Separable microneedle arrays for sustained release of drug

Abstract

To provide separable microneedle arrays and microneedle patches that may achieve sustained release of a drug.SOLUTION: The microneedle arrays may include one or more features that facilitate separation of microneedles, such as a bubble structure. The microneedle arrays may include an effervescent material.SELECTED DRAWING: Figure 1E

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 571,012, filed October 11, 2017, and U.S. Provisional Patent Application No. 62 / 713,857, filed August 2, 2018, which are incorporated by reference herein. [Background technology]

[0002] Microneedles are micron-scale structures that can administer drugs minimally invasively. Microneedles have been used for bolus delivery of drugs and vaccines using either coatings or water-soluble microneedles. Previous studies have reported the use of dissolving microneedles for the delivery of levonorgestrel (LNG) for emergency contraception (Yao, GT et al., Int. J. Pharm. 534, 378-86 (2017)). The patch was worn for up to 2 hours and did not provide sustained drug release.

[0003] Despite advances in contraceptive methods, significant rates of unintended pregnancies remain. High rates of unintended pregnancies can impose economic and emotional burdens on women and society at large. One of the main reasons for unintended pregnancies is the lack of contraceptive methods that meet the needs of diverse populations of women at different stages of their reproductive life cycle.

[0004] Non-hormonal contraceptive methods such as condoms and diaphragms provide a physical barrier for pregnancy protection, but these barrier methods, even with spermicides, usually have relatively high failure rates due to poor patient consent and compliance with correct usage guidelines. Hormonal contraceptive devices such as oral pills, intravaginal rings, intrauterine devices, subcutaneous injections, and implants generally offer better protection but usually require frequent administration, which poses significant compliance problems, or may require delivery by a health care provider, which is particularly problematic in low-income countries.

[0005] Many different contraceptive hormones are safe, effective and low-cost. Some contraceptives are long-acting due to sustained-release formulations, but have limited options for self-administration. Well-established sustained-release methods involve encapsulating the drug in a biodegradable polymer that gently releases the drug by drug diffusion and / or polymer degradation. This approach has been utilized for many pharmaceuticals and has been investigated as an injectable or depot formulation for birth control. However, these formulations typically require administration by trained personnel, thereby limiting patient access. Furthermore, the safety of these methods can be hampered by needle reuse and needle-based injuries.

[0006] There has been prior work on incorporating air bubbles into microneedle patches to provide a barrier between the microneedles and the rest of the patch to prevent migration of material from the microneedles to the rest of the patch and vice versa (e.g., Chu, LY et al., J. Pharm. Sci. 2010, 99(10), 4228-38). However, the air bubble-containing microneedles were not configured to separate from the patch.

[0007] Thus, there is a need for drug delivery methods and devices, including contraceptive delivery methods and devices, or combinations thereof, that are safe, effective, can enable sustained release, can facilitate good patient access and compliance through self-administration, and are relatively inexpensive and therefore suitable for global use.

[0008] In some cases, it may also be desirable to provide drug delivery systems and methods in which no components of the system remain outside the patient's body during extended periods of drug release, e.g., days, weeks, or months. For example, wearable drug delivery systems, e.g., skin-adherent patches, are known in the art, but can undesirably not be easily concealed and / or can be uncomfortable for patients who must wear the systems for extended periods of time. Summary of the Invention

[0009] Provided herein is a detachable microneedle array that can address one or more of the above-mentioned shortcomings. For example, the detachable microneedle patch can overcome one or more of the shortcomings of current birth control by achieving sustained release of drugs such as contraceptive hormones. The detachable microneedle patch advantageously avoids the injection of sustained release formulations by traditional needle and sieve methods. Instead, as described herein, the detachable microneedle patch can be simply and painlessly applied to the skin to cut biodegradable microneedles embedded in the skin for the gradual release of drugs such as contraceptive hormones.

[0010] The microneedle arrays described herein may include features such as internal air bubbles or foam materials that facilitate separation of the microneedles from the device after insertion into the skin, after which the remainder of the device may be detached and discarded. The remainder of the device may be non-sharp waste. The detached microneedles may biodegrade within the skin for sustained release and systematic delivery of the substance of interest.

[0011] In one embodiment, a microneedle array is provided that can be used to administer a substance of interest into biological tissue, such as the skin, of a patient, The microneedle array can release the substance of interest for a sustained period of at least two weeks.

[0012] In some embodiments, a microneedle array for administration into a biological tissue of a patient includes a base substrate having a microneedle surface and an opposite back surface, and two or more solid microneedles extending from the base substrate, at least a tip portion of each microneedle includes a substance of interest, and a bubble structure is at least partially disposed on each of the two or more solid microneedles, and the two or more solid microneedles are configured to penetrate into the biological tissue of the patient under pressure and then break in the bubble structure, for example, by a shear force applied to the array. A primary funnel portion may be disposed between the base substrate and the microneedles and join them. The bubble structure may be at least partially contained in the primary funnel portion. For example, the bubble structure may be disposed on the joining surface of the base substrate (or the primary funnel portion, if present) and the base end of each microneedle.

[0013] In some embodiments, a microneedle array for administering a substance of interest into biological tissue of a patient comprises a base substrate having a microneedle face and an opposing back side, a primary funnel portion extending from the microneedle face of the base substrate, and two or more solid microneedles extending from the primary funnel portion, at least a tip portion of each microneedle comprising the substance of interest, a bubble structure disposed at a mating surface of the primary funnel portion and a base end of each microneedle, and the two or more solid microneedles configured to penetrate into the biological tissue of the patient under pressure and then detach from the primary funnel portion under shear due to fracturing at the bubble structure.

[0014] In some embodiments, the microneedle array comprises a base substrate having a microneedle surface and an opposite back surface, at least one primary funnel portion extending from the microneedle surface of the base substrate, and two or more solid microneedles extending from the at least one primary funnel portion, where the two or more solid microneedles contain a substance of interest and a secondary funnel portion extends from the at least one primary funnel portion. The two or more solid microneedles may be constructed to penetrate into the skin of a patient under pressure and then separate from the secondary funnel portion under shear after penetration. The two or more solid microneedles may include a bubble structure at or near the base end of each microneedle, where the bubble structure may facilitate separation of the microneedle from the secondary funnel portion. The bubble structure may be located at each interface of the two or more microneedles and the secondary funnel portion. In some embodiments, the substance of interest is a therapeutic or prophylactic agent, such as a contraceptive hormone.

[0015] In some embodiments, the microneedle array includes a base substrate having a microneedle face and an opposing back surface, and two or more solid microneedles extending from the base substrate, with at least a tip portion of each microneedle including a substance of interest, and a foam material disposed on a portion of each of the two or more solid microneedles, at least a portion of the base substrate, or a combination thereof. The two or more solid microneedles may be configured to penetrate into a biological tissue of a patient under pressure, and then separate a tip portion of each microneedle from the base substrate when at least a portion of the base substrate and / or a portion of each of the two or more microneedles on which the foam material is disposed at least partially dissolves. A primary funnel portion may be disposed between and join the base substrate and the microneedles. The foam may be at least partially disposed in the primary funnel portion. For example, the foam material may be disposed on the joining surface of the base substrate (or the primary funnel portion, if present) and the base end of each microneedle.

[0016] In some embodiments, the microarray comprises a base substrate having a microneedle face and an opposing back side, at least one primary funnel portion extending from the microneedle face of the base substrate, and two or more solid microneedles extending from the at least one primary funnel portion, the two or more solid microneedles comprising a substance of interest and the secondary funnel portion comprising a first matrix material and a foam material. The two or more solid microneedles may be constructed to penetrate into a patient's skin under pressure and then separate from the secondary funnel portion upon at least partial dissolution of the secondary funnel portion.

[0017] In some embodiments, the microneedle array comprises a base substrate having a microneedle face and an opposing back surface, at least one primary funnel portion extending from the microneedle face of the base substrate, and two or more solid microneedles extending from the at least one primary funnel portion, wherein the two or more solid microneedles comprise a substance of interest, a secondary funnel portion extending from the at least one primary funnel portion, and the two or more solid microneedles are configured to (i) penetrate into the skin of a patient under pressure and then detach from the secondary funnel portion, and (ii) release a therapeutically or prophylactically effective amount of the substance of interest to the patient over a sustained period of at least two weeks. In some embodiments, the substance of interest is a therapeutic or prophylactic agent, such as a contraceptive hormone.

[0018] In another aspect, a microneedle patch is provided that includes any of the microneedle arrays described herein. In some embodiments, the microneedle patch includes a microneedle array as described herein, an adhesive layer, and a handle layer attached to a base substrate, the handle layer including a tab portion that extends away from the two or more solid microneedles and allows a person to hold the tab portion by hand to operate the patch without touching the two or more solid microneedles.

[0019] In yet another aspect, a method of administering a substance of interest to a patient is provided. In some embodiments, the method includes inserting microneedles of an array of microneedles as described herein into a biological tissue of a patient, separating the inserted microneedles from a base substrate (or infundibulum, if present), and releasing the substance of interest from the separated inserted microneedles into the biological tissue. The biological tissue may include skin, and the substance of interest may include a contraceptive hormone, such as progestin. In some embodiments, the separation may include fracturing the cell structure by applying a shear force to the microneedle array, and / or the separation may include dissolution of wall material surrounding the cell structure that thins and results in mechanical failure without applying a shear force. In some embodiments, the separation includes wetting of the foam material with a biological fluid, followed by dissolution of the material that forms part of the microneedles and / or the base substrate (or infundibulum, if present).

[0020] In a further aspect, a method of making a microneedle array is provided. In one embodiment, the method includes: (a) providing a mold having an upper surface, an opposing lower surface, and an opening in the upper surface, the opening leading to a first cavity proximal to the upper surface and a second cavity below the first cavity, the first cavity defining at least one funnel portion, and the second cavity defining at least one microneedle; (b) filling at least the second cavity with a first material through the opening in the mold, the first material including a substance of interest dissolved or suspended in a first liquid vehicle; (c) removing at least a portion of the first liquid vehicle to dry the first material in the mold to form at least tips of microneedles in the second cavity, the tips including the substance of interest; and (d) removing the first cavity and the second material after steps (b) and (c). (e) filling any second cavities unoccupied with a second material comprising a matrix material dissolved or suspended in a second liquid vehicle through the opening in the mold; (e) removing at least a portion of the second liquid vehicle to form (i) at least one funnel portion and (ii) any portion of the at least one microneedle not formed after steps (b) and (c), wherein the at least one funnel portion comprises the second matrix material; and (f) removing the at least one microneedle together with the at least one funnel portion joined thereto from the mold, wherein more of the substance of interest is present in the at least one microneedle than is present in the at least one funnel portion.

