second casting because they should not contact each other. However, in a preferred embodiment, the fourth casting does not dissolve the second casting, but in principle it can, as long as it does not dissolve the first or third casting.

[0073] In some other embodiments, one or more of the castings are formed without the use of a solvent by using a molten composition (e.g., where the structural polymeric material of the shell, core, cap, or backing layer portion is cast at a temperature above its melting point and then cooled / solidified to form that portion of the microneedle patch). However, the temperature of the casting should not be high enough to cause degradation or damage to the drug included in the second casting. For example, a biocompatible polymer with a lower melting point (e.g., polycaprolactone (PCL) or a copolymer thereof) may be preferably used for the second casting because PCL advantageously complexes with the drug at a lower temperature.

[0074] In some such cases, each casting may have a different melting point. For example, the first casting may have the highest relative melting point, the second casting must have a melting point lower than the first casting but higher than the melting point of the third casting, the third casting must have a melting point lower than the second casting but higher than the melting point of the fourth casting, and the fourth casting must have the lowest relative melting point. In these embodiments, the melting points of at least the first and third castings must be high enough to prevent melting upon insertion, i.e., the melting points of the first and third castings must be above body temperature in order to maintain the solid structure of the shell and cover during the extended period of time during which the drug is released in vivo by diffusion of the drug through the shell (and cover).

[0075] In some other embodiments, a combination of molten casting solutions and solvent casting solutions may be used. For example, one casting may be formed from the molten composition and the remaining three castings may be formed from the solvent, two castings may be formed from the molten composition and the remaining two castings may be formed from the solvent, or three castings may be formed from the molten solution and the remaining casting may be formed from the solvent.

[0076] How to use

[0077] The microneedle arrays described herein can be used to apply a variety of substances to biological tissue sites in humans or other mammals. As used herein, the phrase "biological tissue" generally includes any human or mammalian tissue. The biological tissue may be the skin or mucosal tissue of humans or other mammals that need treatment or prevention or cosmetic enhancement. In a preferred embodiment, the method includes applying a microneedle patch comprising a core-shell microneedle array to the skin surface in a manner such that the microneedles penetrate the stratum corneum and enter the living epidermis and possibly the dermis. However, it is envisioned that the device and method may also be suitable for other biological tissues and other animals.

[0078] As used herein, the phrase "penetrating a tissue surface" includes penetrating a biological tissue surface with at least the distal tip of the microneedle. In some embodiments, when the microneedle is separated from the backing layer, the proximal end of the microneedle may be above the tissue surface, substantially flush with the tissue surface, or preferably below the tissue surface.

[0079] The microneedle patch can be self-administered or administered by another subject (eg, a parent, guardian, or healthcare provider).

[0080] The methods described herein further include a simple and effective method of administering a drug to a patient using a microneedle patch. The method may include identifying the application site and preferably disinfecting the area (e.g., wiping with alcohol) before applying the microneedle patch. The microneedle patch is then applied to the patient's skin / tissue and manually pressed into the patient's skin / tissue (e.g., using a thumb or finger) or using a device that facilitates patch application so that the microneedles penetrate the tissue surface.

[0081] Following administration, the backing layer (and any remaining microneedle patch structure) can be removed from the patient's skin or other tissue surface.

[0082] In some preferred embodiments, the microneedle patch described herein is used to apply the drug to the patient's skin over an extended period of time. In some embodiments, the method of application comprises inserting the microneedle of the patch across the stratum corneum (10 to 20 microns outside the skin, which is a barrier for transdermal transmission) and entering the living epidermis and possible dermis. The small size of the microneedle enables the microneedle to cause little or no pain, and targets the intradermal space. The intradermal space is highly vascularized in the dermis and is rich in immune cells in the dermis and epidermis, and provides an attractive path for administering vaccines and other preventive, therapeutic and cosmetic agents. In some preferred embodiments, the drug diffuses from the core portion of the inserted microneedle through one or more shells and / or cover portions to the intradermal space to release the drug into the interstitial fluid in the skin.

[0083] 4A to 4FAn example of a method (400) for administering a drug to a patient's skin using a microneedle as described herein is shown. The method includes providing a microneedle patch 100 as described herein, aligning the microneedle patch 100 with a target site on a surface of skin 402 (410), and inserting the microneedle patch into skin 402 (420) to force the microneedles 120 through at least the stratum corneum 404 and into the living epidermis 406 and possible dermis 408 of the skin. Subsequently, the microneedles 120 are separated from the backing layer 110 (430) so that the microneedles remain embedded in the skin 402. When the backing layer 110 and / or the proximal end 122 of the microneedle are formed of a breakable, water-soluble and / or effervescent material, the separation can occur quickly after insertion, for example, so that the backing 110 can be removed within a few seconds or minutes after the microneedle insertion. When the microneedle 120 remains in the skin 402, the drug 136 diffuses from the core portion 132 only through the shell portion 130 of the microneedle (440), as in Figure 4D In the embodiment, only the cover portion 134 (450) of the microneedle 120 is passed, as Figure 4E or through both the shell 130 and the cap 134 portions of the microneedle (460), as shown in Figure 4F as shown in .

