Core-shell microneedle patch and method

Abstract

A microneedle patch comprising a backing layer and an array of microneedles extending from the backing layer, each microneedle comprising a core portion containing a drug, a shell portion, and a cap portion, the core portion being encapsulated within the shell portion and the cap 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 over an extended period of time.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 342,983, filed May 17, 2022, which is incorporated herein by reference.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under 7200AA20CA00016 awarded by the United States Agency for International Development. The Government has certain rights in this invention. [Background technology]

[0003] Conventional microneedle patches typically deliver a single bolus of therapeutic or prophylactic agent to the skin upon penetration and dissolution of the water-soluble microneedles or water-soluble microneedle coatings. Thus, such conventional microneedle-based delivery technologies are generally not suitable for long-term, sustained release of drugs.

[0004] Although numerous conventional methods of contraception exist, there remains a need for contraceptives that are safe, effective, and easy to obtain and self-administer. Non-hormonal contraceptive methods have high failure rates, usually due to poor patient acceptance and adherence to correct use. Hormonal contraceptives (e.g., oral pills, transdermal patches, subcutaneous injections, implants, and intrauterine devices (IUDs) offer increased protection and improved patient adherence, but still have some drawbacks. For example, the effectiveness of daily oral pills can be reduced with improper use, but they are easy to obtain and self-administer. Long-acting products such as injections, implants, and IUDS have improved efficacy, but require professional administration and / or removal by a health care provider and are therefore more difficult to obtain. Currently, there are no contraceptives that are safe, effective, and self-administered that are long-acting (e.g., provide protection for six months).

[0005] It is therefore desirable to provide microneedles capable of sustained drug release, particularly continuous sustained or zero order release, for a variety of drugs, including but not limited to hormones such as long-acting contraceptives.

[0006] It is also desirable to provide new and improved methods for making microneedle arrays and patches, including arrays of such microneedles, that are capable of slow or sustained release of pharmaceutical agents. 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, each microneedle including a core portion containing a drug and a shell portion and a cap portion, the core portion being encapsulated within the shell portion and the cap portion, the microneedles configured to be inserted into mammalian tissue and separate from the backing layer, the shell portion and / or the cap portion being biodegradable and delaying release of the drug over an extended period of time. The microneedles may be configured to release the drug via diffusion through the shell portion only, through the cap portion only, or through both the shell portion and the cap portion. In some embodiments, there is provided a microneedle patch for administering a contraceptive or other medication, the patch comprising a backing layer including an array of pedestals, and an array of microneedles extending from each of the pedestals, the microneedles each including a core portion comprising a biodegradable polymer having a contraceptive or other medication dissolved or dispersed therein, and a water insoluble shell portion and a cap portion, the core portion being encapsulated within the shell portion and the cap portion, the microneedles being configured to be inserted into mammalian tissue, detach from the pedestal, and then release an effective amount of the contraceptive or other medication via diffusion through only the shell portion, through only the cap portion, or through both the shell portion and the cap portion, over an extended period of at least 30 days.

[0008] In another aspect, there is provided a method of making a microneedle patch, the method including: (i) forming a plurality of microneedles in a mold, each microneedle having a core portion containing a drug and a shell portion and a cap portion that completely surround the core portion; (ii) forming a backing layer connected to a base 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 certain embodiments, the method includes: (i) casting a first composition into a mold having a cavity defining a plurality of microneedles to form a shell portion in the mold; (ii) casting a second composition comprising an agent into the 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 cap portion; and (iv) casting a fourth composition onto the cap portion in the mold to form a backing layer, thereby producing a microneedle patch comprising an array of microneedles extending from the backing layer, each of the microneedles comprising a core portion comprising an agent encapsulated within the shell portion and the cap portion. [Brief description of the drawings]

[0009] 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.

[0010] [Figure 1] FIG. 1 is a perspective view of an array of core-shell microneedles according to one or more embodiments of the present disclosure. [Diagram 2] FIG. 1 is a schematic cross-sectional view of an array of core-shell microneedles, according to one or more embodiments of the present disclosure. [Diagram 3]1 depicts a process for fabricating an array of core-shell microneedles, according to one or more embodiments of the present disclosure. [Figure 4A] 1 depicts an array of core-shell microneedles prior to insertion into the skin, according to one or more embodiments of the present disclosure. [Figure 4B] 1 depicts an array of core-shell microneedles after insertion into the skin and prior to separation from the backing, according to one or more embodiments of the present disclosure. [Figure 4C] 1 depicts an array of core-shell microneedles embedded within the skin after separation from a backing, according to one or more embodiments of the present disclosure. [Figure 4D] 1 depicts drug diffusion from the core of a core-shell microneedle through the shell of the core-shell microneedle in accordance with one or more embodiments of the present disclosure. [Figure 4E] 1 depicts drug diffusion from the core of a core-shell microneedle through the cap of the core-shell microneedle in accordance with one or more embodiments of the present disclosure. [Figure 4F] 1 depicts drug diffusion from the core of a core-shell microneedle through the shell and cap of the core-shell microneedle in accordance with one or more embodiments of the present disclosure. [Figure 5A] FIG. 2 is a micrograph showing a perspective view of an array of core-shell microneedles, according to one or more embodiments of the present disclosure. [Figure 5B] 1 is a micrograph showing a close-up of a core-shell microneedle according to one or more embodiments of the present disclosure. [Figure 5C] FIG. 1 is a micrograph showing a close-up of a peeled core-shell microneedle with a magnified view of the cap peeled from the base, in accordance with one or more embodiments of the present disclosure. [Figure 6A] 1 is a graph comparing cumulative levonorgestrel (LGN) release as a function of time from a core-shell microneedle patch and a conventional microneedle patch according to one embodiment of the present disclosure. [Figure 6B]1 depicts an exemplary core-shell microneedle according to one or more embodiments of the present disclosure. [Figure 6C] 1 depicts an exemplary conventional (core only) microneedle, in accordance with one or more embodiments of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Microneedles, microneedle arrays, and microneedle patches have been developed, in which the microneedles have a drug-containing core that remains isolated (encapsulated) in a shell and cap structure following in vivo insertion and detachment from the microneedle patch, thereby allowing the drug from the isolated microneedle core to be slowly released into the patient's tissue over an extended period of time. Specifically, the shell (and optionally the cap) acts as a diffusion membrane that controls the release of the drug. The shell and cap structure may be formed, for example, of one or more hydrophobic or water-insoluble polymers, which may be biodegradable.

[0012] The microneedles are also configured, for example, to have a geometry, configuration, and mechanical properties that allow them 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.

[0013] In some embodiments, the microneedles can advantageously control drug release over an extended period of time, which can be from 30 days to a year, for example, at least 2, 3, 4, 5, or 6 months. Drug release can occur continuously over an extended period of time, or can be delayed until an extended period of time has passed, which can be particularly useful as a vaccine booster.

[0014] In addition, methods have been developed for making such microneedle arrays and patches, which in preferred embodiments may involve using a single mold to form all of the structural components of the microneedles and backing, making the methods easier and more cost-effective for large-scale production than conventional methods for making microneedles with drug cores.

[0015] Microneedle patch In some embodiments, the microneedle patch includes a backing layer and an array of microneedles extending from the backing layer, the microneedles having a drug-containing core portion, a shell portion, and a cap portion, the core portion being encapsulated (or covered) within the shell portion and the cap portion. The microneedles are configured to be inserted into mammalian tissue. In some preferred embodiments, the microneedles are configured to separate from the backing layer and remain embedded within the tissue. In preferred embodiments, the shell portion and / or the cap portion are biodegradable and delay release of the drug over an extended period of time.