[0021] In one embodiment, the method includes the steps of: (a) providing a mold having an upper surface, an opposing lower surface, and an opening in the upper surface, the opening leading to a first cavity proximal to the upper surface and a second cavity below the first cavity, the first cavity defining at least one funnel portion, and the second cavity defining at least one microneedle; (b) filling at least the second cavity with a first material through the opening in the mold, the first material including a first matrix material and a substance of interest dissolved or suspended in a first liquid vehicle; (c) removing at least a portion of the first liquid vehicle and drying the first material in the mold to form at least a tip of a microneedle in the second cavity, the tip including the substance of interest; and (d) removing the first cavity and a microneedle occupied after steps (b) and (c). (e) removing at least a portion of the second liquid vehicle to dry the second material in the mold to form (i) at least one funnel portion and (ii) any portion of the at least one microneedle not formed after steps (b) and (c), wherein the at least one funnel portion comprises the foam material and the second matrix material; and (f) removing the at least one microneedle together with the at least one funnel portion joined thereto from the mold, wherein more of the substance of interest is located in the at least one microneedle than in the at least one funnel portion.

[0022] Additional aspects will be set forth in part in the description which follows and in part will be obvious from the description or may be learned by practice of the aspects described hereinafter. The advantages described below will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. [Brief description of the drawings]

[0023] [Fig. 1A-1E] 1 illustrates an embodiment of a microneedle array that includes a bubble structure. [Figures 2A-2E] 1 illustrates an embodiment of a microneedle array comprising a foam material. [Figure 3A-3B] 1 illustrates one embodiment of a microneedle patch. [Figure 4A-4I] 1 shows an embodiment of a funnel and a microneedle. [Figure 5A-5C] 1 shows an embodiment of a funnel and a microneedle. [Figure 6] 1 illustrates an embodiment of a process for forming an embodiment of a microneedle array. [Figure 7] FIG. 2 is a block diagram of one embodiment of the process described herein. [Figure 8] 1 illustrates an embodiment of a process for forming an embodiment of a microneedle. [Figure 9] 1 is a graph showing a possible correlation between backing solution volume and size of an embodiment of a cellular structure. [Figure 10] 13 is a graph showing the mechanical behavior of an embodiment of a bubble microneedle patch under compression administered by normal force. [Figure 11] 1 is a graph showing the mechanical behavior of an embodiment of an individual microneedle containing 240 μm cell structures. [Figure 12] 13 is a graph showing the mechanical behavior of an embodiment of a bubble microneedle patch under shear administered by a horizontal force. [Figure 13] 1 is a graph illustrating the detachment efficiency of microneedle embodiments before and after scraping testing. [Figure 14] 1 is a graph showing the penetration, detachment, and delivery efficiency of microneedle embodiments. [Figure 15] 1 is a graph showing the cumulative amount of contraceptive hormone released in vitro by an embodiment of a microneedle patch. [Figure 16]1 is a graph showing the fluorescence intensity of the skin following administration of an embodiment of a Nile red-loaded microneedle patch. [Figure 17] 1 is a graph showing the concentration of contraceptive hormone in plasma during and after administration of an embodiment of a microneedle patch. [Figure 18] 1 is a graph showing the cumulative amount of contraceptive hormone absorbed in vivo following administration of one embodiment of a microneedle patch. [Figure 19] FIG. 1 shows a schematic diagram of application of one embodiment of a microneedle patch with a foam backing to the skin. [Figure 20] FIG. 1 is a schematic diagram of one embodiment of a manufacturing process for producing an embodiment of a microneedle patch having a foam backing. [Figure 21] 1 is a graph showing quantification of detachment time for one embodiment of a microneedle patch having a foam backing. [Figure 22] 13 is a graph showing quantification of the detachment and drug delivery efficiency of an embodiment of a microneedle patch having a foam backing. [Diagram 23] 1 is a graph showing the cumulative amount of contraceptive hormone released in vivo by one embodiment of a microneedle patch having a foam backing in different release media. [Figure 24] 1 is a graph showing the concentration of contraceptive hormone in plasma after application of one embodiment of a microneedle patch having a foam backing. [Diagram 25] 1 is a graph showing normalized erythema intensity following application of one embodiment of a microneedle patch having a foam backing. [Figure 26] 1 is a graph showing the penetration and detachment efficiency of one embodiment of a microneedle patch having a foam backing. [Figure 27] FIG. 1 is a cross-sectional view of one embodiment of a microneedle comprising a foam material. [Figure 28] FIG. 13 is a cross-sectional view of another embodiment of a microneedle comprising a foam material. [Figure 29] FIG. 1 is a cross-sectional view of an embodiment of a microneedle array including an embodiment of a bubble structure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Improved microneedle arrays, microneedle patches and manufacturing methods have been developed. The microneedles described herein can be easily and / or quickly separated from the base of the microneedle patch. As a result, a user only needs to wear the microneedle patch for a few seconds before removing the base, and there is little or no trace of patch use thereafter.

[0025] In some embodiments, the microneedles contain a drug substance or other substance of interest, and the array of these microneedles is particularly suitable for use as or in a drug delivery patch, such as for application to the skin of a patient. Provided herein is a microneedle patch, which in some embodiments can be used to self-administer drugs, such as contraceptives. In some embodiments, the microneedle patch can provide sustained drug release. For example, the microneedle patch can provide long-term contraception by encapsulating contraceptive hormones in biodegradable microneedles for gradual release.

[0026] The microneedles may be made from biodegradable, bioerodible, or bioabsorbable polymers (e.g., polylactic acid and poly(lactic-co-glycolic acid)) that may encapsulate drugs such as contraceptive hormones (e.g., progestins such as levonorgestrel, etonogestrel, or nestelone) for continuous release for at least two weeks, and in some embodiments, four weeks or more.

[0027] The microneedle patches may be well tolerated, leave little visible evidence of use, and / or maintain plasma concentrations of drug at or above human therapeutic levels for at least 2 weeks, and in some embodiments, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

[0028] The microneedle arrays described herein may include features such as a cellular structure or foam material that facilitates separation of the microneedles. As used herein with respect to separation of the microneedles, the terms "facilitate", "facilitating", and the like refer to (i) reducing the minimum force (e.g., shear force) required to achieve separation of the microneedles, (ii) reducing the amount of matrix material that must be dissolved to achieve separation of the microneedles (e.g., a cellular structure may result in thinner walls within the microneedles), (iii) increasing the dissolution rate of the funnel where the microneedles are initially attached, the portion of the microneedle that includes the foam material, or a combination thereof, or (iv) a combination thereof.

[0029] Upon separation of the microneedles, the microneedles of the microneedle array may be embedded in biological tissue, such as the skin of a patient. 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 surface of the biological tissue. Figure 1E, for example, shows a series of four separated fully embedded microneedles.

[0030] Bubble structure In some embodiments, the microneedle of the microneedle patch provided herein comprises a cellular structure. The cellular structure can facilitate the separation of the microneedle from the funnel. For example, the cellular structure can reduce the minimum shear force required to separate the microneedle from the funnel. Although the cellular structure can change the effect of shear force on the microneedle, the cellular structure may not impair the ability of the microneedle to penetrate the skin. In other words, the cellular structure does not undesirably affect the ability of the microneedle to withstand, without destruction, the compressive force applied during normal use that is effective for penetrating biological tissue, such as through the stratum corneum of the patient's skin.

[0031] As used herein, a microneedle array has a "bubble structure" when one or more bubbles of gas are present. In some embodiments, the bubble structure is at or near the base end of the microneedle, which is the end that contacts the funnel. A gas bubble is "at or near the base end of the microneedle" when it is (i) at the interface between the microneedle and the funnel, (ii) within the funnel (i.e., completely defined by the material from which the funnel is formed) and the distance between the tip of the microneedle and the edge of the gas bubble closest to the base end of the microneedle is 125% or less of the length of the microneedle, or (iii) within the microneedle (i.e., completely defined by the material from which the microneedle is formed) and the distance between the tip of the microneedle and the edge of the gas bubble closest to the tip of the microneedle is 75% or more of the length of the microneedle.

[0032] In some embodiments, the gas bubbles of the gas bubble structure are located at the interface between the microneedle and the funnel. The gas bubbles are located at the interface between the microneedle and the funnel when the gas bubbles are partially bounded by (i) the material from which the microneedle is formed, and (ii) the material from which the funnel is formed. For example, X% of the surface area of ​​the gas bubbles can be defined by the material from which the microneedle is formed, and the remaining 100-X% of the surface area of ​​the gas bubbles can be defined by the material from which the funnel is formed.

[0033] In some embodiments, the gas bubble of the bubble structure is within the microneedle and not at or near the base end of the microneedle. For example, the gas bubble may be located within the microneedle and the distance between the tip of the microneedle and the edge of the gas bubble closest to the tip of the microneedle may be less than 75% of the length of the microneedle. In some embodiments, the distance between the tip of the microneedle and the edge of the gas bubble closest to the tip of the microneedle is about 10% to about 74% of the length of the microneedle, about 20% to about 70% of the length of the microneedle, about 30% to about 70% of the length of the microneedle, or about 40% to about 60% of the length of the microneedle.

[0034] The gas of the bubble structure may be or may include air. In some embodiments, the gas of the bubble structure includes an inert gas, such as argon, nitrogen, etc. The body or volume of gas may generally have any shape, but is typically spherical or ellipsoidal. When spherical in shape, the body of gas may be a regular or irregular spherical shape. For example, a spherical body of gas may have portions that are less curvilinear, e.g., flatter, than other portions.