[0084] The shell, cover and other non-drug materials (e.g., matrix materials) of the core portion can be biodegraded at a rate that does not adversely affect the controlled rate of diffusion of the drug therethrough. In this way, once the drug has been released from the microneedle, the remaining shell, cover and matrix materials of the core portion will complete biodegradation.

[0085] Although microneedles are shown, and it is generally preferred that the drug is separated from the backing before release from the core, this is not required. For example, the drug may begin to diffuse from the core through at least the shell and / or cover before and / or during its separation from the backing, or the microneedle may not be separated from the backing at all.

[0086] The present invention may be further understood with reference to the following non-limiting examples.

[0087] Example 1. Design and fabrication of a core-shell microneedle patch for LGN delivery

[0088] To make a core-shell microneedle patch for months-long release of the contraceptive hormone levonorgestrel (LNG), high molecular weight PLLA (L-lactide, ester-terminated; intrinsic viscosity, 0.9 dL / g) was selected as the rate-controlling shell material due to its known crystallinity and extremely slow biodegradation rate, which should enable it to provide a stable diffusion barrier for the controlled release of LNG from the core. PLGA (85 / 15) was selected as the core polymer because this PLGA is biodegradable on a time scale consistent with months-long release of encapsulated LNG, has sufficient mechanical strength for microneedles, and can be formulated using solvents that will not dissolve the PLLA shell during manufacturing. LNG was selected as the contraceptive hormone in the microneedle core due to its potency as a contraceptive hormone, its low solubility in water, and because it has been widely used in commercially available long-acting contraceptive products with good safety and efficacy characteristics. PLA (poly(D,L-lactide, ester-terminated; intrinsic viscosity, 0.5 dL / g) was chosen as the polymer for the microneedle cover because it has a slow degradation rate, has sufficient mechanical strength for microneedles, and can be formulated using solvents that will not dissolve the PLLA shell during fabrication.

[0089] Polydimethylsiloxane (PDMS) (Dow Corning, Midland, MI) molds are used to make microneedle patches. In each PDMS mold 112, the microneedle cavities are arranged in a circular array with a diameter of 1.1 cm. The center-to-center spacing between the microneedles is 900 μm, and each microneedle cavity is a cone with a bottom radius of 150 μm, a height of 600 μm, and a tip radius of approximately 10 μm. Above each microneedle cavity is an area for the patch backing, which contains an array of bases, each of which has a bottom diameter of 600 μm, a top diameter of 150 μm, and a height of 350 μm, which is positioned at the bottom of each microneedle to raise the microneedle above the bottom of the backing, that is, the base structure of the microneedle patch.

[0090] The fabrication process was designed as a series of solution casting steps on a single polysilicon (PDMS) mold, as described in Figure 3 To fabricate the core-shell microneedle patch, three solutions were cast sequentially to make the shell, core, and cap structures of the microneedle.

[0091] The first solution contains 1% (w / v) PLLA in dioxane. To prepare this solution, 0.1 g of PLLA (L-lactide, ester-terminated; intrinsic viscosity, 0.9 dL / g; Durect, Birmingham, AL) was dissolved in 10 mL of dioxane (Sigma-Aldrich, St.Louis, MO). Dioxane was selected as the primary solvent because it is a good solvent for PLLA and it can expand into the PDMS mold, which helps form the "skin" of PLLA on the mold cavity wall. In this way, a shell structure can be formed on the inner surface of the mold cavity without allowing PLLA to accumulate substantially in the tip of the needle cavity. Twenty microliters of this first casting solution are applied to the surface of the microneedle mold and then centrifuged at 3200 g for 20 minutes to form a PLLA film in the mold that will become the outer shell of the microneedle.

[0092] Next, a second casting solution was prepared for the core consisting of 8% (w / v) solids, PLGA / LNG (60% / 40%, w / w) in diethylene glycol dimethyl ether / water (95% / 5%, v / v). To make this solution, 0.096 g of PLGA (D,L-lactide, ester-terminated; 85 / 15 lactide / glycolide molar ratio; intrinsic viscosity, 0.5 dL / g; Durect) and 0.064 g of LNG (Chemo Industriale Chimica S.RL, Saronno, Italy) were dissolved in a mixture of 1.5 mL of diethylene glycol dimethyl ether (Sigma-Aldrich) and 0.5 mL of tetrahydrofuran (THF, Thermo Fisher Scientific, Waltham, MA), and then LNG was precipitated by slowly evaporating the THF to produce a colloidal suspension of LNG particles within the PLGA solution. For example, as described in U.S. Publication 2022 / 0401715, precipitation of LNG in the second casting solution can help prevent soluble LNG from migrating into the shell and / or cap, where it can cause faster release of LNG after the microneedle patch is inserted into the tissue. After evaporating substantially all of the THF, additional diethylene glycol dimethyl ether and deionized (DI) water are added to obtain a final casting solution including LNG, PLGA diethylene glycol dimethyl ether, and water.