[0016] In some preferred embodiments, the microneedles are configured to release the drug via diffusion through the shell portion only, through the cap portion only, or through both the shell and cap portions. The drug is considered to be released from the core by diffusion (i.e., through the biodegradable polymer shell and / or cap) even if the shell or cap is biodegrading during the drug release process.

[0017] The shell and cap portions may be formed of essentially any suitable biocompatible material that is capable of separating the core portion in vivo over an extended period of time, and preferably is substantially water-insoluble so as to be capable of biodegrading during and / or after performing this function.

[0018] In some preferred embodiments, the shell and cap portions are formed of one or more biodegradable polymers. In some embodiments, the shell and cap 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.

[0019] In some preferred embodiments, the backing layer comprises one or more water-soluble materials that facilitate separation of the microneedles from the backing layer, subsequent in vivo insertion of the microneedles, and exposure of the backing layer to interstitial fluid or other liquids. In some embodiments, the backing layer comprises polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), one or more sugars, such as sucrose, or combinations thereof. In some embodiments, the backing layer comprises an effervescent material that reacts and effervesces upon exposure of the backing layer to interstitial fluid or other liquids, which may accelerate separation of the microneedles from the backing layer. For example, the backing layer may comprise sodium bicarbonate, citric acid, or another effervescent material, as described, for example, in U.S. Patent Application Publication No. 2020 / 0238065 to Prausnitz et al.

[0020] In other embodiments, the interface between the backing layer and the cap portion includes a mechanical weakness such that the microneedles can "split" from the backing. For example, the mechanical weakness can be in the form of a cavity or bubble that reduces the strength of the interface between the backing and the cap. The microneedle patch can include a pedestal formed at the interface between the backing layer and each of the cap portions of the microneedles. The pedestal can be, for example, an integrally formed (e.g., molded) part of the backing layer.

[0021] The core portion may consist of one or more drugs, or more frequently, comprises one or more drugs dispersed in a suitable matrix material. The core matrix material may further control the release of the drug, for example, acting as a rate-limiting barrier to diffusion. In some embodiments, the core matrix material comprises a biodegradable polymer in which the drug is dissolved or dispersed. In some embodiments, the core biodegradable polymer comprises poly(lactide-co-glycolide) (PLGA).

[0022] As mentioned above, the microneedles may be configured to separate from the backing layer. This separation may be triggered by a process including aqueous dissolution of the material forming at least a portion of the backing layer, as also described above. Alternatively or additionally, a mechanical shear or axial force may be applied to the backing layer followed by insertion of the microneedle, which creates a mechanical break between the microneedle and the backing layer, for example at the interface between the cap portion and the backing layer. In some embodiments, the microneedles are configured to separate within a period of 1 minute after the microneedle is inserted into the skin or other mammalian tissue. In some other embodiments, the microneedles are configured to separate within a period of 1 minute to 10 minutes, such as 2 minutes to 9 minutes, 3 minutes to 8 minutes, 4 minutes to 6 minutes, or preferably 5 minutes. In some further embodiments, the microneedles are configured to separate in less than 1 minute, such as 45 seconds, 30 seconds, 15 seconds, 10 seconds, or preferably 5 seconds.

[0023] Based on the drug of choice, the materials selected for the other structural components of the microneedle, and the thickness of the shell and cap portions, the release of the drug from the separate microneedles can be continuous for a period of one month to one year. As used herein, "continuous release" refers to any mechanism of drug release that occurs over a predetermined period of time. For example, the continuous release can be a constant release profile, a release profile in which there is an initial burst of release, an inactive period, followed by a constant release, or a variable release profile with short periodic bursts of release throughout the predetermined period of time. In some embodiments, the microneedles are configured to continuously release the drug from the separate microneedles for a period of two months to six months. In some embodiments, the drug comprises a steroid. In some embodiments, the drug comprises a hormone, such as levonorgestrel or another contraceptive hormone.

[0024] The agent may be intended for systemic administration or effect, or may be targeted to the tissue at the delivery site. For example, the agent may be effective in treating a skin condition, i.e., the agent is administered to the skin to treat or prevent a skin condition, such as eczema, psoriasis, rosacea, acne, etc.

[0025] In some embodiments, the agent is a vaccine used to prevent infectious diseases such as influenza, measles, COVID, etc.

[0026] In some preferred embodiments, the shell and cap portions are not formed with a composition containing a drug, so that the entire drug payload is located in the core portion during manufacturing. In some cases, even during manufacturing, a small amount of drug may be present in the shell and cap, but the goal in such cases is that the fraction of drug in the shell and cap (even after storage) is less than 10% by weight, 5% by weight, or less than 2% by weight. In some other embodiments, the shell and / or cap portions also intentionally contain a drug. The drug may be the same as or different from the drug in the core portion.

[0027] One example of a microneedle patch having an array of microneedles is depicted in FIG. 1. The microneedle patch 100 includes a backing layer 110 from which extend microneedles 120 in a 10×10 array. The phrases "backing layer" and "base substrate" or "substrate" are used interchangeably herein. Each microneedle 120 has a proximal end 122 attached directly to the backing layer 110 or indirectly attached via one or more proximal portions or pedestals 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 end 122 and the distal end 126 of the microneedle 120. Other geometries are possible.

[0028] The microneedles of the microneedle patch are designed to be inserted into the skin or another biological tissue and detach from the backing layer immediately after insertion. In some embodiments, the microneedles 120 and / or the backing layer 110, preferably the base 124, include features such as pre-break regions, porous cell structures, foam materials, and / or water-soluble materials that facilitate separation of the microneedles 120 from the backing 110. As used herein with respect to separation of the microneedles, the terms "facilitating", "facilitating", and the like refer to features that (i) reduce the minimum force (e.g., axial or shear force) required to achieve separation of the microneedles, (ii) reduce the amount of backing material that must be dissolved to achieve separation of the microneedles (e.g., cell structures may provide thinner walls to the microneedles), (iii) increase the dissolution rate of the backing layer to which the microneedles are attached, or (iv) a combination thereof.

[0029] Upon detachment, the microneedle may 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, all of the structure of the embedded microneedle is below the tissue surface.

[0030] In some embodiments, the backing layer 110 or more preferably the base 124 comprises an effervescent material to facilitate separation of the microneedles from the backing. As used herein, the phrase "effervescent material" refers to a material or combination of materials that generates a gas upon contact with an aqueous liquid. When the microneedle patch comprises an effervescent material, the effervescent material may react upon contact with an aqueous liquid, such as a biological fluid (e.g., interstitial fluid) on, in, or under the living tissue, thereby generating a gas to facilitate dissolution of the backing. In some preferred embodiments, the backing layer 110 comprises polyvinylpyrrolidone (PVP) with ethanol, sodium bicarbonate, and citric acid to generate effervescence that facilitates separation of the microneedles from the backing.

[0031] In some embodiments, the backing layer 110 comprises a water-soluble material effective to facilitate separation of the microneedles from the backing. As used herein, the phrases "water-soluble material", "hydrophilic material", and the like refer to a material or combination of materials that dissolves or substantially dissolves upon contact with an aqueous liquid. When the microneedle patch comprises a water-soluble material, the water-soluble material may contact an aqueous liquid, such as a biological fluid (e.g., interstitial fluid) above, in, or below a living 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.

[0032] In some other embodiments, the interface between the backing layer and the cap portion includes a mechanical weakness such that the microneedle may be "split" from the backing. For example, the mechanical weakness may be in the form of a cavity or bubble that reduces the strength of the interface between the backing and the cap.