[0035] The gas bubbles in the bubble structure have a diameter (if spherical) or a maximum diameter (if ellipsoidal), and the ratio of the diameter or maximum diameter of the gas bubbles to the width of the microneedle at the microneedle-funnel interface is about 0.5:1 to about 3:1, about 0.5:1 to about 2.5:1, about 0.5:1 to about 2:1, about 0.5:1 to about 1.9:1, about 0.5:1 to about 1.8:1, about 0.5:1 to about 1.7:1, about 0.5:1 to about 1.8 ... 1 to about 1.6:1, about 0.5:1 to about 1.5:1, about 0.5:1 to about 1.4:1, about 0.5:1 to about 1.3:1, about 0.5:1 to about 1.2:1, about 0.5:1 to about 1.1:1, about 0.5:1 to about 1:1, about 0.5:1 to about 0.99:1, about 0.6:1 to about 0.99:1, about 0.7:1 to about 0.99:1, about 0.8:1 to about 0.99:1, or about 0.9:1 to about 0.99:1. For example, if the microneedle has a width of 300 μm at the microneedle-funnel interface, a gas bubble at or near the base end of the microneedle may have a diameter or maximum diameter of about 150 μm to about 900 μm. In an array of microneedles having a cellular structure, the cellular structures may have substantially the same diameter or maximum diameter, or the cellular structures may have different diameters and maximum diameters. As described herein, the diameter or maximum diameter of the cellular structures may be controlled and thus selected based on one or more desired characteristics. For example, a relatively large cellular structure may be selected to reduce the minimum shear force required to achieve separation of the microneedles.

[0036] The gas bubbles of the cell structure may be centered or off-centered relative to the sides of the microneedles and / or funnels, e.g., relative to a central axis extending from the base to the tip of the microneedle. An array of microneedles may include cell structures that are centered, off-centered, or a combination thereof. A bubble is "centered" when the shortest distance from the center of the bubble to any side of the funnel or microneedle is substantially the same.

[0037] In one embodiment, as illustrated in Figure 1A (plan view) and Figure 1B (side cross-sectional view), the microneedle array 105 includes a base substrate 110 having a microneedle face 115 and an opposing back surface 120. The microneedle array 105 also includes three sets of microneedles 130, each set having a primary funnel portion 125 extending from the microneedle face 115 of the base substrate 110, and a secondary funnel portion 135 extending from the primary funnel portion 125. At the interface of each secondary funnel portion 135 and the microneedles 130 is an air bubble structure 140. Each primary funnel portion 125 extends in a direction (D) parallel to the base substrate 110. In this embodiment, the microneedles 130 and the funnel portions 125, 135 each contain the same substance of interest and excipients.

[0038] The secondary funnel portion is highly advantageous in many embodiments, for example, to facilitate insertion of the microneedle fracture / separation area located below the surface of the skin or other biological tissue, such that a substantial portion of the separated microneedle does not protrude from the biological tissue, for example, preventing proper and complete delivery of a dose of a substance of interest. However, in some other embodiments, this outcome may be of little or no concern. Thus, in some embodiments, the secondary funnel portion is omitted, and the microneedles extend directly from the primary funnel portion. For example, a bubble structure may be disposed at the interface of the primary funnel portion and the base end of each microneedle. The microneedles are configured to penetrate into the biological tissue under pressure, and then separate from the primary funnel portion under shear, due to fracture in the bubble structure.

[0039] The microneedle array 105 of Figures 1A and 1B may be placed on a tissue surface such as skin, and upon application of a compressive force (CF), the microneedles 130 and a portion of the secondary funnel 135 may penetrate the tissue surface 150, as shown in Figure 1C (side cross-sectional view). Application of a shear force (SF) to the microneedle array 105 causes the microneedles 130 to separate from the secondary funnel 135, as shown in Figure 1D (side cross-sectional view). The base substrate 110, primary funnel portion 125, and secondary funnel portion 135 may then be removed from the tissue surface. The microneedles 130 remain embedded within the tissue, as shown in Figure 1E (side cross-sectional view).

[0040] 29 shows a cross-sectional view of one embodiment of a microneedle array 2900. The microneedle array 2900 includes a base substrate 2910 having a microneedle face 2911 and an opposing back surface 2912. The microneedle array 2900 includes solid microneedles 2920 extending from the microneedle face 2911 of the base substrate 2910. The solid microneedles 2920 have an obelisk shape and include a tip portion 2921 that includes a substance of interest. Each of the solid microneedles 2920 also includes a bubble structure 2930. The solid microneedles 2920 are configured to fracture at the bubble structure 2930 and separate at least the tip portion 2921 of each microneedle from the base substrate 2910. The cell structure 2930 of the microneedle array 2900 may facilitate separation of the microneedles 2920 by (i) reducing the minimum shear force required to fracture the microneedles 2920 in the cell structure 2930, (ii) reducing the wall thickness of the microneedles 2920 at or adjacent to the cell structure 2920, thereby reducing the amount of microneedle-forming matrix material that needs to be dissolved to fracture the microneedles 2920 in the cell structure 2930, or a combination thereof. The microneedles shown in FIG. 29 are obelisk shaped, however other microneedle shapes (e.g., conical, cylindrical) may include cell structures that are not at or near the interface of the microneedle and funnel.

[0041] Foam material In some embodiments, the microneedle array includes a foam material. The foam material may be located anywhere that facilitates separation of the microneedle from the base or separation of the tip of the microneedle from the base of the microneedle. The foam material may be located in all or a portion of the funnel. For example, a portion of the funnel adjacent to the base end of the microneedle may include the foam material. The foam material may be located in a portion of the microneedle, particularly including the base end of the microneedle and / or adjacent to the base end of the microneedle. The foam material may be located in (i) all or a portion of the funnel and (ii) a portion of the microneedle. In some embodiments, the microneedle may extend from a funnel portion that includes the foam material (e.g., a secondary funnel portion). In some embodiments, the microneedle may extend from a funnel portion that does not include the foam material, but the foam material is included in the microneedle, e.g., a portion of the microneedle including and / or adjacent to the base end of the microneedle. As used herein, the phrase "foam material" refers to a material or combination of two or more materials that generate gas when contacted with an aqueous liquid.

[0042] When only a portion of the funnel comprises a foamed material, the portion of the funnel that comprises the foamed material may comprise a water soluble matrix material and the portion of the funnel that does not comprise the foamed material may comprise a water soluble or water insoluble matrix material.

[0043] When the microneedle array includes a foam material, the foam material may react when contacted with an aqueous liquid, such as a biological fluid (e.g., interstitial fluid) on, in, or under the biological tissue, thereby generating a gas. Alternatively, the aqueous liquid may be provided externally. For example, the aqueous liquid may be applied to the microneedle array, the biological tissue surface, or a combination thereof. The generated gas may form bubbles in the infundibulum. The generated gas may quickly impart porosity or increase the porosity of the infundibulum. In addition to generating gas, the foam material may also generate water, which may increase the rate at which the infundibulum containing the foam material and / or water-soluble excipients or matrix materials dissolve. The generated water may also increase the rate at which the foam material dissolves, thus reacting to generate gas.

[0044] Thus, the rate at which the funnel dissolves may be increased by (i) the porosity or increased porosity imparted by the gas evolved by the foam material, (ii) water produced by the foam material, if applicable, or (ii) a combination of these.

[0045] In some embodiments, the effervescent material comprises an acid and a salt. The acid can be an organic acid, such as citric acid. The salt can be a salt that imparts a basic pH (i.e., >7) to the water in which it is hydrolyzed. The salt can be sodium bicarbonate.

[0046] In some embodiments, the effervescent material includes citric acid and sodium bicarbonate. Upon contact with biological fluids on, in, or under biological tissue, the sodium bicarbonate and citric acid may dissolve in one another and react to produce carbon dioxide and water. The carbon dioxide may increase the porosity of the infundibulum, and the water may contribute to dissolving more of the material from which the infundibulum is formed, the citric acid, and sodium bicarbonate, thereby stimulating the reaction between the citric acid and the sodium bicarbonate, further increasing the rate of dissolution of the infundibulum.

[0047] When the foam material is included in the funnel, the foam material and the material from which the funnel is formed may be present in the funnel in a weight ratio of about 0.1:1 to 1:0.1, about 0.2:1 to 1:0.2, about 0.3:1 to 1:0.3, about 0.4:1 to 1:0.4, about 0.5:1 to 1:0.5, about 0.5:1 to about 1:1, about 0.6:1 to about 1:1, about 0.7:1 to about 1:1, about 0.8:1 to about 1:1, about 1:1 to about 1:0.8, about 1:1 to about 1:0.7, about 1:1 to about 1:0.6, or about 1:1 to about 1:0.5. For example, the foam material may be in powder form dispersed in the matrix material that forms the funnel of the microneedle array. The structural components of the microneedle array that include the foam material generally include at least 10% foam material by weight.

[0048] When the effervescent material includes two components, such as an acid and a salt, the ratio of the components can be selected to generate a desired amount of gas. This ratio can vary depending on the equivalence factor of one or more of the components.

[0049] 2A (plan view) and 2B (side cross-sectional view), the microneedle array 205 includes a base substrate 210 having a microneedle face 215 and an opposing back surface 220. The microneedle array 205 also includes three sets of microneedles 230, each set having a primary funnel portion 225 extending from the microneedle face 215 of the base substrate 210, and a secondary funnel portion 235 extending from the primary funnel portion 225.

[0050] The secondary funnel portion 235 includes a foam material. Each primary funnel portion 225 extends in a direction (D) parallel to the base substrate 210. In this embodiment, the microneedles 230 include the substance of interest and the primary funnel portion 135 does not include a foam material.

[0051] The microneedle array 205 of Figures 2A and 2B may be placed on a tissue surface 150, such as skin, and upon application of a compressive force (CF), the microneedles 230 and a portion of the secondary funnels 235 may penetrate the tissue surface 250, as shown in Figure 2C (side cross-sectional view). Thus, the secondary funnels 235 may contact biological fluids, e.g., interstitial fluid, below the tissue surface 250, which wets and activates the foam material. The foam may increase the rate at which the secondary funnels 235 dissolve and subsequently separate from the microneedles 230, as shown in Figure 2D (side cross-sectional view). The base substrate 210, the primary funnel portion 225, and the secondary funnel portion 235 may then be removed from the tissue surface. The microneedles 130 remain embedded within the tissue, as shown in Figure 2E (side cross-sectional view).

[0052] The secondary funnel portion can be highly advantageous for facilitating wetting of the foam material and providing that the dissolution / separation region of the microneedles is located below the surface of the skin or other biological tissue, due to the benefits discussed above. However, in some other embodiments, the secondary funnel portion is omitted and the microneedles extend directly from the primary funnel portion. The structure of the microneedle array and the placement of the foam material may vary. For example, FIG. 27 shows an embodiment of a microneedle array 2505 including a base substrate 2510 having a microneedle face 2515 and an opposing back surface 2520. The microneedle array 2505 includes a primary funnel portion 2525 from which the microneedles 2530 extend. The primary funnel portion 2525 and the base portion of each of the microneedles 2530 include a foam material. The tips of the microneedles 2530 do not include a foam material. FIG. 28 shows another embodiment of a microneedle array 2605 including a base substrate 2610 having a microneedle face 2615 and an opposing back surface 2620. The microneedle array 2605 includes a primary funnel portion 2625 from which the microneedles 2630 extend. The microneedles 2630 include a base portion 2626 that includes a foam material. The foam material is not present at the tips of the microneedles 2630 or the primary funnel portion 2625. In these figures, the secondary funnel portion has been omitted and the microneedles extend directly from the primary funnel portion.