[0093] Fifteen microliters of the second casting solution was applied to the top of the PDMS mold inside the shell, and then centrifuged at 3200 g for 20 minutes to form the core portion of the microneedle in the mold. Then 20 μL of diethylene glycol dimethyl ether / water (95% / 5%, w / w) was pipetted onto the top of the mold, and after waiting for 5 minutes, the mold was centrifuged at 3200 g for 20 minutes to wash the residual casting solution on the top of the mold into the mold cavity. After this, the mold was dried under vacuum in an oven at 60° C. for 12 hours.

[0094] The third casting solution for the cap contained 3.5% (w / v) dimethylacetamide in PLA (D,L-lactide, ester-terminated; intrinsic viscosity, 0.5 dL / g; Durect). Dimethylacetamide was used as a solvent because it is a good solvent for the medium viscosity D,L-PLA used in the cap, but not the high viscosity PLLA used in the shell. In addition, its solubility properties, low volatility, and low mold swelling tendency (i.e., unlike dioxane) minimize the formation of a PLA film on the PDMS mold surface above the microneedle cap during the casting process, which is critical to allowing the microneedles to be detached after insertion into the skin.

[0095] This solution is applied to the top of the dried mold, followed by centrifugation at 3200 g for 20 minutes to form a cap and seal the core within the cap and shell. The sealed core-shell structure effectively eliminates any holes or gaps that would allow LNG to leak from the core during the slow release process. After this, the mold is placed in a 60° C. oven under vacuum for 12 hours for another drying cycle.

[0096] As a final fabrication step, 80 μL of a backing solution consisting of 18% (w / v) PVA (molecular weight: 6 kDa; Sigma-Aldrich) and 18% (w / v) sucrose (Sigma-Aldrich) dissolved in deionized water was applied to the dried PDMS mold surface to form a patch backing.

[0097] After air drying for 3 hours, the molds were transferred to a desiccator for 2 days before being demolded with adhesive tape.

[0098] Example 2. Characterization of core-shell microneedle patches

[0099] The core-shell microneedle has a conical shape connected to a conical base at the bottom, which is designed to facilitate deeper insertion of the microneedle into the skin, such as FIG. 5A to FIG. 5CAs shown in . Closer inspection by scanning electron microscopy (SEM) shows the interface layer between the conical microneedles and the base, which is the PLA cap, and a thin layer of the PLLA shell covering the outer microneedle surface. Inside the microneedles, there is a mixture of LNG crystals and PLGA polymers, which forms the core portion of the microneedle that acts as a drug reservoir. In this way, the microneedle core including LNG and PLGA polymers is completely coated by the outer shell cover polymer bag made of PLLA / PLA. After dissolving in acetonitrile, the LNG loading of 0.28±0.01mg per patch was determined by ultra-performance liquid chromatography (UPLC) of the microneedles.

[0100] To further examine the core-shell microneedle structure, confocal microscopy revealed a core labeled with red fluorescence using Nile Red dye surrounded by a shell and cap labeled with green fluorescence using fluorescein isothiocyanate (FITC). This imaging further confirmed that the core-shell microneedle structure was revealed by SEM and designed by the fabrication procedure.

[0101] As an additional test to investigate whether LNG is localized in the microneedle core, confocal Raman microscopy was used to compare the composition distribution in core-shell microneedles with microneedle cores fabricated without a shell.

[0102] The microneedle patch was cut in half with a razor blade and incubated in 50 mL of water for 15 minutes to dissolve the water-soluble backing. The microneedle tips were collected and placed on a glass slide covered with aluminum foil and dried in a desiccator for at least 4 days before cutting the microneedles perpendicular to their central axis with a razor blade to obtain cross sections. The cross sections were then drawn using confocal Raman microscopy (inViaQontor, Renishaw, Wotton-under-Edge, UK) at an excitation wavelength of 785 nm and an exposure time of 1 second at 300 mW. 1050.08 cm was collected every 2 μm along the x-axis and y-axis using a 50x long working distance objective. -1 To 2083.76cm -1 Raman spectrum of -1 With 1700cm -1 Characteristic LNG peaks were observed between 1700cm -1 Characteristic PLA and PLGA peaks were observed at 40°C. Spectra were processed and peak sizes were quantified by signal-to-baseline ratio and converted into false color images using WiRE 5 software (Renishaw, New Mills, UK). At least 6 microneedle tips were examined in each experimental group.

[0103] In the core-only microneedle, LNG and PLGA were distributed throughout the microneedle. In contrast, LNG was encapsulated in the core section of the core-shell microneedle and surrounded by an outer layer of PLLA / PLA that formed the shell and cap and also contained LNG. Raman microscopy images also confirmed a shell thickness of approximately 20 μm.

[0104] It is difficult to distinguish the Raman spectra signals between PLLA, PLA, and PLGA because these polymers have a high Raman signal at 1770 cm -1 The peak shows similar signal intensity, and it is therefore reported as a combined PLGA / PLA signal. The PLGA Raman signal obtained in the core of the core-shell microneedle is presented as weaker than the PLGA signal in the center of the core sample only. However, the quantitative analysis of the PLGA signal value in the core is similar in the core-shell and core samples only. The significantly weaker PLGA signal in the core of the core-shell sample can be explained by the strong PLLA / PLA signal produced by the dense shell, which makes the PLGA core appear as weaker to avoid the saturation of the PLLA / PLA signal of the shell due to the automatic calibration of the signal intensity.