[0033] As shown in FIG. 2, the microneedle patch 110 includes microneedles 120, each of which includes a shell portion 130, a core portion 132, and a cap portion 134 adjacent to the backing layer 110. The shell portion 130 may surround most sides of the core portion 132, and the cap portion 134 covers where the shell 130 does not cover, such that the shell 130 and cap 134 together surround the core region 132. In some preferred embodiments, the core 132 may be in the shape of a cone, such that the shell 130 is in the shape of a hollow cone and the cap 134 is in the shape of a truncated cone. While it is preferred that the shell 130 and cap 134 completely surround the core 132, it will be understood that the shell 130 and / or cap 134 may have gaps, cracks, or other imperfections such that the shell 130 and cap 134 do not completely encase the core 132.

[0034] In some embodiments, the length of the microneedles may be about 50 μm to 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 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).

[0035] In some embodiments, the length of the pedestal 124 can be between about 50 μm and 1000 μm, between about 100 μm and about 750 μm, between about 100 μm and about 500 μm, between about 200 μm and about 400 μm, or between about 500 μm and 1000 μm.

[0036] In some embodiments, the shell 130 and the cap 134 comprise a biocompatible polymer with an expected degradation time of greater than six months. In some embodiments, the biocompatible polymer is hydrophobic and / or water insoluble. For example, the biocompatible polymer 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 upon contact with aqueous liquids, except when the material biodegrades after contact with the aqueous liquid to produce water soluble degradation products. In some preferred embodiments, the shell 130 and the cap 134 comprise different biocompatible polymers. For example, the shell 130 comprises PLLA and the cap 134 comprises PLA.

[0037] In some embodiments, the core portion 132 includes 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.

[0038] A wide range of drugs may be formulated for delivery to biological tissues using the core-shell microneedle patch disclosed herein. As used herein, the term "drug" refers to prophylactic, therapeutic, or diagnostic agents useful in medical applications, as well as agents used in cosmetics, cosmeceuticals, tattoos, and other non-medical applications. The drug may be any suitable active pharmaceutical ingredient or allergen. In some embodiments, the drug may be selected from small molecules and larger biotechnologically produced or purified molecules (e.g., peptides, proteins, DNA, RNA, aptamers). In some preferred embodiments, the drug is a hormone or steroid. Hormones include levonorgestrel, etonogestrel, nestrone, and other progestins, as well as contraceptive hormones such as estrogen, estradiol, and other estrogens. In some embodiments, the drug has a dermatological indication. In some embodiments, the drug comprises a vaccine. Examples of vaccines include vaccines for infectious diseases, therapeutic vaccines for cancer, neurological disorders, allergies, and smoking cessation, or other addictions.

[0039] In some embodiments, the microneedles in a given array of microneedles all contain the same drug. In some other embodiments, the microneedles in a given array of microneedles may contain different drugs. For example, the drug may be different in each microneedle, in different rows of microneedles, or in sections / regions of the microneedle array. For example, the drug may be different in the core, shell, and / or cap of the microneedle.

[0040] In some preferred embodiments, the core portion 132 is designed to continuously release the agent from the microneedle via diffusion through the shell portion 130 and / or cap portion 134 at a controlled rate over an extended period of time. In some embodiments, the extended period of time is one month, two months, three months, four months, five months, six months, one year, or longer. In some embodiments, the release rate is substantially zero order, which is achieved by diffusion across a rate-controlling membrane provided by the shell portion and / or cap portion of the microneedle. In some other embodiments, the release rate is substantially first order. In further embodiments, the release is pulsatile over the duration of the release (e.g., a single bolus is administered daily over an extended treatment period).

[0041] 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 a handle layer, on the side of the backing layer opposite the microneedles. Examples of such other additional structural components are described in U.S. Patent No. 10,265,511 to McAllister et al., which is incorporated herein by reference.

[0042] Method for producing microneedle array and microneedle patch The microneedles described herein can be made by any suitable process. However, in some preferred embodiments, the array of microneedles is made using a molding process that is advantageously highly scalable. In particularly preferred embodiments, the manufacturing process involves a series of solution casting steps carried out in the same mold, which is suitable for low-cost mass production. This is in contrast to efforts by others to make core-shell microneedles, where the shell, core, cap, and backing layers of the patch are each manufactured individually using separate molds and processes, and then assembled into a complete microneedle patch using a process that requires many more steps.

[0043] The filling and molding steps described herein may be referred to as "casting". In some embodiments, casting methods, molds, and other equipment may be adapted from those known in the art, such as those described in U.S. Patent No. 10,828,478 to McAllister et al., which is incorporated herein by reference. The method for making the microneedles is preferably carried out under a minimum ISO 7 (Class 10,000) process or ISO 5 (Class 100) process.

[0044] In certain embodiments, a method for making a microneedle patch includes (i) forming a plurality of microneedles in a mold, each microneedle having a core portion containing a drug, and a shell portion and a cap portion surrounding the core portion, (ii) forming a backing layer connected to the base end of each of the plurality of microneedles, and then (iii) removing the backing layer and the microneedles from the gold mold, thereby producing a microneedle patch. The method may further include forming an array of pedestals for each of the microneedles. For example, the mold may include a funnel-shaped portion near the opening, such that the pedestals (i.e., the funnel-shaped portion) are formed simultaneously with the formation of the backing layer. In this way, the backing layer includes an array of pedestals, each connected to the base end of one of the plurality of microneedles.

[0045] In certain embodiments, a method for making microneedles includes (i) casting a first composition into a mold having a cavity defining a plurality of microneedles to form a shell portion of the mold, (ii) casting a second composition comprising an agent into the 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 cap portion, and (iv) casting a fourth composition onto the cap portion in the mold to form a backing layer, thereby producing a microneedle patch comprising an array of microneedles extending from the backing layer, each of the microneedles comprising a core portion comprising an agent encapsulated within the shell portion and the cap portion. In some preferred embodiments, the first, second, third, and fourth compositions each comprise a fluid comprising a polymeric structural material dissolved in a solvent, and the solvent of the second, third, and fourth compositions is substantially a non-solvent for the polymeric structural material of the first, second, and third compositions, respectively. For example, the polymeric structural materials of the first, second, and third compositions can each be a different biodegradable polymer, and the polymeric structural material of the fourth composition can be a water-soluble polymer, such that a different solvent can be selected for each polymer that does not dissolve or degrade the polymeric structural portion of the microneedles formed in the preceding step. The solvent of the composition can be a substantially non-solvent for the drug present in the second composition.

[0046] Centrifugation, drying, and / or vacuum may be used to aid in forming each of the portions of the microneedle patch. For example, centrifugation and / or vacuum may help to uniformly distribute the first composition within the mold to form a shell and / or remove any excess third composition so that the microneedles are uniformly capped.

[0047] An example of a manufacturing process 300 for making the core-shell microneedles described herein is shown in FIG. 3. The manufacturing process includes at least five steps: (1) a first cast-fill step (310) to form a shell portion; (2) a second cast-fill step (320) to form a core portion; (3) a third cast-fill step (330) to form a cap portion; (4) a fourth cast-fill step (340) to form a backing layer; and (5) a step of demolding the resulting microneedle patch (350). The mold is a negative mold for the microneedles and at least a part of the backing layer. A suitable microneedle mold typically contains an array of 10 to 1000 microneedles and may be made of silicone or other elastomeric materials as known in the art.

[0048] To form the shell portion of the microneedle, a first cast composition is prepared and then transferred onto the mold (310). This may be referred to as the first cast. In some embodiments, the first cast 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 end capped), and the solvent is dioxane or another suitable solvent that can expand in the mold to form a "skin" of the first cast on the mold cavity walls. The mold with the first cast is then centrifuged to evenly distribute the first cast to coat the mold and form a film that is a uniform shell portion (315). The mold and film are typically dried (e.g., by heat and vacuum) to remove the solvent and convert the film into a solid shell.