[0053] Microneedle Arrays and Patches The microneedle array includes a base substrate and two or more microneedles extending from the surface of the base substrate. Each microneedle has a proximal end that is directly attached to the base substrate or indirectly attached through one or more funnels, and a distal tip that is sharp and effective for penetrating biological tissue. The microneedle has a tapered sidewall between the proximal and distal ends. The microneedle can generally have any cross-sectional shape, such as circular, polygonal, etc.

[0054] In some embodiments, the microneedle, or a portion thereof, is substantially conical. In some embodiments, the microneedle, or a portion thereof, is obelisk-shaped. In some embodiments, obelisk-shaped microneedles may be advantageous because the wide angle at the tip of the microneedle may allow a relatively high load of material to be placed at or near the tip.

[0055] The funnel may be integrally formed with the microneedle. The outer surface of the funnel may be distinguished from the microneedle portion of the structure by a distinct change / expansion in the angle of the surfaces that define the different parts of the protruding structure, which may be seen as expanding rapidly in at least one dimension (e.g., radially) as it progresses from the distal end to the proximal end of the microneedle. At its base end, the funnel is wider than its microneedle end. This expansion may be designed so that the funnel is inserted little or not at all into the target tissue layer or space. For example, when the microneedle array includes a foam material dispersed in the funnel, the expansion may be designed to allow at least a portion of the funnel to be inserted into the target tissue layer so that biological fluids, such as interstitial fluid, can contact the funnel.

[0056] In certain embodiments, a microneedle array is provided for administration of contraceptive hormones or other substances of interest to biological tissue such as the skin, the array comprising a base substrate having a microneedle face and an opposing back surface, at least one primary funnel portion extending from the microneedle face of the base substrate, and two or more solid microneedles extending from the at least one primary funnel portion, the two or more solid microneedles containing the substance of interest and a secondary funnel portion extending from the at least one primary funnel portion. The primary and secondary funnel portions may contain 0% to 20% of the substance of interest present within the combination of the two or more solid microneedles and the primary and secondary funnel portions from which the two or more solid microneedles extend. This embodiment advantageously avoids wasting the drug within the funnel portion. In some embodiments, the primary and secondary funnel portions contain 0% of the substance of interest.

[0057] 3A (perspective view) and FIG. 3B (side cross-sectional view) show an example of a microneedle array 305 as part of a microneedle patch 300, with each microneedle 330 extending from a funnel portion 325. Each microneedle 330 includes a bubble structure 331 at the interface of the microneedle 330 and the funnel portion 325. The microneedle array 305 has a microneedle face 315 and an opposing back face 320. An adhesive layer 335 is applied to the opposing back face 320 of the microneedle array. The microneedle array 305 is attached to a handling layer by the adhesive layer 335. The handling layer 340 includes a tab portion 345 that extends away from the microneedle array. The tab portion 345 allows a person to manually hold and manipulate the microneedle patch 300 without having to touch the microneedles 330. The adhesive cover 350 is attached to a portion of the adhesive layer 335 that overlies the tab portion 345 of the handling layer 340. The adhesive cover 350 allows a person to manually hold and manipulate the microneedle patch 300 without having to touch the adhesive layer 335. Although a cellular structure is shown in the embodiment shown in Figures 3A and 3B, other embodiments of the microneedle patch do not include a cellular structure, but instead have the secondary funnel portion 325, a portion of the microneedle 330 (e.g., the base end of the microneedle 330), or a combination thereof that includes a foam material.

[0058] An optional mechanical force indicator 355 is disposed between the adhesive layer 335 and the handling layer 340. The mechanical force indicator can be used to indicate to a person the amount of force and / or pressure applied to the patch during its use. For example, in one embodiment, the indicator is configured to provide a signal when the force applied to the patch by the user (in the course of applying the patch to the patient's skin to insert one or more microneedles into the patient's skin) meets or exceeds a predefined threshold. The predefined threshold is the minimum force or some amount greater than the minimum force required for a particular microneedle patch to be effectively applied to the patient's skin. That is, the force required to properly insert the microneedles, e.g., completely, into the patient's skin.

[0059] The length of the microneedles (LMN) can be about 50 μm to 2 mm. In most cases, they are about 200 μm to 1200 μm, and ideally about 500 μm to 1000 μm. The length (height) of the funnel (L FUN ) can be about 10 μm to 1 cm. In most cases, the funnel is about 200 μm to 2000 μm, more preferably about 500 μm to 1500 μm. FUN / L MN Ratio L can be about 0.1 to 10, more typically about 0.3 to 4, and more preferably about 0.5 to 2, or about 0.5 to 1, although ratios of about 1 to 2 are also useful. FUN / L MN may be less than about 1 or may be greater than about 1. MN +L FUN may be about 60 μm to 1.2 cm, more typically about 300 μm to 1.5 mm, and more preferably about 700 μm to 1.2 mm. MN +L FUN may be greater than about 1 mm, greater than about 1.2 mm, or greater than about 1.5 mm.

[0060] Microneedle volume (V MN The volume of the funnel (V) can be about 1 nl to 100 nl. In most cases, it is about 5 nl to 20 nl. FUN ) may be about 1 nl to 20,000 nl, more typically about 5 nl to 1000 nl, and more preferably about 10 nl to 200 nl. FUN N MN may be about 0.1 to 100, more typically about 0.5 to 20, and more preferably about 1 to 10 or about 2 to 5.

[0061] The cross-sectional area of ​​the microneedle (or the combined cross-sectional area of ​​the microneedle and the bubble structure, if applicable) that is in contact with the funnel (A MN-FUN ) is approximately 300 μm 2 ~800,000μm 2In most cases, it is about 10,000 μm2 to 500,000 μm2, and more preferably about 50,000 μm2 to 200,000 μm2. The cross-sectional area of ​​the funnel-base interface (A FUN-BASE ) is approximately 301 μm 2 ~8×10 7 μm 2 and more typically about 10,000 μm 2 ~5×10 6 μm 2 and more preferably about 100,000 μm 2 ~2×10 6 μm 2 It is. FUN-BASE / A MN-FUN is always greater than 1 as the funnel extends outward from the microneedle. FUN-BASE / A MN-FUN is about 1.1 to 2500, more typically about 1.5 to 100, and more preferably about 2 to 10.

[0062] Two or more microneedles may be disposed on the base substrate at any suitable density, for example, a plurality of microneedles may be arranged in a uniform or staggered row in an array, where each microneedle is separated from its nearest neighbor by a distance approximately equal to the height of the microneedle.

[0063] The width at the microneedle-funnel interface (W MN-FUN ) is about 20 μm to 1000 μm. In most cases, it is about 100 μm to 500 μm, more preferably about 200 μm to 400 μm. FUN-BASE ) is about 30 μm to 1 cm, more typically about 300 μm to 1500 μm, and more preferably about 500 μm to 1000 μm. FUN-BASE / W MN-FUN is always greater than 1 as the funnel extends outward from the microneedle. FUN-BASE / W MN-FUN is about 1.1 to 50, more typically about 1.5 to 10, and more preferably about 2 to 5.

[0064] A microneedle patch may contain different microneedles. For example, different microneedles of a microneedle patch may contain materials of different compositions, including different active substances and / or excipients and / or other materials. Microneedles containing materials of the same composition may be joined to a common funnel. In addition to different materials being loaded into different microneedles, rows, regions, the microneedles and funnels themselves may have a separation layer of material. The separation layer may appear stacked or striped, and the separation layer may be in the form of a shell layer that starts inward from the sidewall of the cavity in the mold.

[0065] funnel part In some embodiments, the microneedle patches provided herein advantageously include one or more funnels between the base substrate and the microneedles themselves. The addition of a funnel (sometimes referred to herein as a "funnel", "funnel section", "base", "primary funnel section", "secondary funnel section", or "funnel lead-in") confers certain advantages to its use, its manufacture, or both its use and manufacture.

[0066] First, by incorporating funnels into the microneedle patch, the difficulty of tissue insertion can be reduced because they lift the microneedles from their base or backing layer, allowing the microneedles to contact and penetrate the target tissue more easily without the need to lengthen the microneedles. This can increase the efficiency of microneedle insertion (e.g., the success rate of microneedle penetration) and reduce the amount of force required to successfully apply the microneedle patch. That is, a greater number of the microneedle population penetrates the tissue (e.g., 80% or 90% or 95% or more of the microneedles in the patch) or a greater proportion of each microneedle penetrates into the skin (e.g., 50% or 75% or 80% or 90% or 95% or more of the length or volume of the microneedles in the patch on average). The end result of either of these measures of microneedle penetration success rate is that the majority of the target substance administered by the microneedle is delivered into the tissue.

[0067] Such an approach in microneedle design can also advantageously provide microneedle insertion with little or no funnel insertion after applying minimal force. That is, the resulting insertion depth of the funneled microneedle is less sensitive to the application of excessive force during patch application, since the rapid expansion of the funnel area prevents insertion, resulting in insertion up to the microneedle-funnel interface at most. This allows the microneedle to be inserted with only simple thumb pressure, thumb pressure with a mechanism to indicate that the minimum required force has been applied, or a simpler, less aggressive applicator that cannot rely on impact. For example, when an array of longer microneedles is pressed against the skin, it is possible for the microneedles to only be partially inserted and still penetrate shallowly. However, the actual depth of microneedle insertion is very difficult to control, since the minimum force required varies due to differences between individuals (e.g., skin type) and application sites (e.g., location on the patient's body). Thus, the insertion force to partially insert an array of longer microneedles will vary, with applying too short or too long a force resulting in inappropriate microneedle insertion depth. This is mitigated when using microneedles with funnel retractions, as the rapid expansion of the funnel limits the depth of insertion. When minimal (or greater) force is applied, the depth of insertion is consistent.

[0068] Second, the addition of a funnel can significantly reduce manufacturing challenges since it greatly increases the target area during the mold filling step as the funnel extends outward from the microneedle cavity. This larger area target (i.e., funnel-base interface) greatly relaxes the positional precision required for the deposition / filling system compared to a mold that does not include a funnel, where the target area is the microneedle-base interface. In addition, the volume to fill a funneled microneedle can be many times larger than the microneedle itself, thereby also reducing this constraint.