[0105] Example 3. Sealing of the core in a core-shell microneedle patch

[0106] The slow release from the core-shell microneedle is due to the effective encapsulation of the drug inside the shell-lid pocket. In order to evaluate the sealing effect of the core-shell microneedle in vitro, a solution of 18% (w / v) PVA and 1% (w / v) fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA) dissolved in phosphate buffered saline (PBS) was used to make a second casting solution for the core portion of the microneedle, while keeping the shell and lid formulations the same. Each microneedle patch was placed in 20 mL PBS, and at 0 hours, 0.5 hours, 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, and 96 hours, the morphology and fluorescence of the microneedle were imaged using bright field and fluorescence microscopy (SZX16, Olympus, Tokyo, Japan) fluorescence optics.

[0107] The fluorescence intensity of FITC-BSA in the microneedle core remained intense for 1 hour in PBS, after which it gradually dimmed over 3 to 4 days. In contrast, microneedles made of the same core material with a shell but no cap, or with neither a cap nor a shell, dissolved in 25 minutes or 2 minutes, respectively. This indicates a significant diffusion barrier created by the shell and cap surrounding the core.

[0108] Example 4. Core-shell microneedle patch inserted into the skin in vitro

[0109] To evaluate the penetration, detachment and delivery efficiency of the microneedle patch, the patch backing was changed to an effervescent backing made of pure anhydrous ethanol (Koptec, King of Prussia, PA) containing 13% (w / v) PVP and 4% (w / v) citric acid (Sigma-Aldrich) with two molecular weights (360 / 55kDa, 50 / 50%, w / v; Sigma-Aldrich), wherein 5% (w / v) sodium bicarbonate (Sigma-Aldrich) was suspended in the solution. PVP was selected as the matrix material of the backing because it was dissolved in ethanol during manufacture and dissolved in water during application of the microneedle patch to the skin. After air drying for 1 hour, the mold was placed in a desiccator overnight to completely dry at room temperature (20°C to 25°C), after which a layer of adhesive paper was gently attached to the top surface of the PDMS mold and used to carefully peel off the patch from the mold. The demolded microneedle patch was stored in a desiccator until use.

[0110] These microneedle patches, which included Nile red dye, were inserted by pressing the porcine exoskeleton with the thumb for 10 seconds, followed by waiting another 50 seconds without pressure for the effervescent backing to dissolve and separate the microneedles from the patch backing. After removal of the patch backing, the skin containing the implanted microneedles was examined by optical microscopy (Osbarin, Tokyo, Japan) to identify detached microneedles embedded in the skin. In some cases, a swab was gently and repeatedly scraped over the microneedle patch-treated site for 10 seconds to remove any detached microneedles that partially protruded above the skin surface.

[0111] After 1 minute of application to the skin, about 95% of the microneedles per patch were detached from the patch backing and remained in the skin, and more than 90% of the model drug (fluorescent dye) was delivered to the skin. After detachment from the patch backing, the penetration depth of the core-shell microneedles was approximately 250 μm into the skin. This demonstrates effective microneedle detachment and delivery in the skin using a core-shell microneedle patch with an effervescent patch backing.

[0112] To analyze only the penetration of the microneedle patch, the patch was applied to the skin by the thumb and then immediately removed. The skin was then covered with gentian violet solution (Humco, Linden, TX) for 10 minutes to stain the sites of microneedle penetration, followed by cleaning with an alcohol swab to remove residual dye from the skin surface.

[0113] The penetration and detachment efficiencies were calculated by dividing the number of colored spots (i.e., due to gentian violet staining or the presence of fluorescent microneedles in the skin) by the number of microneedles in the patch (i.e., 112). The delivery efficiency was calculated by dividing the amount of Nile red dye (measured by fluorescence spectrometry) in the skin (determined by subtracting the amount of dye in the microneedles remaining on the patch after use from the amount of dye in the microneedles of the patch before use) by the amount of dye in the microneedle patch before use.

[0114] Example 5. Release of LNG from core-shell microneedle patches in vitro

[0115] Studying the Release Kinetics of LNG from Core-Shell Microneedles in Vitro The in vitro release data can reasonably predict the in vivo release behavior. This is because previous work has demonstrated good in vitro to in vivo correlation of LNG release from microneedles formulated with PLA and PLGA in rats when compared to release of LNG in release media including PBS containing 20% ​​ethanol at 37°C.

[0116] To evaluate the in vitro release of LNG from the microneedle patch, a release medium of PBS (137mM NaCl, 2.68mM KCl, 10.14mM Na2HPO4, 1.76mM KH2PO4) was used with added 20% (w / v) ethanol to better mimic the in vivo release kinetics of other PLGA-based microneedles in rats. Specifically, one microneedle patch was placed in 1L of release medium in a glass container. The glass container was incubated at 37°C in an oscillator water bath oscillating at 80rpm. At predetermined time points (0, 1, 3, 7, 14, 21, 28 days, and every 7 days after reaching the point of 182 days), 1mL of release medium was collected and replaced with the same amount of fresh medium.