[0049] Next, a second cast composition is prepared and then transferred onto the mold to form the core portion of the microneedle (320). This may be referred to as the second cast. In some embodiments, the second cast is formed by dissolving or dispersing the drug and a suitable structural material for the core 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 an 85 / 15 lactide / glycolide molar ratio (ester end cap) and the solvent is diglyme / water (95% / 5%, v / v). The mold with the second cast is then centrifuged to draw the cast material into the mold and into the interior of the shell (325). The mold and film are typically dried (e.g., by heat and vacuum) to remove the solvent and solidify the core portion. In this case, the second casting solvent (diglyme / water) is essentially a non-solvent for the PLLA shell created by the first cast.

[0050] Next, a third cast composition is prepared and then transferred onto the mold (330) to form the cap portion of the microneedle. This may be referred to as the third cast. In some embodiments, the third cast 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 end cap) and the solvent is dimethylacetamide. The mold with the third cast is then centrifuged to draw the cast material into the mold so that the microneedles are uniformly capped and to remove any excess third cast (335). The mold and film are typically dried (e.g., by heat and vacuum) to remove the solvent and solidify the cap portion. In this case, the third cast solvent (dimethylacetamide) is substantially a non-solvent for the PLLA shell formed by the first cast.

[0051] Next, a fourth cast composition is prepared and then transferred onto the mold (340) to form the backing layer of the microneedle patch. This may be referred to as the fourth cast. In some embodiments, the fourth cast 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 solvent mixture. In one embodiment, the structural material is a combination of PVA and sucrose to obtain the desired combination of mechanical strength and water solubility. In another embodiment, polyvinylpyrrolidone (PVP) may be combined with sodium bicarbonate and citric acid in ethanol, which generates effervescence upon contact with the aqueous interstitial fluid in the skin to facilitate separation of the microneedles from the backing layer. Absolute ethanol is a suitable solvent because it dissolves the citric acid and supports the suspension of sodium bicarbonate, but does not cause their aqueous effervescent reaction during manufacture. PVP can serve as a suitable matrix material for the backing layer because it dissolves in ethanol during manufacturing and in water during application of the microneedle patch to the skin.

[0052] The mold with the fourth cast is then dried (e.g., by heat and vacuum) to remove the solvent and solidify the backing layer, where the fourth cast solvent (water or ethanol) is substantially a non-solvent for all three polymers of the microneedles, i.e., PLA found in the third cast, PLGA in the second cast, and PLLA found in the first cast.

[0053] After the final cast is substantially dry, the core-shell microneedle patch is removed, ie, demolded, from the mold (350).

[0054] As mentioned above, each of the casts may contain a solvent with different dissolving properties to prevent the previously cast composition from dissolving during the manufacture of the microneedle patch. In some embodiments, the solvent of the second, third, and fourth casts must not dissolve the polymer of the first cast. In some embodiments, the first cast solvent must be at least different from the second cast solvent, the second cast solvent must be at least different from the first and third cast solvents, the third cast solvent must be at least different from the second and fourth cast solvents, and the fourth cast solvent must be at least different from the third cast solvent. In some other embodiments, each cast contains a different solvent. In general, the second and fourth casts should not contact each other, so it is not important whether the fourth cast dissolves the second cast. However, in a preferred embodiment, the fourth cast does not dissolve the second cast, but in principle it can dissolve it as long as it does not dissolve the first or third casts.

[0055] In some other embodiments, one or more of the casts are formed without solvent by using a molten composition, for example, the structural polymeric material of the shell, core, cap, or backing layer part is cast at a temperature higher than its melting point, and then cooled / solidified to form that part of the microneedle patch. However, the temperature of the cast should not be high enough to cause decomposition or damage to the drug contained in the second cast. For example, a biocompatible polymer with a lower melting point, such as polycaprolactone (PCL) or its copolymers, may not be preferred for use in the second cast, since PCL is advantageously combined with the drug at a lower temperature.

[0056] In some such cases, each cast may have a different melting point. For example, the first cast may have the highest relative melting point, the second cast must have a melting point lower than that of the first cast but higher than that of the third cast, the third cast must have a melting point lower than that of the second cast but higher than that of the fourth cast, and the fourth cast must have the lowest relative melting point. In these embodiments, the melting points of at least the first and third casts must be high enough to prevent melting upon insertion, i.e., the melting points of the first and third casts must be higher than body temperature to maintain the solid structure of the shell and cap during long-term in vivo drug release by diffusion of drug through the shell (and cap).

[0057] In some other embodiments, a combination of melt-cast solutions and solvent-cast solutions may be used, for example, one cast may be formed with the molten composition and the remaining three casts may be formed with a solvent, two casts may be formed with the molten composition and the remaining two casts may be formed with a solvent, or three casts may be formed with a molten solution and the remaining cast may be formed with a solvent.

[0058] How to use The microneedle arrays described herein can be used to administer various substances into biological tissue sites of humans or other mammals. 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 prevention or cosmetic enhancement. In a preferred embodiment, the method includes applying a microneedle patch comprising an array of core-shell microneedles to a skin surface in a manner that causes the microneedles to penetrate the stratum corneum and enter the viable epidermis and possibly the dermis. However, it is envisioned that the device and method may also be adapted to other biological tissues and other animals.

[0059] As used herein, the phrase "penetrating a tissue surface" includes at least the distal tip of the microneedle penetrating the biological tissue surface. In some embodiments, upon separation of the microneedle from the backing layer, the proximal end of the microneedle may be above the tissue surface, may be substantially flush with the tissue surface, or may preferably be below the tissue surface.

[0060] Microneedle patches can be self-administered or can be administered by another individual (e.g., a parent, guardian, or healthcare professional).

[0061] The methods described herein further include a simple and effective method of administering a drug to a patient by 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, either 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.

[0062] Following administration, the backing layer (and any remaining microneedle patch) may be removed from the patient's skin or other tissue surface.

[0063] In some preferred embodiments, the microneedle patch described herein is used to administer drugs to the skin of a patient over an extended period of time. In some embodiments, the administration method involves inserting the microneedles of the patch across the stratum corneum (the outer 10-20 microns of skin that is a barrier to transdermal transport) into the viable epidermis and possibly the dermis. The small size of the microneedles allows for targeting of the intradermal space with 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 route for administering vaccines and other prophylactic, therapeutic, and cosmetic agents. In some preferred embodiments, the drug diffuses from the core portion of the inserted microneedle through the shell and / or cap portion into the intradermal space, releasing the drug into the interstitial fluid in the skin.

[0064] 4A-4F illustrate one example of a method (400) for administering a medicament to a patient's skin using microneedles as described herein. The method includes providing a microneedle patch 100 as described herein, aligning the microneedle patch 100 with a target site on the surface of the skin 402 (410), and inserting the microneedle patch into the skin 402 (420) to push the microneedle 120 through at least the stratum corneum 404 and into the viable epidermal 406 and possibly dermal 408 layers of the skin. The microneedle 120 is then separated from the backing layer 110 (430) such that the microneedle remains embedded within the skin 402. Separation may occur immediately after insertion, for example, if the backing layer 110 and / or proximal end 122 of the microneedle are formed of a breakable water-soluble and / or foamable material, allowing removal of the backing 110 within seconds or minutes of inserting the microneedle. While the microneedle 120 remains within the skin 402, the drug 136 diffuses from the core portion 132 either through only the shell portion 130 of the microneedle (440), as in FIG. 4D, through only the cap portion 134 of the microneedle 120 (450), as shown in FIG. 4E, or through a portion of both the shell 130 and the cap 134 of the microneedle (460), as shown in FIG. 4F.