[0069] Other advantages and benefits of the developed microneedle array design and manufacturing method are described throughout the remainder of this specification. It is certain that the improved manufacturing method is applicable to microneedle arrays that include a funnel as well as to microneedle arrays that do not include a funnel.

[0070] The funnel can be formed in a variety of different configurations. The funnel can have tapered walls (steep or shallow), "step" walls, tapered walls that eventually become vertical, hemispherical walls, or a combination thereof. The funnel can be symmetrical or asymmetrical. Some of these configurations are illustrated in the cross-sectional views shown in Figures 4A-4I.

[0071] Each of the microneedle configurations shown in Figures 4A-4F (cross-sectional side views) includes a bubble structure 401 at or near the base end of the microneedle. Figure 4A shows a conical funnel 410 with straight tapered sidewalls and microneedles 400 extending therefrom. Figure 4B shows a funnel 420 with stepped sidewalls and microneedles 400 extending therefrom. Figure 4C shows a funnel 430 with sidewalls having both tapered and non-tapered (vertical) sections and microneedles 400 extending therefrom. Figure 4D shows an axisymmetric funnel 440 with sidewalls and microneedles 300 extending therefrom that taper at a different angle on one side 441 of the funnel compared to another (e.g., opposite) side 442 of the funnel. Figure 4E shows a shallow conical funnel 450 with straight tapered sidewalls and microneedles 400 extending therefrom. FIG. 4F shows a hemispherical shaped funnel 460 having curved sidewalls and microneedles 400 extending therefrom.

[0072] Each of the microneedle configurations shown in Figures 4G-4I (cross-sectional side views) includes a funnel portion containing a foam material. When a foam material is included in the funnel portion, the funnel portion can be configured to contact a biological fluid, e.g., interstitial fluid, upon penetration of the biological tissue by the microneedle array. Figure 4G shows a conical funnel portion 410 having a straight tapered sidewall and microneedles 400 extending therefrom. Figure 4H shows a funnel portion 430 having a sidewall with both tapered and non-tapered (vertical) portions and microneedles 400 extending therefrom. Figure 4I shows an axisymmetric funnel portion 440 having a sidewall that tapers at a different angle at one side 441 of the funnel compared to another (e.g., opposite) side 442 of the funnel and microneedles 300 extending therefrom. Funnel portions containing foam material such as those shown in Figures 4G-4I can be used in the microneedle patches shown in Figures 3A and 3B. In some embodiments, the foam material is present in only a portion of the funnel. In some embodiments, the foam material is present in a portion of the microneedle, such as the base end of the microneedle. When the foam material is present in a portion of the microneedle, the foam material may not be present in the funnel portion corresponding to the microneedle, or the foam material may be present in at least a portion of the funnel portion corresponding to the microneedle.

[0073] A single microneedle array or patch may have funnels with two or more different geometric shapes. For example, an array may include one row of microneedles with funnels of a first size or shape, and a second row of microneedles with funnels of a second size or shape. Such differences may be usefully designed, for example, to deliver two different substances of interest.

[0074] Manufacturing and use considerations also influence the selection of funnel geometry. For example, the density (i.e., spacing) of the microneedles and funnels in the array can also be balanced with the microneedle / funnel geometry to allow for easy needle insertion with little or no funnel insertion (i.e., the closer the microneedles are spaced, the more difficult the insertion will generally be). As another example, during manufacturing, a volume of solution is deposited into the funnel of the mold, and upon drying / curing, the solute will essentially migrate into the microneedles of the mold and their tips. The funnel shape is designed in one embodiment to facilitate and maximize this solute migration.

[0075] The funnel extends from where it joins the microneedle in at least one dimension. In most cases, it extends radially. As shown in Figures 5A, 5B and 5C, the minor angle α is located between a line extending from the funnel-microneedle interface to where the funnel meets the base and a line extending from the same location and perpendicular to the central axis of the microneedle. The angle α is less than about 90° but greater than about 10°. In most cases, the angle is between about 30° and 75°, more preferably between about 45° and about 60°.

[0076] Each microneedle can be associated with one funnel, and each funnel is associated with one microneedle. Alternatively, one microneedle can be associated with more than one funnel. Alternatively, one funnel can be associated with more than one microneedle. Generally, the number of microneedles per patch is ≧ the number of funnels. However, the number of funnels can exceed the number of microneedles when funnels are used in series. The number of microneedles per patch is generally 1-10,000, in most cases about 20-1000, more preferably about 50-500. The number of funnels per patch is generally about 1-10,000, and in most cases about 5-500, and more preferably about 10-500. The ratio of funnels to microneedles is about 0.01-10, more typically about 0.05-4, and more preferably 0.1-1. In some cases, the ratio of funnels to microneedles is about 1. In other cases, the ratio of funnels to microneedles is about 2 or greater. In some cases, all of the microneedles in a row are associated with the same funnel. In some cases, some of the microneedles are associated with funnels and others are not. In some cases, the number of funnels with which each microneedle is associated in a patch is not the same for all microneedles or for all funnels.

[0077] Funnels can also be used in series, i.e., in a collection of funnels, where a first funnel (i.e., primary funnel portion) (base end) feeds a number of other funnels (i.e., secondary funnel portions). For example, each microneedle can have its own funnel, and a row or section of the patch of microneedles and funnels can be joined to a larger elongated funnel. This is particularly useful when loading multiple active substances into a microneedle patch for some reason (e.g., the active substances are formulated differently for stability and / or release kinetics and are incompatible with each other). For example, some microneedles may release the active substance rapidly, thereby providing an immediate burst to quickly raise the blood concentration of the active substance to the therapeutic range, while other microneedles may be designed to release the active substance slowly to maintain the blood concentration of the active substance within the therapeutic range for an extended period of time. Alternatively, a single large funnel can be joined to the entire patch of microneedles (with or without their own separate funnels). This can be useful for loading a single active substance.

[0078] Target substance / drug substance A wide range of substances can be formulated for delivery to biological tissue using the present microneedles and methods. As used herein, the term "substance of interest" includes drug substances, allergens, vitamins, cosmetics, cosmeceuticals, diagnostic agents, markers (e.g., color dyes or radioactive dyes or markers), and other substances that are desirable to introduce into biological tissue. "Substance of interest" may be referred to herein as "active substances." In preferred embodiments, the biological tissue is human or other mammalian tissue, including, but not limited to, skin, ocular tissue, or other mucous membranes (e.g., buccal, nasal, gastrointestinal, rectal, etc.) of humans or other mammals. In alternative embodiments, the biological tissue is plant tissue.

[0079] In some embodiments, the substance of interest is a preventive, therapeutic, or diagnostic agent useful for medical or veterinary use. In some embodiments, the substance of interest is a preventive or therapeutic agent, which may be referred to herein as an API. In some embodiments, the API is selected from suitable proteins, peptides, and fragments thereof, which may be naturally occurring, synthetic, or recombinantly produced. Representative examples of types of APIs for delivery include antibiotics, antivirals, analgesics, anesthetics, antihistamines, anti-inflammatories, anticoagulants, allergens, vitamins, and antitumor agents.

[0080] In some embodiments, the substance of interest is a hormone. The hormone may include a contraceptive hormone, such as progestin. Examples of contraceptive hormones include levonorgestrel, etonogestrel, and nestrone. The hormone may include glucagon-like peptide-1 (GLP-1). The hormone may include testosterone. The hormone may include estrogen, such as ethinyl estradiol.

[0081] In one embodiment, the substance of interest comprises a vaccine. Examples of vaccines include vaccines for infectious diseases, cancer, neurological diseases, allergies, and therapeutic vaccines for smoking cessation or other addictions. Some examples of current and future vaccines for the prevention of anthrax, cervical cancer (Human Papilloma Virus), dengue fever, diphtheria, Ebola, Hepatitis A, Hepatitis B, Hepatitis C, Haemophilus influenzae b (Hib), HIV / AIDS, Human Papilloma Virus (HPV), influenza (seasonal and epidemic), Japanese encephalitis (JE), Lyme disease, malaria, measles, meningococcal, monkeypox, mumps, whooping cough, pneumococcus, polio, rabies, rotavirus, rubella, shingles (herpes zoster), smallpox, tetanus, typhoid, tuberculosis (TB), chickenpox (varicella), West Nile, and yellow fever.

[0082] In another embodiment, the substance of interest comprises a therapeutic agent. The therapeutic agent may be selected from small molecules or larger biotechnologically produced or purified molecules (e.g., peptides, proteins, DNA, RNA). Examples of therapeutic agents (which may include analogs and antagonists thereof) include insulin, insulin-like growth factor, insultropin, parathyroid hormone, pramlintide acetate, growth hormone releasing hormone, growth hormone releasing factor, mecasermin, factor VIII, factor IX, antithrombin III, protein C, protein S, β-glucocerebrosidase, alglucosidase-α, laronidase, idursulfase, galsulphase, agalsidase-β, α -1 protease inhibitors, lactase, pancreatic enzymes, adenosine deaminase, pooled immunoglobulin, human albumin, erythropoietin, darbepoetin-α, filgrastim, pegfilgrastim, sargramostim, oprelvekin, human follicle-stimulating hormone, human chorionic gonadotropin, lutropin-α, interferon (alpha, beta, gamma), aldesleukin, alteplase, reteplase, tenecteplase, urokinase, factor VIIa, drotrecogin-α, sargramostim ... chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin, human chorionic gonadotropin Kecalcitonin, exenatide, octreotide, divotermin-α, recombinant human bone morphogenetic protein 7, histrelin acetate, palifermin, becaplermin, trypsin, nesiritide, botulinum toxin (types A and B), collagenase, human deoxyribonuclease I, hyaluronidase, papain, l-asparaginase, peg-asparaginase, rasburicase, lepirudin, bivalirudin, streptokinase, anistreplase, bevacizumab, cetuximab, panitumumab , alemtuzumab, rituximab, trastuzumab, abatacept, anakinra, adalimumab, etanercept, infliximab, alefacept, efalizuman, natalizumab, eculizumab, antithymocyte globulin, basiliximab, daclizumab, muromonab-CD3, omalizumab, palivizumab, enfuvirtide, abciximab, pegvisomant, Crotalidene polyvalent Fab (sheep), digoxin immune serum Fab (sheep), ranibizumab,Denileukin diftitox, ibritumomab tiuxetan, gemtuzumab ozogamicin, tositumomab, I-tositumomab, anti-rhesus (rh) immunoglobulin G, desmopressin, vasopressin, deamino[Val4,D-Arg8]arginine vasopressin, somatostatin, somatotropin, bradykinin, bleomycin sulfate, chymopapain, glucagon, epoprostenol, cholecystokinin, oxytocin, corticotropin, prostaglandin, pentagetide, thymosin alpha 1, alpha 1 antitrypsin, fentanyl, lidocaine, epinephrine, sumatriptyline These include, but are not limited to, acetaminophen, benztropine methanesulfonate, liraglutide, fondaparinux, heparin, hydromorphone, omacetaxine mepesuccinate, pramlintide acetate, thyrotropin alpha, glycopyrrolate, dihydroergotamine mesylate, bortezomib, triptorelin pamoate, teduglutide, methylnaltrexone bromide, pasireotide, ondansetron hydrochloride, droperidol, triamcinolone hexacetonide, aripiprazole, estradiol valerate, morphine sulfate, olanzapine, methadone hydrochloride, and methotrexate.