[0117] Collected samples were analyzed by UPLC (Acquity, Waters Corp. Milford, MA) equipped with a UV detector to quantify LNG concentration. LNG was analyzed by Acquity UPLC ethylene bridged hybrid (BEH) C 18 The separation was performed on a column (100 mm x 2.1 mm id; 1.7 μm particle size) at 50°C. A mixture of acetonitrile containing 0.1% formic acid and water containing 0.1% formic acid (55:45 ratio, v / v) comprised the mobile phase. The injection volume was 10 μL with a flow rate of 0.3 mL min -1 The UV absorbance of LNG was measured at 245 nm.

[0118] Cumulative LNG release (600) for the 182-day study is plotted over time as Fig. 6A As residual LNG remained in the microneedles at the end of the study, the release profile was extrapolated by continuing the release profile at the average release rate until 100% release was achieved, and this value was reported as the duration of LNG release.

[0119] Core-only microneedle patch 620 (e.g. Figure 6C ) exhibited a burst release of 22.6±2.0% of LNG on the first day, whereas from the core-shell microneedle patch 610 (e.g. Figure 6B) was only 5.8±0.5% LNG on the first day, indicating that LNG encapsulation in the shell-lid pouch significantly reduced the burst release (two-tailed Student's t-test, p<0.001).

[0120] The monolithic core-only microneedle patch 620 achieved a typical first-order release of LNG in 2.1±0.2 months, while the core-shell microneedle 610 achieved a significantly longer and closer to zero-order release curve in 6.2±0.1 months (two-tailed Studden's t-test, p<0.001). The average LNG release rate of the core-only microneedle patch 620 was 1.6±0.3% per day, which was significantly faster than the core-shell microneedle patch 610, which released 0.6±0.2% of LNG per day (two-tailed Studden's t-test, p<0.01). In summary, these data indicate that the core-shell microneedle patch 610 effectively encapsulates LNG within a rate-controlling shell cover pocket to significantly reduce the drug release rate and achieve 6-month release kinetics.

[0121] Some embodiments of the present disclosure may be described in light of one or more of the following:

[0122] Embodiment 1. A microneedle patch comprising: a backing layer; and a microneedle array extending from the backing layer, wherein each of the microneedles comprises: a core portion comprising a drug; and a shell portion and a cover portion, wherein the core portion is encapsulated within the shell portion and the cover portion, wherein the microneedles are configured to be inserted into mammalian tissue and separated from the backing layer, and wherein the shell portion and / or the cover portion are biodegradable and delay the release of the drug for an extended period of time.

[0123] Embodiment 2. The microneedle patch of embodiment 1, wherein the microneedles are configured to release the drug via diffusion through only the shell portion, only the cover portion, or through both the shell portion and the cover portion.

[0124] Embodiment 3. The microneedle patch according to embodiment 1 or 2, wherein the shell portion comprises polylactide (PLA) or poly(L-lactide) (PLLA).

[0125] Embodiment 4. The microneedle patch according to any one of embodiments 1 to 3, wherein the cover portion comprises polylactide (PLA) or poly(L-lactide) (PLLA).

[0126] Embodiment 5. The microneedle patch according to any one of embodiments 1 to 4, wherein the backing layer is formed of a water-soluble polymer.

[0127] Embodiment 6. The microneedle patch according to any one of embodiments 1 to 5, wherein the backing layer comprises polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), sucrose or a combination thereof.

[0128] Embodiment 7. The microneedle patch according to any one of embodiments 1 to 6, wherein the backing layer comprises sodium bicarbonate, citric acid and / or other effervescent materials.

[0129] Embodiment 8. The microneedle patch according to any one of embodiments 1 to 7, wherein the core portion comprises a biodegradable polymer having the drug dispersed therein.

[0130] Embodiment 9. The microneedle patch of claim 8, wherein the biodegradable polymer of the core portion comprises poly(lactide-co-glycolide) (PLGA).

[0131] Embodiment 10. The microneedle patch according to any one of embodiments 1 to 9, further comprising a base located between the backing layer and each of the cover portions of the microneedles.

[0132] Embodiment 11. The microneedle patch according to embodiment 10, wherein the base is integrally formed with the backing layer.

[0133] Embodiment 12. A microneedle patch according to any one of embodiments 1 to 11, wherein the microneedles are configured to be separated from the backing layer by a method comprising: (i) aqueous dissolution of a material forming at least a portion of the backing layer, the material optionally comprising an effervescent material; and / or (ii) rupture at the interface of the cover portion and the backing layer.

[0134] Embodiment 13. The microneedle patch of embodiment 12, wherein the fracture is caused by air pockets at the interface of the cover portion and the backing layer.

[0135] Embodiment 14. The microneedle patch according to embodiment 12 or 13, wherein the cover portion comprises a hydrophobic material and the backing layer comprises a hydrophilic material, so that the interface between the cover portion and the backing layer is weak and easily broken.

[0136] Embodiment 15. The microneedle patch of any one of embodiments 1 to 14, wherein the microneedles are configured to detach within a period of 1 minute or less after the microneedles are inserted into mammalian tissue.

[0137] Embodiment 16. The microneedle patch according to any one of embodiments 1 to 15, which is configured to continuously release the drug from the isolated microneedles over a period of 1 month to 1 year.