[0065] The shell, cap, and other non-drug materials (e.g., matrix materials) of the core portion may biodegrade at a rate that does not adversely affect the controlled diffusion rate of the drug therethrough. In this manner, release of the drug from the microneedle completes biodegradation of the remaining shell, cap, and matrix materials of the core portion.

[0066] It has been shown, and is often preferred, that the microneedles separate from the backing before the drug is released from the core, but this is not required, for example, the drug may begin to diffuse from the core at least through the shell and / or cap before and / or during separation from the backing, or the microneedles may not separate from the backing at all.

[0067] The present invention can be further understood with reference to the following non-limiting examples.

[0068] Example 1: Design and fabrication of a core-shell microneedle patch for releasing LGN To create a core-shell microneedle patch for the release of the contraceptive hormone levonorgestrel (LNG) over a period of months, high molecular weight PLLA (L-lactide, ester end-capped, intrinsic viscosity 0.9 dL / g) was selected as the rate-controlling shell material due to its known crystallinity and very slow biodegradation rate, which should allow 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 it is biodegradable on a time scale consistent with the release of encapsulated LNG over a period of months, has sufficient mechanical strength for the microneedles, and can be formulated using solvents that do not dissolve the PLLA shell during fabrication. LNG was selected as the contraceptive hormone in the microneedle core because it is potent as a contraceptive hormone, has low solubility in water, and is widely used in commercially available long-acting contraceptive products with good safety and efficacy profiles. PLA (poly(D,L-lactide, ester end-capped, intrinsic viscosity 0.5 dL / g) was chosen as the polymer for the microneedle caps because it has a slow degradation rate, sufficient mechanical strength for the microneedles, and can be formulated using solvents that do not dissolve the PLLA shell during fabrication.

[0069] To fabricate the microneedle patches, molds of polydimethylsiloxane (PDMS) (Dow Corning, Midland, MI) were used. In each PDMS mold, 112 microneedle cavities were arranged in a circular array with a diameter of 1.1 cm. The center-to-center spacing between the microneedles was 900 μm, and each microneedle cavity was cone-shaped with a base radius of 150 μm, a height of 600 μm, and a tip radius of about 10 μm. Above each microneedle cavity was an area for backing the patch, which included an array of pedestals, each with a base diameter of 600 μm, a top diameter of 150 μm, and a height of 350 μm, and the pedestals were positioned at the base of each microneedle to raise the microneedle above the base of the backing, i.e., the base structure of the microneedle patch.

[0070] The fabrication process was designed as a series of solution casting steps onto a single silicone (PDMS) mold, as described with respect to Figure 3. To fabricate the core-shell microneedle patches, three solutions were cast in sequence to create the shell, core, and cap structures of the microneedle.

[0071] The first solution contained 1% (w / v) PLLA in dioxane. To prepare this solution, 0.1 g of PLLA (L-lactide, ester end-capped, 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 main solvent because it is a good solvent for PLLA and helps it expand into the PDMS mold and form a "skin" of PLLA on the mold cavity walls. In this way, a shell structure can be formed on the inner surface of the mold cavity without substantial accumulation of PLLA at the tip of the needle cavity. 20 microliters of this first casting solution was applied to the surface of the microneedle mold and then centrifuged at 3200 g for 20 minutes to form a film of PLLA that would become the outer shell of the microneedles in the mold.

[0072] Next, a second casting solution was prepared for the core, consisting of 8% (w / v) solids, PLGA / LNG (60% / 40%, w / w) in diglyme / water (95% / 5%, v / v). To make this solution, 0.096 g of PLGA (D,L-lactide, ester end-capped, 85 / 15 lactide / glycolide molar ratio, intrinsic viscosity 0.5 dL / g, Durect) and 0.064 g of LNG (Chemo Industriale Chimica SRL Saronno, Italy) were dissolved in a mixture of 1.5 mL of diglyme (Sigma-Aldrich) and 0.5 mL of tetrahydrofuran (THF, Thermo Fisher Scientific, Waltham, MA), and then the LNG was precipitated by slow evaporation of the THF to produce a colloidal suspension of LNG particles in the PLGA solution. For example, as described in U.S. Patent Application Publication No. 2022 / 0401715, precipitation of LNG in the second casting solution may help prevent migration of soluble LNG into the shell and / or cap, where LNG may be released more quickly after the microneedle patch is inserted into tissue. After evaporation of essentially all of the THF, additional diglyme and deionized (DI) water were added to obtain a final casting solution containing LNG, PLGA, diglyme, and water.

[0073] Fifteen microliters of the second casting solution was added to the top of the PDMS mold in the shell and then centrifuged at 3200 g for 20 minutes to form the cores of the microneedles in the mold. Then, 20 μL of diglyme / water (95% / 5%, w / w) was pipetted onto the mold, and after waiting 5 minutes, the mold was centrifuged at 3200 g for 20 minutes to wash the residual casting solution on the mold into the mold cavity. The mold was then dried in a 60° C. oven under vacuum for 12 hours.

[0074] The third casting solution for the cap contained 3.5% (w / v) PLA (D,L-lactide, ester end-capped, intrinsic viscosity 0.5 dL / g, Durect) in dimethylacetamide. Dimethylacetamide was used as the solvent because it is a good solvent for the medium viscosity D,L-PLA used for the cap, but not for the high viscosity PLLA used for the shell. Additionally, its solubility properties, low volatility, and low mold swelling tendency (i.e., unlike dioxane) minimized the formation of a PLA film on the PDMS mold surface above the microneedle cap during the casting process, which is important to allow peeling of the microneedles after insertion into the skin.

[0075] This solution was applied onto the dried mold and then centrifuged at 3200g for 20 minutes to form the cap and encapsulate the core within the cap and shell. Sealing the core-shell structure is effective to eliminate any holes or gaps that would allow LNG to leak out of the core during the release process. The mold was then placed in a 60°C oven with vacuum for 12 hours for another drying cycle.

[0076] As a final fabrication step, 80 μL of backing solution consisting of 18% (w / v) PVA (molecular weight: 6 kDa, Sigma-Aldrich) and 18% (w / v) sucrose (Sigma-Aldrich) dissolved in DI water was added to the dried PDMS mold surface to form a patch backing.

[0077] After air drying for 3 hours, the molds were transferred to a desiccator and stored for 2 days, and then released with adhesive tape.

[0078] Example 2: Characterization of Core-Shell Microneedle Patches As shown in Figures 5A-5C, the core-shell microneedles have a conical shape connected to a tapered base, designed to facilitate the insertion of the microneedle deep into the skin. Closer examination by scanning electron microscopy (SEM) showed an interface layer between the conical microneedle and the base, which is a PLA cap, as well as a thin layer, which is a PLLA shell, covering the outer microneedle surface. Inside the microneedle was a mixture of LNG crystals and PLGA polymer that formed the core of the microneedle acting as a drug reservoir. In this way, the microneedle core containing LNG and PLGA polymer was completely enveloped by the outer shell-cap polymer pocket made of PLLA / PLA. A loading of 0.28 ± 0.01 mg of LNG per patch was determined by ultra-performance liquid chromatography (UPLC) of the microneedles after dissolution in acetonitrile.

[0079] To further examine the core-shell microneedle structure, confocal microscopy revealed that the core, labeled with red fluorescence using Nile Red dye, was surrounded by a shell and cap, labeled with green fluorescence using fluorescein isothiocyanate (FITC). This imaging further verified the core-shell microneedle structure shown by SEM and designed by the fabrication procedure.

[0080] As an additional test to investigate whether LNG was localized within the microneedle core, confocal Raman microscopy was used to compare the compositional distribution of core-shell microneedles with microneedle cores fabricated without a shell.