[0083] In some embodiments, the substance of interest is a vitamin, herb, or dietary supplement known in the art.Non-limiting examples include 5-HTP (5-hydroxytryptophan), acai berry, acetyl-L-carnitine, activated charcoal, aloe vera, alpha lipoic acid, apple cider vinegar, arginine, angelica tree, ashwagandha, astaxanthin, barley, bee pollen, beta alanine, beta carotene, beta glucan, biotin, bitter melon, black cherry, black cohosh, black currant, black tea, branched ahaine amino acids, bromelain (bromelain), calcium, camphor, chamomile, chasteberry, chitin, and the like. Tosan, Chlorella, Chlorophyll, Choline, Chondroitin, Chromium, Cinnamon, Citicoline, Coconut Juice, Coenzyme Q10, Conjugated Linoleic Acid, Cordyceps Sinensis, Cranberry, Creatine, D-Mannose, Damiana, Deer Velvet, DHEA, DMSO, Echinacea, EDTA, Elderberry, Emu Oil, Evening Primrose Oil, Fenugreek, Feverfew, Folic Acid, Forskolin, GABA (Gamma Aminobutyric Acid), Gelatin, Ginger, Ginkgo Biloba, Ginseng, Glycine, Glucosamine, Glucosamine Sulfate, Glycine ... Glutathione, ursin, grape seed extract, green coffee, guarana, guggul, gymnema, hawthorn, hibiscus, holy basil, horny goat weed, inulin, iron, krill oil, L-carnitine, L-citrulline, L-trypothophan, lactobacillus, magnesium, magnolia, milk thistle, MSM (methylsulfonylmethane), nicotinic acid, olive, omega-3 fatty acids, oolong tea, oregano, passionflower, pectin, phenylalanine, phosphatidylserine, potassium, probiotics, progesterone These include: erythritol, quercetin, ribose, red koji, reishi mushroom, resveratrol, rose hips, saffron, SAM-e, saw palmetto, schapodoris, sea buckthorn, selenium, senna, slippery elm, hypericum perforatum, nettle, tea tree oil, theanine, tribulus terrestris, turmeric (curcumin), tyrosine, valerian, vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, whey protein, witch hazel, xanthan gum, xylitol, yohimbe, and zinc.

[0084] A microneedle patch may contain a single substance of interest or may contain two or more substances of interest, in which case different substances may be provided together in one of the microneedles, or some microneedles in the array of microneedles contain one substance of interest and other microneedles contain another substance of interest.

[0085] The API is desirably provided in a stable formulation or composition (i.e., one in which the biologically active material therein essentially retains its physical and / or chemical stability and / or biological activity upon storage). Stability can be measured at a selected temperature for a selected period of time as known in the art.

[0086] In some embodiments, the substance of interest is provided as a "dry" or "dried" solid to form one or more microneedles, and is solubilized in vivo following insertion of the microneedles into the patient's biological tissue. As used herein, the term "dry" or "dried" refers to a composition from which a substantial portion of any water has been removed to produce a solid phase composition. The term does not require a complete lack of moisture (e.g., an API or a formulation containing the API may have a moisture content of about 0.1% to about 25% by weight).

[0087] The substance of interest may be included in the formulation together with one or more excipients and other additives, as described in more detail below.

[0088] Matrix Materials / Excipients The matrix material forms the microneedles, the funnel portion, including the primary funnel portion and the secondary funnel portion, and optionally the majority of the base substrate. The microneedles, the primary funnel portion, and the secondary funnel portion may be formed from the same or different matrix materials. The matrix material typically includes a biocompatible polymeric material, alone or in combination with other materials. A foam material may be dispersed within the matrix material used to form the funnel portion, a portion of the microneedle, or a combination thereof. A substance of interest may be dispersed within the matrix material used to form the microneedle and / or the funnel portion.

[0089] The matrix material may be biodegradable, bioerodible, and / or bioabsorbable. One or more matrix materials may be selected based on the rate at which the one or more matrix materials will biodegrade, bioerode, or bioabsorb. In some embodiments, the matrix material is water-soluble. A water-soluble matrix material may dissolve within minutes to tens of minutes upon contact with a fluid, such as a biological fluid.

[0090] In some embodiments, the microneedles are formed from a biodegradable, bioerodible, and / or bioabsorbable matrix material that encapsulates a substance of interest that is released upon degradation, erosion, absorption, or a combination thereof, of the matrix material.

[0091] In some embodiments, the microneedles are formed from a water-soluble matrix material that encapsulates biodegradable polymer microparticles. The biodegradable polymer microparticles then encapsulate the substance of interest. When the microneedles come into contact with biological fluids, they can dissolve relatively quickly, leaving behind biodegradable polymer microparticles that slowly degrade and release the substance of interest (e.g., within biological tissue).

[0092] In some embodiments, the majority of the microneedles are formed from a matrix material comprising polylactic acid, polylactic-glycolic acid, polycaprolactone, or a combination thereof. In some embodiments, the funnel portion, including the primary funnel portion and / or the secondary funnel portion, is formed from a matrix material, but comprises polyvinyl alcohol, a carbohydrate, or a combination thereof. In some embodiments, the carbohydrate is sucrose. In some embodiments, the funnel portion, including the primary funnel portion and / or the secondary funnel portion, is formed from a matrix material comprising polyvinylpyrrolidone. However, other matrix materials are envisioned.

[0093] As used herein, the terms "matrix material" and "excipient" are used interchangeably when referring to any excipient that is not volatilized or otherwise removed during drying and formation of the microneedles and funnels.

[0094] The fluid solution used in the mold filling process described herein may contain any of a variety of excipients. The excipients may be those commonly used in pharmaceutical formulations or new ones. In a preferred embodiment, the excipients are those found in FDA approved drug products (see Inactive Ingredients Search for Approved Drugs at http: / / www.accessdata.fda.gov / scripts / cder / iig / index.Cfm). One or more or none of the following categories of excipients may be used: stabilizers, buffers, bulking agents or fillers, adjuvants, surfactants, disintegrants, antioxidants, solubilizers, lyo-protectants, antimicrobials, anti-adherents, colorants, lubricants, viscosity enhancers, glidants, preservatives, materials for sustaining or controlling delivery (e.g., biodegradable polymers, gels, depot-forming materials, etc.). Also, a single excipient may serve the role of more than one formulation. For example, sugars may be used as stabilizers and bulking agents, or buffers may be used both to buffer the pH and to protect the active agent from oxidation.Some examples of excipients include lactose, sucrose, glucose, mannitol, sorbitol, trehalose, fructose, galactose, dextrose, xylitol, maltitol, raffinose, dextran, cyclodextrin, collagen, glycine, histidine, calcium carbonate, magnesium stearate, serum albumin (human and / or animal origin), gelatin, chitosan, DNA, hyaluronic acid, polyvinylpyrrolidone, polyvinyl alcohol, polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), polyethylene glycol (PEG, PEG 300, PEG 400, PEG 600, PEG 3350, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1100, PEG 1200, PEG 1300, PEG 1400, PEG 1500, PEG 1600, PEG 1700, PEG 1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG 2300, PEG 2400, PEG 2500, PEG 2600, PEG 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3100, PEG 3200, PEG 3350, PEG 3400, PEG 3500, PEG 3600, PEG 3700, PEG 3800, PEG 3900, PEG 4000, PEG 4000, PEG 4000, PEG 5000, PEG 4000, PEG 4000), Cellulose, Methylcellulose, Carboxymethylcellulose, Sodium Carboxymethylcellulose, Hydroxypropylmethylcellulose, Acacia, Lecithin, Polysorbate 20, Polysorbate 80, Pluronic F-68, Sorbitan Trioleate (Span 85), EDTA, Hydroxypropylcellulose, Sodium Chloride, Sodium Phosphate, Ammonium Acetate, Potassium Phosphate, Sodium Citrate, Sodium Hydroxide, Sodium Carbonate, Tris Base-65, Tris Acetate, Tris HCl-65, Citric Acid These include, but are not limited to, acid buffers, talc, silica, fats, methylparaben, propylparaben, selenium, vitamins (A, E, C, retinyl palmitate, and selenium), amino acids (methionine, cysteine, arginine), citric acid, sodium citrate, benzyl alcohol, chlorobutanol, cresol, phenol, thimerosal, EDTA, acetone sodium bisulfate, ascorbyl palmitate, ascorbate, castor oil, cottonseed oil, alum, aluminum hydroxide, aluminum phosphate, calcium hydroxyphosphate, paraffin oil, squalene, Quil A, IL-1, IL-2, IL-12, Freund's complete adjuvant, Freund's incomplete adjuvant, killed Bordetella pertussis, Mycobacterium bovis, and toxoids.The one or more selected excipients may be selected to enhance the stability of the substance of interest during drying or storage of the microneedle device, while also providing bulk and / or mechanical properties to the microneedle array.

[0095] In some preferred embodiments, the microneedles are made of a biodegradable matrix material that encapsulates the API, and when inserted into a patient, the entire microneedle separates within the skin and slowly degrades. In some other embodiments, the microneedles are made of a water-soluble matrix material that encapsulates biodegradable polymer microparticles that encapsulate the API. When inserted into the skin, the microneedles quickly separate from the backing (by bubbling or foaming), and the microneedles themselves also dissolve relatively quickly, leaving behind microparticles within the skin that slowly biodegrade and release the API.