[0138] Embodiment 17. The microneedle patch according to any one of embodiments 1 to 16, which is configured to continuously release the drug from the isolated microneedles over a period of 2 to 6 months.

[0139] Embodiment 18. The microneedle patch of any one of embodiments 1 to 17, wherein the drug comprises a steroid.

[0140] Embodiment 19. The microneedle patch of any one of embodiments 1 to 17, wherein the drug comprises a hormone, such as levonorgestrel, etonogestrel, norgestrel acetate, or another contraceptive hormone.

[0141] Embodiment 20. The microneedle patch according to any one of embodiments 1 to 17, wherein the drug is effective for treating skin diseases.

[0142] Embodiment 21. The microneedle patch of any one of Embodiments 1 and 3 to 15, wherein the drug comprises a vaccine.

[0143] Embodiment 22. The microneedle patch according to any one of embodiments 1 to 21, wherein the shell portion and / or the cap portion comprises a drug that is the same as or different from the drug in the core portion.

[0144] Embodiment 23: A microneedle patch for administering contraceptives or other drugs, the patch comprising: a backing layer comprising a base array; and a microneedle array extending from each of the bases, each of the microneedles comprising: a core portion comprising a biodegradable polymer in which a contraceptive or other drug is dissolved or dispersed; and a water-insoluble, and preferably non-porous shell portion and a cover portion; wherein the core portion is enclosed within the shell portion and the cover portion, wherein the microneedles are configured to be inserted into mammalian tissue, separated from the base, and then release an effective amount of the contraceptive or other drug via diffusion through only the shell portion, only through the cover portion, or through both the shell portion and the cover portion over an extended period of at least 30 days.

[0145] Embodiment 24. The microneedle patch of Embodiment 23, wherein the shell portion and the cover portion are formed of a biodegradable polymer.

[0146] Embodiment 25. The microneedle patch of Embodiment 23 or 24, wherein the shell portion comprises poly(L-lactide) (PLLA), and wherein the cap portion comprises polylactic acid (PLA).

[0147] Embodiment 26. The microneedle patch according to any one of embodiments 22 to 25, wherein the water-soluble polymer comprises polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), sucrose or a combination thereof.

[0148] Embodiment 27. The microneedle patch of any one of embodiments 22 to 26, wherein the extended period of time is 2 months to 6 months.

[0149] Embodiment 28. The microneedle patch of any one of embodiments 22 to 27, wherein the contraceptive agent comprises levonorgestrel, etonogestrel, norgestrel acetate, or another contraceptive hormone.

[0150] Embodiment 29. A method for making a microneedle patch, the method comprising: (i) forming a plurality of microneedles in a mold, wherein each microneedle has a core portion comprising a drug, and a shell portion and a cover portion completely surrounding the core portion; (ii) forming a backing layer connected to the bottom end of each of the plurality of microneedles; and then (iii) removing the backing layer and the microneedles from the mold, thereby producing a microneedle patch.

[0151] Embodiment 30. The method of embodiment 29, wherein the backing layer comprises an array of bases, each base being connected to the bottom end of one or more of the plurality of microneedles.

[0152] Embodiment 31. The method of Embodiment 29 or 30, wherein the microneedle is configured to release the drug via diffusion from the core portion through the shell portion and / or through the cap portion of the microneedle.

[0153] Embodiment 32. A method comprising: (i) casting a first composition in a mold having a cavity defining a plurality of microneedles to form a shell portion in the mold; (ii) casting a second composition comprising a drug into an interior space defined by the shell portion in the mold to form a core portion; (iii) casting a third composition onto the core portion in the mold to form a cover portion; and (iv) casting a fourth composition onto the cover portion in the mold to form a backing layer, thereby producing a microneedle patch comprising an array of microneedles extending from the backing layer, wherein each of the microneedles comprises a core portion, the core portion comprising a drug, enclosed within a shell portion and a cover portion.

[0154] Embodiment 33. A method according to embodiment 32, wherein the first composition, the second composition, the third composition and the fourth composition each comprise a fluid, wherein the fluid comprises a polymer structural material dissolved in a solvent, wherein the solvent of the first composition is at least different from the solvent of the second composition, the solvent of the second composition is at least different from the solvents of the first composition and the third composition, and the solvent of the third composition is at least different from the solvents of the second composition and the fourth composition, and the solvent of the fourth composition is different from the solvent of at least the third composition.

[0155] Embodiment 34. The method of embodiment 33, wherein the polymeric structural materials of the first composition, the second composition, and the third composition each comprise a biodegradable polymer.

[0156] Embodiment 35. The method of embodiment 33 or 34, wherein the polymer structural material of the fourth composition comprises a water-soluble polymer.

[0157] Embodiment 36. The method of any one of embodiments 32 to 35, wherein the first composition comprises PLLA dissolved in dioxane.

[0158] Embodiment 37. The method of any one of embodiments 32 to 36, wherein the second composition comprises PLGA dissolved in a mixture of diethylene glycol dimethyl ether and water.

[0159] Embodiment 38. The method of any one of embodiments 32 to 37, wherein the third composition comprises PLA dissolved in dimethylacetamide.