[0081] The microneedle patches were cut in half with a razor blade and warmed in 50 mL of water for 15 min to dissolve the water-soluble backing. The tips of the microneedles were collected and placed on a glass slide covered with aluminum foil and dried in a desiccator for at least 4 days, followed by cutting the microneedles perpendicular to their central axis with a razor blade to obtain cross sections. The cross sections were then mapped by confocal Raman microscopy (Via Qontor, Renishaw, Wotton-under-Edge, UK) with an excitation wavelength of 785 nm, operated at 300 mW with a 1 s exposure time. A 50x long working distance objective was used to measure 1050.08 cm every 2 μm along the x and y axes. -1 ~2083.76cm -1 The Raman spectrum was collected at 1600 cm -1 ~1700cm -1 The characteristic LNG peak was observed at 1700 cm -1 Characteristic PLA and PLGA peaks were observed at 100 nm. Spectra were processed to quantify peak sizes by signal-to-baseline ratio and converted to pseudocolor images by WiRE5 software (Renishaw, New Mills, UK). At least six microneedle tips were examined in each experimental group.

[0082] In the core-only microneedles, the LNG and PLGA were distributed throughout the microneedle. In contrast, the LNG was encapsulated in the core section of the core-shell microneedle and was surrounded by an outer layer of PLLA / PLA that formed a shell and cap, which also contained the LNG. Raman microscopy images also confirmed a shell thickness of approximately 20 μm.

[0083] PLLA, PLA, and PLGA have a peak at 1770 cm -1It was difficult to distinguish the Raman spectra between these polymers, as they exhibited similar signal intensities of 100 nm and were therefore reported as a combined PLGA / PLA signal. The PLGA Raman signal in the core of the core-shell microneedles appeared weaker than the PLGA signal in the center of the core-only sample. However, quantitative analysis of the PLGA signal values ​​in the core was similar to the core-shell and core-only samples. The apparent weakness of the PLGA signal in the core of the core-shell sample can be explained by the strong PLLA / PLA signal generated by the dense shell, which made the PLGA core appear weaker due to the automatic calibration of the signal intensity to avoid saturation of the shell PLLA / PLA signal.

[0084] Example 3: Sealing of the core of a core-shell microneedle patch The sustained release from the core-shell microneedles is a result of the efficient encapsulation of the drug inside the shell-cap pocket. To evaluate the sealing effect of the core-shell microneedles in vitro, a second casting solution used to fabricate the core part of the microneedle was made using a solution of 18% (w / v) PVA and 1% (w / v) fluorescein isothiocyanate-labeled serum albumin (FITC-BSA) dissolved in phosphate buffered saline (PBS) while keeping the shell and cap formulations the same. Each microneedle patch was placed in 20 mL of PBS, and the microneedle morphology and fluorescence were imaged using bright field and fluorescence optics by fluorescence microscopy (SZX16, Olympus, Tokyo, Japan) at 0 h, 0.5 h, 1 h, 3 h, 6 h, 12 h, 24 h, 48 h, 72 h, and 96 h.

[0085] The fluorescence intensity of FITC-BSA in the microneedle cores remained strong in PBS for 1 h, then gradually weakened over 3-4 days. In contrast, microneedles made with the same core material, with a shell but no cap, or with neither a cap nor a shell, dissolved in 25 min or 2 min, respectively. This demonstrates the significant diffusion barrier created around the core by the shell and cap.

[0086] Example 4: Ex vivo insertion of core-shell microneedle patches into the skin To evaluate the penetration, peeling, and delivery efficiency of the microneedle patch, the patch backing was changed to a foamable backing made of 13% (w / v) PVP with two molecular weights (360 / 55 kDa, 50 / 50%, w / v, Sigma-Aldrich) and 4% (w / v) citric acid (Sigma-Aldrich) in pure absolute ethanol (Koptec, King of Prussia, PA) with 5% (w / v) sodium bicarbonate (Sigma-Aldrich) suspended in the solution. PVP was selected as the matrix material for the backing due to its solubility in ethanol during fabrication and in water during application of the microneedle patch to the skin. After air drying for 1 h, the mold was placed in a desiccator at room temperature (20°C-25°C) overnight to completely dry, after which a layer of adhesive paper was gently stuck onto the top surface of the PDMS mold and used to carefully peel the patch from the mold. The released microneedle patch was stored in a desiccator until use.

[0087] These microneedle patches containing Nile Red dye were inserted into ex vivo skin from pigs by pressing with a thumb for 10 seconds, then waiting for an additional 50 seconds without pressure to allow for dissolution of the foam backing and separation of the microneedles from the patch backing. After removal of the patch backing, the skin containing the embedded microneedles was examined by optical microscopy (Olympus, Tokyo, Japan) to confirm the detached microneedles embedded in the skin. In some cases, a cotton swab was gently and repeatedly rubbed across the site of microneedle patch treatment for 10 seconds to remove any detached microneedles that partially protruded above the skin surface.

[0088] After application to the skin for 1 minute, about 95% of the microneedles per patch were detached from the patch backing and retained in the skin, and more than 90% of the model drug (fluorescent dye) was delivered to the skin. The penetration depth of the core-shell microneedles into the skin after separation from the patch backing was about 250 μm. This demonstrates the effective detachment and delivery of microneedles in the skin using the core-shell microneedle patch with the foam patch backing.

[0089] To assess only microneedle patch penetration, the patch was applied to the skin with a thumb and quickly removed. The skin was then covered with gentian violet solution (Humco, Linden, TX) for 10 minutes to stain the microneedle penetration site, and then cleaned with an alcohol-based swab to remove residual dye from the skin surface.

[0090] Penetration and peel efficiency was 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). Delivery efficiency was calculated by dividing the amount of Nile Red dye in the skin (measured by fluorescence spectrometry) (determined by subtracting the residual microneedle dye 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.

[0091] Example 5: Release of LNG from core-shell microneedle patches in vitro The release kinetics of LNG from core-shell microneedles in vitro was studied. The in vitro release data could reasonably predict the in vivo release behavior, since previous studies showed good in vitro and in vivo correlation of LNG release in rats from microneedles formulated with PLA and PLGA when compared to LNG release at 37° C. in a release medium consisting of PBS containing 20% ​​ethanol.

[0092] To evaluate the in vitro release of LNG from the microneedle patches, PBS (137 mM NaCl, 2.68 mM KCl, 10.14 mM NaCl, 2.5 mM KCl, 1.0 mM NaCl) supplemented with 20% (w / v) ethanol was used. 2 HPO 4 , 1.76 mM KH 2 PO 4 ) release medium was used 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 warmed in a shaker water bath at 37°C with shaking at 80 rpm. At predetermined time points (0, 1, 3, 7, 14, 21, 28 days, and every 7 days thereafter until the 182-day time point was reached), 1mL of release medium was collected and replaced with the same amount of fresh medium.

[0093] The collected samples were analyzed by UPLC (Acquity, Waters Corp., Milford, MA) equipped with a UV detector to quantify the LNG concentration. LNG was analyzed using Acquity UPLC Ethylene-Bridged Hybrids (BEH) C at 50 °C. 18 Separation was performed on a column (100 mm x 2.1 mm ID, 1.7 μm particle size). 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 and the flow rate was 0.3 mL / min. The UV absorption of LNG was measured at 245 nm.

[0094] The cumulative LNG release (600) was plotted over time over the 182-day experiment, as shown in Figure 6 A. Because residual LNG remained in the microneedles at the end of the study, the release curve was extrapolated by continuing the release at the average release rate until 100% release was achieved, and this value was reported as the duration of LNG release.