[0096] Microneedle patch The microneedle array described above may be combined with one or more other components to generate a microneedle patch, such as a patch that can be applied manually to a patient's biological tissue, e.g., skin. For example, the microneedle array may be combined with an adhesive layer that can be used to facilitate fixing the patch to the patient's skin during administration of the substance of interest. A backing or handle layer may further be included to facilitate manipulation of the patch, as described above and illustrated in Figures 3A-3B.

[0097] The backing layer may be made of various materials and may be the same or different from the tab portion. In some embodiments, the backing layer may be a composite or multi-layer material that includes materials with various properties to provide desired properties and functions. For example, the backing material may be flexible, semi-rigid, or rigid, depending on the particular application. As another example, the backing layer may be substantially impermeable, protecting one or more microneedles (or other components) from moisture, gas, and contaminants. Alternatively, the backing layer may have other degrees of permeability and / or porosity, depending on the degree of protection desired. Non-limiting examples of materials that may be used for the backing layer include various polymers, elastomers, foams, paper-based materials, foil-based materials, metallized films, and nonwoven and woven materials.

[0098] The microneedle patch may include any one or more of the features and / or configurations described in U.S. Patent Application Publication No. 2017 / 0050010, which are incorporated herein by reference.

[0099] Method for producing a microneedle array The embodiments of the manufacturing methods described herein are used to make microneedle arrays, including a base substrate having one or more microneedles extending therefrom, as generally described. Generally speaking, the methods include a molding process that is advantageously highly scalable. The process involves providing a suitable mold, filling the mold with a suitable fluidized material, drying the fluidized material to form the microneedles, funnels, if included, and the base substrate, and then removing the formed part from the mold. These filling and drying steps may be referred to herein as "casting." The methods herein may include one or more of the features, components, and / or techniques described in U.S. Patent Application Publication No. 2017 / 0050010, which are incorporated herein by reference.

[0100] FIG. 6 illustrates one embodiment of a molding process that includes two castings. In this embodiment, a mold 601 is provided and then filled with a first fluidized material 602, which is then dried, thereby forming the microneedles of a microneedle array 606. The mold 602 is then filled with a second fluidized material 604, which is then dried, thereby forming the corresponding funnels of each microneedle of the microneedle array 606. The second fluid material includes a matrix material and a foam material. The microneedle array 606 is then removed from the mold 601. In a preferred embodiment, the first fluidized material 602 includes the substance of interest and the second fluidized material 604 does not include the substance of interest. A process flow diagram of one method of making a microneedle array as described herein is illustrated in the block flow diagram shown in FIG.

[0101] In some embodiments, the method includes the steps of: (a) providing a mold having an upper surface, an opposing lower surface, and an opening in the upper surface, the opening leading to a first cavity proximal to the upper surface and a second cavity below the first cavity, the first cavity defining at least one funnel portion, and the second cavity defining at least one microneedle; (b) filling at least the second cavity with a first material through the opening in the mold, the first material comprising a first matrix material and a substance of interest dissolved or suspended in a first liquid vehicle; (c) removing at least a portion of the first liquid vehicle to dry the first material in the mold to form at least a tip of a microneedle in the second cavity, the tip comprising the substance of interest; and (d) removing any of the first cavities and any of the microneedles that are unoccupied after steps (b) and (c). (e) removing at least a portion of the second liquid vehicle and drying the second material in the mold to form (i) at least one funnel portion and (ii) any portion of the at least one microneedle not formed after steps (b) and (c), wherein the at least one funnel portion comprises the foam material and the second matrix material; and (f) removing from the mold the at least one microneedle together with the at least one funnel portion joined thereto, wherein more of the substance of interest is located in the at least one microneedle than in the at least one funnel portion.

[0102] FIG. 8 illustrates another embodiment of a molding process that includes two castings. In this embodiment, a mold 801 is provided and then filled with a first fluidized material 802, which is subsequently dried, thereby forming the microneedles of a microneedle array 806. Thereafter, the mold 802 is filled with a second fluidized material 804, and air bubbles 807 are trapped between the microneedles and the second fluidized material. The second fluidized material 804 is then dried, thereby forming corresponding funnels of each microneedle of the microneedle array 806. The second fluidized material includes a matrix material. The microneedle array 806 is then removed from the mold 801. In a preferred embodiment, the first fluidized material 802 includes the substance of interest and the second fluidized material 804 does not include the substance of interest.

[0103] In some embodiments, the method includes the steps of: (a) providing a mold having an upper surface, an opposing lower surface, and an opening in the upper surface, the opening leading to a first cavity proximal to the upper surface and a second cavity below the first cavity, the first cavity defining at least one funnel portion, and the second cavity defining at least one microneedle; (b) filling at least the second cavity through the opening in the mold with a first material comprising a first matrix material and a substance of interest dissolved or suspended in a first liquid vehicle; (c) removing at least a portion of the first liquid vehicle and drying the first material in the mold to form at least a tip portion of a microneedle in the second cavity, the tip portion comprising the substance of interest; and (d) removing the first cavity and, if any are unoccupied after steps (b) and (c), the second cavity through the opening in the mold. (e) removing at least a portion of the second liquid vehicle to dry the second material in the mold to form (i) at least one funnel portion and (ii) any portion of the at least one microneedle not formed after steps (b) and (c), wherein the at least one funnel portion comprises the second matrix material; and (f) removing the at least one microneedle from the mold together with the at least one funnel portion attached thereto, wherein more of the substance of interest is located in the at least one microneedle than in the at least one funnel portion.

[0104] Methods for manufacturing microneedle arrays and patches are preferably carried out under a minimum of ISO 5(100), ISO 7, or ISO 8 process. Terminal sterilization may be utilized when compatibility of the sterilization method with the active material is demonstrated.

[0105] filling The composition of the filling solution generally reflects the desired materials in the final microneedle array, except for solvent, which may be substantially removed during processing.

[0106] In a preferred embodiment, the substance of interest is preferentially loaded into the microneedles and their tips, rather than into the funnels. The substance of interest is part of the filling material that is transferred into the mold. The filling material may also include a liquid vehicle. The filling material may be in the form of a solution, a slurry or suspension of particles, a melt, a powder or particles, or any combination of these forms. One or more of these forms may be used in a multi-step filling process. The "filling material" may be referred to herein as a "solution" or a "fluid material."

[0107] In various loading steps, the loading material may include a liquid vehicle. The term "liquid vehicle" may be referred to herein as "solvent" or "carrier fluid." In various embodiments, the loading material may include (1) solvent only, (2) no solvent, (3) matrix material only, (4) a combination of solvent and matrix material without the substance of interest, (5) a combination of solvent and substance of interest only, or (6) a combination of solvent, substance of interest, and matrix material. The solvent may be water, an organic solvent such as a volatile organic solvent, or a combination thereof. Some examples are acetic acid, heptane, acetone, isobutyl acetate, anisole, isopropyl acetate, 1-butanol, methyl acetate, 2-butanol, 3-methyl-1-butanol, methyl acetate, 2-butanol, methyl-1 ... Class 3 solvents include ethanol, butyl acetate, methyl ethyl ketone, tert-butyl methyl ether, methyl isobutyl ketone, dimethyl sulfoxide, 2-methyl-1-propanol, ethanol, pentane, ethyl acetate, 1-pentanol, ethyl ether, 1-propanol, ethyl formate, 2-propanol, formic acid, and propyl acetate. When the microneedle array includes a foam material, the liquid vehicle that includes the foam material should be a non-aqueous liquid vehicle. As used herein, the term "non-aqueous" refers to a liquid that contains less than 1% water by volume.

[0108] The microneedle and funnel cavities may be completely filled, partially filled, or overfilled. The filling step is generally followed by a drying or curing step. The drying or curing step can be accomplished by heating or vacuum (e.g., to evaporate the solvent), cooling or pressure (to solidify the matrix material), exposure to light (e.g., polymerization due to ultraviolet light exposure), or a combination thereof. This drying or curing step may completely, substantially, or only partially dry or cure the deposited material. In general, a solution will transport more active material into the microneedles and their tips if its viscosity is low, it has a high surface energy in the funnel, and it is not saturated with the active material (i.e., the active material is highly soluble in the solvent). However, none of these three features are required, and they have been found to typically allow for more preferential loading of the microneedles and their tips.

[0109] In a preferred embodiment, a two-step filling process is used, where the first filling step includes the substance of interest that is substantially transferred into the microneedle and its tip during the drying / curing process. This is followed by a second filling step and a subsequent drying / curing process. This second filling step includes a matrix material(s) that gives the microneedles and funnels their mechanical structure and can be overfilled to create the base substrate or a portion of the base substrate. The second filling step can result in trapping air bubbles between the material applied during the first filling step and the material applied during the second filling step.

[0110] One embodiment of a process involving two or more filling steps is as follows: The mold can be filled with a first solution containing the active substance (as well as possible excipients) and then dried. The mold can be filled again with the same solution and dried. This can be repeated until the desired amount of active substance is loaded into the microneedle. This is followed by one or more final filling steps in which the mold is filled with excipients (which can be the same or different excipients as in the previous filling) without the active substance, which upon drying provides the mechanical structure to the microneedle.

[0111] In one embodiment, the filling solution is provided to have low viscosity. A filling solution with a relatively low viscosity is more fluid and can flow down the microneedle more easily as it dries. In the embodiment in which the solution contains an active substance, it is generally preferred that the viscosity of the solution is less than about 100 cp, more preferably less than about 50 cp, more preferably less than about 10 cp, or more preferably less than about 5 cp. The viscosity of the filling solution can be modified to control the size and / or shape of the bubble structure.

[0112] In one embodiment, a centrifuge or similar device is used to rotate the mold to create a force vertical and directed into the mold, creating an attractive force to drive the solution down into the microneedles as it dries / hardens. This process can also be useful to drive larger molecules (e.g., active substances) down into the microneedles and their tips while the filler fluid is still in solution. The term "larger molecules" is used to mean molecules larger than those of the liquid vehicle, or solvent, and can include nanoparticles, microparticles, and other particles that are composed of many molecules.

[0113] In various embodiments, the microneedle molding process includes one or more of the following steps, application of vibration, ultrasound, pressure, vacuum, electromagnetic fields, and centrifugation before, during, and / or after any or all of the mold filling steps.