[0160] Embodiment 39. The method of any one of embodiments 32 to 38, wherein the fourth composition comprises PVA and sucrose dissolved in water.

[0161] Embodiment 40. The method of any one of embodiments 32 to 39, wherein the fourth composition comprises PVP, sodium bicarbonate, and citric acid dispersed or dissolved in anhydrous ethanol.

[0162] Embodiment 41. The method of any one of embodiments 32 to 40, further comprising centrifuging the mold after casting of the first composition to promote formation of a film in the mold that will become the shell.

[0163] Embodiment 42. The method of any one of embodiments 32 to 41, further comprising drying the contents of the mold after each of the castings.

[0164] Embodiment 43. The method of any one of Embodiments 32 to 42, further comprising removing the microneedle patch from the mold.

[0165] Embodiment 44. A method of administering a drug to a patient, the method comprising: (i) inserting microneedles of a microneedle patch according to any of the preceding embodiments into the skin of the patient; (ii) separating the microneedles from the backing layer; and then (iii) releasing the drug from the core portion of the microneedles, wherein the shell portion and / or the cover portion are biodegradable and delay the release of the drug for an extended period of time, optionally wherein the release is via diffusion through the shell portion of the microneedles.

[0166] Embodiment 45. The method of embodiment 44, further comprising releasing the drug from the core portion via diffusion through the cap portion of the microneedle.

[0167] Embodiment 46. The method of embodiment 44 or 45, wherein the drug is released continuously over a period of at least one month.

[0168] Embodiment 47. The method of embodiment 46, wherein the time period is 2 months to 6 months.

[0169] Embodiment 48. The method of any one of embodiments 44 to 47, wherein the drug comprises levonorgestrel, etonogestrel, norgestrel acetate, or another contraceptive hormone.

[0170] As used herein, the term "about" indicates a value of a given amount, and may include amounts ranging within 10% of the stated value, or optionally within 5% of the value, or in some embodiments within 1% of the value.

[0171] Although the present disclosure has been described with reference to several 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 may be modified to incorporate any number of variations, alterations, substitutions, or equivalent arrangements not described herein but commensurate with the spirit and scope of the present disclosure.

Claims

1. A microneedle patch, comprising: Backing layer; and A microneedle array extending from the backing layer, each of the microneedles comprising: a core portion, which includes the drug, and a shell portion and a cap portion, wherein the core portion is enclosed within the shell portion and the cap portion, wherein the microneedle is configured to be inserted into mammalian tissue and separated from the backing layer, and Wherein the shell portion and / or the cover portion are biodegradable and delay the release of the drug for an extended period of time.

2. The microneedle patch of claim 1, wherein the microneedles are configured to release the drug via diffusion through only the shell portion, only the cover portion, or through both the shell portion and the cover portion. 3 . The microneedle patch according to claim 1 , wherein the shell portion comprises polylactide (PLA) or poly(L-lactide) (PLLA). 4 . The microneedle patch according to claim 1 , wherein the cap portion comprises polylactide (PLA) or poly(L-lactide) (PLLA). The microneedle patch according to claim 1 , wherein the backing layer is formed of a water-soluble polymer. 6 . The microneedle patch according to claim 5 , wherein the backing layer comprises polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), sucrose or a combination thereof.

7. The microneedle patch according to claim 5, wherein the backing layer comprises sodium bicarbonate, citric acid and / or other effervescent materials.

8. The microneedle patch according to claim 1, wherein the core portion comprises a biodegradable polymer in which the drug is dispersed.

9. The microneedle patch of claim 8, wherein the biodegradable polymer comprises poly(lactide-co-glycolide) (PLGA).

10. The microneedle patch of claim 1, further comprising a base located between the backing layer and each of the cover portions of the microneedles. The microneedle patch according to claim 10 , wherein the base is formed integrally with the backing layer.

12. The microneedle patch of claim 1 , wherein the microneedles are configured to be separated from the backing layer by a method comprising: (i) aqueous dissolution of a material forming at least a portion of the backing layer, the material optionally comprising an effervescent material; and / or (ii) rupture at the interface of the cover portion and the backing layer.

13. The microneedle patch of claim 12, wherein the fracture is caused by air pockets at the interface of the cover portion and the backing layer.

14. The microneedle patch of claim 12, wherein the cover portion comprises a hydrophobic material, and the backing layer comprises a hydrophilic material, so that the interface of the cover portion and the backing layer is weak and easily broken.

15. The microneedle patch of claim 12, wherein the microneedles are configured to detach within a period of 1 minute or less after the microneedles are inserted into mammalian tissue.

16. The microneedle patch of claim 1, which is configured to continuously release the drug from the isolated microneedles over a period of 1 month to 1 year.

17. The microneedle patch of claim 16, which is configured to continuously release the drug from the isolated microneedles over a period of 2 to 6 months.

18. The microneedle patch of claim 1, wherein the drug comprises a steroid.

19. The microneedle patch of claim 1, wherein the drug comprises a hormone such as levonorgestrel, etonogestrel, norgestrel acetate, or another contraceptive hormone.