[0095] For example, the core-only microneedle patch 620 of FIG. 6C exhibited a burst release of 22.6±2.0% LNG on day 1, whereas the burst release from the core-shell microneedle patch 610 of FIG. 6B, for example, was only 5.8±0.5% LNG on day 1, indicating that LNG encapsulation within the shell-cap pocket significantly reduced burst release (two-tailed Student's t-test, p<0.001).

[0096] The monolithic core-only microneedle patch 620 achieved a typical first-order release of LNG over 2.1±0.2 months, while the core-shell microneedle 610 achieved a significantly longer and near-zero order release over 6.2±0.1 months (two-tailed Student'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 that of the core-shell microneedle patch 610, which released 0.6±0.2% LNG per day (two-tailed Student's t-test, p<0.01). Overall, these data demonstrate that the core-shell microneedle patch 610 effectively encapsulates LNG within a rate-controlling shell-cap pocket to significantly reduce the drug release rate and achieve release kinetics over 6 months.

[0097] Some embodiments of the present disclosure can be described in consideration of one or more of the following.

[0098] Embodiment 1. A microneedle patch comprising a backing layer and an array of microneedles extending from the backing layer, each microneedle comprising a core portion containing a drug and a shell portion and a cap portion, the core portion being encapsulated within the shell portion and the cap portion, the microneedles configured to be inserted into mammalian tissue and separate from the backing layer, the shell portion and / or the cap portion being biodegradable and delaying release of the drug over an extended period of time.

[0099] Embodiment 2. A microneedle patch as described in embodiment 1, wherein the microneedles are configured to release the drug via diffusion through the shell portion only, through the cap portion only, or through the shell portion and the cap portion.

[0100] Embodiment 3. A microneedle patch according to embodiment 1 or 2, wherein the shell portion comprises polylactide (PLA) or poly(L-lactide) (PLLA).

[0101] Embodiment 4. A microneedle patch according to any one of embodiments 1 to 3, wherein the cap portion comprises polylactide (PLA) or poly(L-lactide) (PLLA).

[0102] Embodiment 5. A microneedle patch according to any one of embodiments 1 to 4, wherein the backing layer is formed from a water-soluble polymer.

[0103] Embodiment 6. A microneedle patch according to any one of embodiments 1 to 5, wherein the backing layer comprises polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), sucrose, or a combination thereof.

[0104] Embodiment 7. A 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.

[0105] Embodiment 8. A microneedle patch described in any one of embodiments 1 to 7, wherein the core portion comprises a biodegradable polymer in which a drug is dispersed.

[0106] Embodiment 9. The microneedle patch of claim 8, wherein the biodegradable polymer of the core portion comprises poly(lactide-co-glycolide) (PLGA).

[0107] Embodiment 10. A microneedle patch described in any one of embodiments 1 to 9, further comprising a seat between the backing layer and each of the cap portions of the microneedles.

[0108] Embodiment 11. A microneedle patch as described in embodiment 10, wherein the base is integrally formed with the backing layer.

[0109] Embodiment 12. A microneedle patch according to any one of embodiments 1 to 11, wherein the microneedles are configured to separate from the backing layer by a process comprising: (i) aqueous dissolution of a material forming at least a portion of the backing layer, the material optionally comprising a foamable material; and / or (ii) rupture of the interface of the cap portion and the backing layer.

[0110] Embodiment 13. A microneedle patch as described in embodiment 12, wherein the fracture is caused by an air pocket at the interface of the cap portion and the backing layer.

[0111] Embodiment 14. A microneedle patch as described in embodiment 12 or 13, wherein the cap portion comprises a hydrophobic material and the backing layer comprises a hydrophilic material, such that the interface between the cap portion and the backing layer is weak and susceptible to breakage.

[0112] Embodiment 15. A microneedle patch described in any one of embodiments 1 to 14, wherein the microneedles are configured to detach within a period of 1 minute after the microneedles are inserted into mammalian tissue.

[0113] Embodiment 16. A microneedle patch according to any one of embodiments 1 to 15, configured to continuously release a drug from the separated microneedles over a period of one month to one year.

[0114] Embodiment 17. A microneedle patch according to any one of embodiments 1 to 16, configured to continuously release a drug from the separated microneedles over a period of 2 to 6 months.

[0115] Embodiment 18. A microneedle patch described in any one of embodiments 1 to 17, wherein the drug comprises a steroid.

[0116] Embodiment 19. A microneedle patch according to any one of embodiments 1 to 17, wherein the medicament comprises a hormone, such as levonorgestrel, etonogestrel, nestorone, or another contraceptive hormone.

[0117] Embodiment 20. A microneedle patch according to any one of embodiments 1 to 17, wherein the drug is effective in treating a skin disease.

[0118] Embodiment 21. A microneedle patch described in any one of embodiments 1 and 3 to 15, wherein the drug comprises a vaccine.

[0119] Embodiment 22. A microneedle patch described in any one of embodiments 1 to 21, wherein the shell portion and / or the cap portion contain a drug that is the same as or different from the drug in the core portion.

[0120] Embodiment 23. A microneedle patch for administering a contraceptive or other medication, the patch comprising a backing layer comprising an array of pedestals, and an array of microneedles extending from each of the pedestals, the microneedles each comprising a core portion comprising a biodegradable polymer having a contraceptive or other medication dissolved or dispersed therein, and a water insoluble, preferably non-porous shell portion and a cap portion, the core portion being encapsulated within the shell portion and the cap portion, the microneedles being configured to be inserted into mammalian tissue, detach from the pedestal, and then release an effective amount of the contraceptive or other medication via diffusion through only the shell portion, through only the cap portion, or through both the shell portion and the cap portion, over an extended period of at least 30 days.

[0121] Embodiment 24. A microneedle patch as described in embodiment 23, wherein the shell portion and the cap portion are formed of a biodegradable polymer.

[0122] Embodiment 25. A microneedle patch as described in embodiment 23 or 24, wherein the shell portion comprises poly(L-lactide) (PLLA) and the cap portion comprises polylactic acid (PLA).

[0123] Embodiment 26. A microneedle patch according to any one of embodiments 22 to 25, wherein the water-soluble polymer comprises polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), sucrose, or a combination thereof.

[0124] Embodiment 27. A microneedle patch according to any one of embodiments 22 to 26, wherein the long term is 2 months to 6 months.

[0125] Embodiment 28. A microneedle patch according to any one of embodiments 22 to 27, wherein the contraceptive agent comprises levonorgestrel, etonogestrel, nestorone, or another contraceptive hormone.

[0126] Embodiment 29. A method of making a microneedle patch comprising: (i) forming a plurality of microneedles in a mold, each microneedle having a core portion containing a drug, and a shell portion and a cap portion that completely surround the core portion; (ii) forming a backing layer connected to a base 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.

[0127] Embodiment 30. The method of embodiment 29, wherein the backing layer comprises an array of pedestals, each connected to the proximal end of one or more of the plurality of microneedles.

[0128] Embodiment 31. The method of embodiment 29 or 30, wherein the microneedle is configured to release the agent via diffusion from the core portion through the shell portion and / or through the cap portion of the microneedle.

[0129] Embodiment 32. A method comprising: (i) casting a first composition into 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 cap portion; and (iv) casting a fourth composition onto the cap portion in the mold to form a backing layer, thereby producing a microneedle patch comprising an array of microneedles extending from the backing layer, each of the microneedles comprising a core portion comprising a drug encapsulated within the shell portion and the cap portion.

[0130] Embodiment 33. The method of embodiment 32, wherein the first, second, third, and fourth compositions each comprise a fluid comprising a polymeric structural material dissolved in a solvent, and the solvent of the first composition is different from the solvent of at least the second composition, the solvent of the second composition is different from the solvent of at least the first and third compositions, the solvent of the third composition is different from the solvent of at least the second and fourth compositions, and the solvent of the fourth composition is different from the solvent of at least the third composition.

[0131] Embodiment 34 The method of embodiment 33, wherein the polymeric structural materials of the first, second, and third compositions each comprise a biodegradable polymer.

[0132] Embodiment 35. The method of embodiment 33 or 34, wherein the polymeric structural material of the fourth composition comprises a water soluble polymer.

[0133] Embodiment 36 The method of any one of embodiments 32-35, wherein the first composition comprises PLLA dissolved in dioxane.

[0134] Embodiment 37. The method of any one of embodiments 32-36, wherein the second composition comprises PLGA dissolved in a mixture of diglyme and water.

[0135] Embodiment 38 The method of any one of embodiments 32-37, wherein the third composition comprises PLA dissolved in dimethylacetamide.

[0136] Embodiment 39. The method of any one of embodiments 32 to 38, wherein the fourth composition comprises PVA and sucrose dissolved in water.

[0137] Embodiment 40. The method of any one of embodiments 32-39, wherein the fourth composition comprises PVP, sodium bicarbonate, and citric acid dispersed or dissolved in absolute ethanol.

[0138] Embodiment 41. The method of any one of embodiments 32-40, further comprising centrifuging the mold following pouring of the first composition to promote formation of a film that becomes the shell in the mold.

[0139] Embodiment 42. The method of any one of embodiments 32-41, further comprising drying the contents of the mold following each casting.

[0140] Embodiment 43. The method of any one of embodiments 32-42, further comprising removing the microneedle patch from the mold.

[0141] Embodiment 44. A method of administering a drug to a patient, comprising: (i) inserting a microneedle of a microneedle patch described in any one of the preceding embodiments into the patient's skin; (ii) separating the microneedle from the backing layer; and then (iii) releasing the drug from the core portion of the microneedle, wherein the shell portion and / or cap portion are biodegradable and delay release of the drug over an extended period of time, and optionally the release is via diffusion through the shell portion of the microneedle.

[0142] 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.

[0143] Embodiment 46 The method of embodiment 44 or 45, wherein the agent is released continuously for at least one month.

[0144] Embodiment 47. The method of embodiment 46, wherein the period is 2 months to 6 months.

[0145] Embodiment 48. The method of any one of embodiments 44 to 47, wherein the medicament comprises levonorgestrel, etonogestrel, nestorone, or another contraceptive hormone.

[0146] The term "about," as used herein, denotes a given quantity value and can include amounts within a range of within 10% of the stated value, or optionally, within 5% of that value, or in some embodiments, within 1% of that value.

[0147] 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. It is a microneedle patch, Backing layer, An array of microneedles extending from the backing layer, wherein each of the microneedles is The core part containing the drug, The device comprises a shell portion and a cap portion, the core portion being enclosed within the shell portion and the cap portion, and an array of microneedles, The microneedle is configured to be inserted into mammalian tissue and separated from the backing layer. A microneedle patch wherein the shell portion and / or the cap portion are biodegradable and delay the release of the drug over a long period of time.

2. The microneedle patch according to claim 1, wherein the microneedle is configured to release the drug through diffusion through only the shell portion, only the cap portion, or both the shell portion and the cap 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).

5. 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 polyvinylpyrrolidone (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 foaming material.

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 according to claim 8, wherein the biodegradable polymer comprises poly(lactide-co-glycolide) (PLGA).

10. The microneedle patch according to claim 1, further comprising a base between the backing layer and each of the cap portions of the microneedles.

11. The microneedle patch according to claim 10, wherein the base is integrally formed with the backing layer.

12. The microneedle patch according to claim 1, wherein the microneedles are configured to separate from the backing layer by a process comprising (i) aqueous dissolution of a material forming at least a portion of the backing layer, wherein the material optionally includes a foaming material, and / or (ii) rupture of the interface between the cap portion and the backing layer.

13. The microneedle patch according to claim 12, wherein the rupture is caused by an air pocket at the interface between the cap portion and the backing layer.

14. The microneedle patch according to claim 12, wherein the cap portion contains a hydrophobic material and the backing layer contains a hydrophilic material so that the interface between the cap portion and the backing layer is fragile and susceptible to fracture.

15. The microneedle patch according to claim 12, wherein the microneedles are configured to separate within one minute of being inserted into mammalian tissue.

16. The microneedle patch according to claim 1, configured to continuously release the drug from the separated microneedles over a period of one month to one year.

17. The microneedle patch according to claim 16, configured to continuously release the drug from the separated microneedles over a period of two to six months.

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

19. The microneedle patch according to claim 1, wherein the drug comprises a hormone such as levonorgestrel, etonogestrel, nestron, or another contraceptive hormone.

20. The microneedle patch according to claim 1, wherein the drug is effective in treating skin diseases.

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

22. The microneedle patch according to claim 1, wherein the shell portion and / or the cap portion contains the same or a different agent as the agent in the core portion.

23. A microneedle patch for administering contraceptives or other medications, A backing layer including the base array, An array of microneedles extending from each of the aforementioned bases, wherein each of the microneedles is A core portion containing a biodegradable polymer in which a contraceptive or other drug is dispersed, The device comprises an array of microneedles including a water-insoluble shell portion and a cap portion, wherein the core portion is enclosed within the shell portion and the cap portion. A microneedle patch in which the microneedles are inserted into mammalian tissue, separated from the base, and then released an effective amount of the contraceptive or other drug via diffusion through only the shell portion, only the cap portion, or both the shell portion and the cap portion over a period of at least 30 days.

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

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

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

27. The microneedle patch according to claim 23, wherein the aforementioned long period is 2 months to 6 months.

28. A microneedle patch according to any one of claims 23 to 27, wherein the contraceptive comprises levonorgestrel, etonogestrel, nestron, or another contraceptive hormone.

29. A method for making a microneedle patch, The method involves forming multiple microneedles within a mold, wherein each microneedle has a core portion containing a drug, and a shell portion and a cap portion that completely surround the core portion. Form a backing layer connected to the proximal end of each of the plurality of microneedles, and then A method comprising removing the backing layer and microneedles from the mold, thereby generating a microneedle patch.

30. The method according to claim 29, wherein the backing layer includes an array of bases, each of which is connected to one or more of the proximal ends of the plurality of microneedles.

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

32. It is a method, A first composition is poured into a mold having cavities defining multiple microneedles, thereby forming a shell portion within the mold. A second composition containing the drug is poured into the internal space defined by the shell portion within the mold to form a core portion. The third composition is poured onto the core portion within the mold to form the cap portion. This includes pouring a fourth composition onto the cap portion within the mold to form a backing layer, A method for generating a microneedle patch comprising an array of microneedles extending from the backing layer, wherein each of the microneedles comprises a core portion containing the drug, which is enclosed within the shell portion and the cap portion.

33. The method according to claim 32, wherein each of the first, second, third, and fourth compositions comprises a fluid containing a polymer structural material dissolved in a solvent, the solvent of the first composition being different from at least the solvent of the second composition, the solvent of the second composition being different from at least the solvents of the first and third compositions, the solvent of the third composition being different from at least the solvents of the second and fourth compositions, and the solvent of the fourth composition being different from at least the solvent of the third composition.

34. The method according to claim 33, wherein the polymer structural material of the first, second, and third compositions each comprises a biodegradable polymer.

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

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

37. The method according to claim 32, wherein the second composition comprises PLGA dissolved in a mixture of diglym and water.

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

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

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

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

42. The method according to any one of claims 32 to 40, further comprising drying the contents of the mold following each of the pours.

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

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