20. The microneedle patch of claim 1, wherein the drug is effective in treating a skin disease.

21. The microneedle patch of claim 1, wherein the drug comprises a vaccine.

22. The microneedle patch of claim 1, wherein the shell portion and / or the cap portion comprises a drug that is the same as or different from the drug in the core portion.

23. A microneedle patch for administering a contraceptive agent or other drug, comprising: a backing layer comprising an array of pedestals; and an array of microneedles extending from each of the bases, each of the microneedles comprising: The core portion includes a Biodegradable polymers containing contraceptives or other drugs, and a water-insoluble shell portion and a cap portion, wherein the core portion is enclosed within the shell portion and the cap portion, The microneedles are configured to be inserted into mammalian tissue, separated from the base, and then release an effective amount of the contraceptive agent or the other drug via diffusion through only the shell portion, only the cover portion, or through both the shell portion and the cover portion over an extended period of at least 30 days.

24. The microneedle patch of claim 23, wherein the shell portion and the cover portion are formed of a biodegradable polymer.

25. The microneedle patch of claim 24, wherein the shell portion comprises poly(L-lactide) (PLLA), and wherein the cap portion comprises polylactic acid (PLA).

26. The microneedle patch of claim 23, wherein the water-soluble polymer comprises polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), sucrose, or a combination thereof.

27. The microneedle patch of claim 23, wherein the extended period of time is from 2 months to 6 months.

28. The microneedle patch of any one of claims 23 to 27, wherein the contraceptive agent comprises levonorgestrel, etonogestrel, norgestrel acetate, or another contraceptive hormone.

29. A method for making a microneedle patch, the method comprising: forming a plurality of microneedles in a mold, wherein each microneedle has a core portion including a drug, and a shell portion and a cap portion completely surrounding the core portion; forming a backing layer connected to the bottom end of each of the plurality of microneedles; and then The backing layer and the microneedles are removed from the mold, thereby producing a microneedle patch.

30. The method of claim 29, wherein the backing layer comprises an array of pedestals, each pedestal being connected to the bottom end of one or more of the plurality of microneedles.

31. The method of claim 29 or 30, wherein the microneedle is configured to release the drug via diffusion from the core portion through the shell portion and / or through the cap portion of the microneedle.

32. A method comprising: casting a first composition in a mold having a cavity defining a plurality of microneedles to form a shell portion in the mold; casting a second composition including a drug into an interior space defined by the shell portion in the mold to form a core portion; casting a third composition onto the core portion in the mold to form a cap portion; and casting a fourth composition onto the cover portion in the mold to form a backing layer, Thereby a microneedle patch is produced, the microneedle patch comprising an array of microneedles extending from the backing layer, wherein each of the microneedles comprises the core portion, the core portion comprising the drug, enclosed within the shell portion and the cover portion.

33. The method of claim 32, wherein the first composition, the second composition, the third composition, and the fourth composition each comprise a fluid comprising a polymer structural material dissolved in a solvent, wherein the solvent of the first composition is at least different from the solvent of the second composition, the solvent of the second composition is at least different from the solvents of the first composition and the third composition, and the solvent of the third composition is at least different from the solvent of the second composition and the fourth composition, and the solvent of the fourth composition is different from the solvent of at least the third composition.

34. The method of claim 33, wherein the polymeric structural materials of the first composition, the second composition, and the third composition each comprise a biodegradable polymer.

35. The method of claim 33, wherein the polymeric structural material of the fourth composition comprises a water-soluble polymer.

36. The method of claim 32, wherein the first composition comprises PLLA dissolved in dioxane.

37. The method of claim 32, wherein the second composition comprises PLGA dissolved in a mixture of diethylene glycol dimethyl ether and water.

38. The method of claim 32, wherein the third composition comprises PLA dissolved in dimethylacetamide.

39. The method of claim 32, wherein the fourth composition comprises PVA and sucrose dissolved in water.

40. The method of claim 32, wherein the fourth composition comprises PVP, sodium bicarbonate, and citric acid dispersed or dissolved in anhydrous ethanol.

41. The method of any one of claims 32 to 40, further comprising centrifuging the mold after the casting of the first composition to promote formation of a film in the mold that will become the shell.

42. The method of any one of claims 32 to 40, further comprising drying the contents of the mold after each of the casts.

43. The method of any one of claims 32 to 40, further comprising removing the microneedle patch from the mold.

44. A method of administering a drug to a patient, the method comprising: inserting the microneedles of the microneedle patch according to any one of claims 1 to 28 into the skin of a patient; separating the microneedles from the backing layer; allowing the shell portion and / or the cover portion to biodegrade in vivo; and The drug is released over an extended period of time.

45. The method of claim 44, wherein the drug is released from the core portion of the microneedle via diffusion through the shell portion of the microneedle.

46. ​​The method of claim 44, wherein the drug is released from the core portion of the microneedle via diffusion through the cap portion of the microneedle.

47. The method of claim 44, wherein the drug is released continuously over the extended period of time of at least one month.

48. The method of claim 44, wherein the drug is released continuously over the extended period of time of 2 to 6 months.

49. The method of claim 44, wherein the drug comprises levonorgestrel, etonogestrel, norgestrel acetate, or another contraceptive hormone.

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