[0114] Filling per microneedle is difficult using conventional microneedle molds due to the small target size (e.g., leading to misalignment and missing individual microneedle reservoirs in the mold) and the small volume that needs to be deposited (e.g., extremely small deposition volumes lead to increased variability in the deposited volume). This becomes even more difficult in mass production. However, funnel-to-funnel (i.e., depositing the fill material into individual funnel-shaped cavities) and "blanket" filling (i.e., covering the area of ​​the mold surface that contains multiple individual microneedles / funnel-shaped cavities) is much easier because the target area can be many times larger than the opening area of ​​the individual microneedle cavities. In funnel-to-funnel filling, the fill volume (i.e., the volume of the microneedle and funnel) and the target area (i.e., the area of ​​the funnel-base interface) are advantageously many times larger than the fill volume and target area of ​​the microneedle alone, which can greatly reduce the variation in the deposited volume (e.g., 5nl±1nl is 5nl±20%, and 100nl±1nl is 100nl±1%, i.e., a 20-fold difference in absolute variation in this situation) and the deviation of the drop relative to the target. In blanket filling, the entire area is covered with solution, thereby further reducing volume and position constraints. The volume deposited by the blanket method can be less than, equal to, or larger than the combined volume of the microneedle and funnel. Any excess solution is removed (e.g., wiped off, air purged) once the microneedle and funnel cavities are filled.

[0115] The volume of solution deposited in the microneedle mold can be controlled by the volume of the cavities in the mold (i.e., filling the cavities completely with solution and then cleaning the surface), or by the filler (i.e., dispensing or dispensing a controlled volume, mass, etc.). In microneedle arrays produced by multiple filling steps, these volume control methods can both be used. For example, a solution containing an active agent is blanket coated over the entire surface, the microneedle and funnel cavities are filled, the solution is removed from the surface of the mold, the solution is dried, a second solution is deposited in an amount controlled by the filler, and the second solution is dried.

[0116] In some embodiments, the second solution includes a matrix material that forms a funnel that contacts the base end of the microneedle, and the volume of the second solution deposited on the microneedle mold is adjusted to control the size of the bubble structure. In some embodiments, increasing the volume of the second solution deposited on the mold decreases the size of the resulting bubble structure. In the embodiment shown in FIG. 9, second solutions having volumes of 30 to 90 μL produced bubble structures with depths of 310 to 105 μm, respectively.

[0117] In some embodiments, fluid handling / dispensing techniques / systems known in the art that can deposit solutions onto molds are used. Some are suitable for "blanket" coating (localized or full patch), targeted deposition, or both. Some examples of fluid handling / dispensing systems are syringes or other pumps coupled with a dispensing head (Tecan / Cavro, Gilson, Hamilton), automated pipette systems (Tecan, Biotek, Eppendorf), screen printing or other mask and clean type systems, slot coating or similar systems, inkjet printing systems (MicroFab), pin or capillary array dispensing techniques, active substance capillary systems (Innovadyne's Nanodrop), aerosol or spray-based systems, dipping, brushing, stamping, surface chemistry controlled deposition (PRINT-Particle Replication In Non-wetting Templates), acoustic-based systems (Picoliter, Inc.), and any combination of these deposition techniques (e.g., BioJet by BioDot, which is a hybrid of a syringe pump and inkjet). The filling head may be automated and moved, the mold may be moved, or both may be moved to deposit the solution at the desired location. This can be in the form of a single cavity, multi-cavity plate, or continuous reel-to-reel process.

[0118] Many drying and / or curing methods can be used throughout the manufacturing process. Heat can be applied in the form of a batch process, but it may be preferred to integrate it into a semi-batch or continuous process. Some of the drying methods that solidify the solution by removing the solvent by evaporation include: 1) heat-by convection, conduction (i.e., hot plate or heated surface), and / or radiation (heat lamp, IR or NIR light); 2) convection-dry, dried, sterile air or nitrogen blower; 3) exposure to vacuum-reduced pressure; 4) natural heat drying; 5) desiccation; 6) lyophilization or freeze drying; 7) dielectric drying (e.g., RF or microwave); 8) supercritical drying; and 7) application of a combination of one or more drying methods.

[0119] Some curing methods (hardening of the material resulting from polymerization / crosslinking or reversible polymerization / crosslinking of polymer chains) are brought about by electron beam, heat, or chemical additives / reactions. Curing triggers can include timed ultraviolet radiation (e.g., UV light), pressure, heat, etc.

[0120] As used herein, the terms "drying," "dried," or "drying," when referring to materials (e.g., matrix material and / or substance of interest) in a mold, refer to materials that are at least partially solidified. In embodiments, the microneedles may be removed from the mold before they are completely dry. In one embodiment, the microneedles are removed from the mold after they are dry and in an operative state. However, in a preferred embodiment, the microneedles are removed from the mold when they are in a rubbery state but strong enough to be pulled or peeled from the mold. This has been found to improve release without microneedle breakage. As used herein, the term "operable state" means that the microneedles are hard enough to be used for their intended purpose, e.g., to penetrate skin. As used herein, the term "rubber state" means that the microneedles are not in an operative state because they are too soft and flexible to penetrate their intended target tissue, e.g., skin. When a microneedle, such as one made of bulk / matrix material including polyvinyl alcohol and sugar, undergoes a drying process, its moisture content is reduced and it enters a rubbery state prior to entering an operational state.

[0121] How to Use Microneedle Arrays The microneedle arrays and patches provided herein can be self-administered or administered by another individual (e.g., a parent, guardian, minimally trained medical personnel, professionally trained medical personnel, and / or other person). The microneedle patches provided herein can be handled and administered directly by the person applying the patch without requiring the use of an applicator to apply the necessary force / pressure, thereby allowing for a very convenient, unobtrusive (i.e., thin and patch-like) microneedle patch (e.g., the total patch thickness, including any application aid, does not exceed 2 cm, more preferably 1.5 cm, more preferably 1 cm, more preferably 0.5 cm).

[0122] In some embodiments, the method of using a microneedle array comprises a simple and effective method of administering a substance of interest with 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. If necessary, the application site may be allowed to dry before applying the microneedle patch. The patch is then applied to the patient's skin / tissue and pressed manually (e.g., using a thumb or finger) against the patient's skin / tissue by applying sufficient pressure to insert one or more microneedles into the patient's skin / tissue.

[0123] The microneedles then separate from the microneedle patch when the funnel dissolves if the funnel comprises a foam material. When a foam material is included in the funnel, the microneedle patch may separate from the microneedle patch within about 10 seconds to about 120 seconds after the microneedle patch is pressed into the patient's skin / tissue. In some embodiments, the microneedle patch separates from the microneedle within about 40 seconds to about 60 seconds after the microneedle patch is pressed into the patient's skin / tissue.

[0124] When the microneedle patch includes a bubble structure, a shear force is applied to the microneedle patch after the microneedle patch is pressed into the skin / tissue of the patient. The shear force may be applied to any part of the microneedle patch. For example, the shear force may be applied by pulling on the tab portion. As a further example, the shear force may be applied by pressing on the base structure and / or the funnel portion. The shear force may be applied for a time effective to separate the microneedle patch from the microneedle patch. The shear force may be applied in one or more directions. The shear force may be generated as part of a relatively continuous motion that starts moving substantially perpendicular to the tissue surface and then changes direction (suddenly or gradually) to a direction substantially parallel to the tissue surface. In this way, a single motion (i.e., pressing against the back of the microneedle array or patch) can first generate a force that inserts the microneedles into the tissue and then generate a shear force that separates the microneedles from the array or patch. In some embodiments, the shear force is applied 0.01 seconds to 60 seconds, or 1 second to 60 seconds after insertion of the microneedle, hi some embodiments, the shear force is applied instantaneously upon insertion of the microneedle.

[0125] After the microneedles are separated from the patch, the patch may be removed from the patient's skin / tissue. The patch may be removed by manually grasping and pulling the tab portion (e.g., between thumb and finger) and discarding the patch. Now that the microneedles have been separated from the patch, the patch may be discarded as non-sharps waste.

[0126] In some embodiments, after microneedle detachment, the microneedles may readily dissolve (within minutes to tens of minutes), in some embodiments, the microneedles may dissolve, bioerode, biodegrade, and / or bioabsorb over days, weeks, or months.

[0127] In some embodiments, the microneedle patches described herein are used to deliver one or more substances of interest (e.g., vaccines, therapeutic agents, vitamins) into the body, tissues, cells, and / or organs. In some embodiments, the microneedles are used to deliver active agents into the skin by inserting the microneedles across the stratum corneum (the outer 10-20 microns of the skin, which is a barrier to transdermal transport) and into the viable epidermis and dermis. The small size of the microneedles allows for targeting the intradermal space while causing little or no pain. The intradermal space is highly vascularized and rich in immune cells, providing an attractive passageway for administering both vaccines and therapeutic agents. The microneedles are preferably dissolvable, and upon entering the intradermal space, they dissolve in biological fluids and release the active agent into the skin. The microneedles may be formulated to release the active agent over an extended period of time. The extended period may be at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 3 months, at least 6 months, at least 9 months, or at least 1 year.

[0128] In one embodiment, a method is provided for administering a substance of interest to a patient, the method comprising providing one of the microneedle arrays described herein and applying microneedles of the array to a tissue surface of the patient, where insertion of the microneedles of the array into the skin is performed by hand without the use of a separate or inherent applicator device. In this particular context, the term "applicator device" refers to a mechanical device that provides its own force, such as by spring action, that serves as an initial force to drive the microneedle array against the tissue surface, separate from any force that a user may apply to hold the device and / or microneedles against the tissue surface.

[0129] Unless otherwise defined below in this specification or the remainder of the specification, all technical or scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. In describing and claiming the present embodiments, the following terms shall be used in accordance with the definitions set forth below.

[0130] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless clearly stated otherwise. Thus, for example, reference to "a component" may include a combination of two or more components, and reference to "a buffer" may include a mixture of buffers, and the like.

[0131] As used herein, the term "about" indicates that a given quantity value can include an amount within a range of within 10% of the indicated value, optionally within 5% of that value, and in some embodiments, within 1% of that value. EXAMPLES

[0132] Example 1 - Fabrication of rapidly detachable microneedle arrays The studies described in Examples 1-6 herein were designed with the objective of developing a microneedle patch having rapidly detachable microneedles that slowly release levonorgestrel (LNG) and maintain LNG plasma concentrations above human therapeutic levels for one month.

[0133] The approach began by formulating an embodiment of a microneedle patch that met the following criteria: (i) a sharp tip and mechanical strength suitable for penetration into the skin, (ii) incorporation of air bubbles into the microneedle patch-back interface that allows for rapid microneedle detachment within the skin after application of mild shear, (iii) encapsulation of LNG in microneedles formulated to release LNG at a steady rate that maintains LNG plasma concentrations above human therapeutic levels over a one-month period, (iv) use of well-established biocompatible materials, (v) no generation of sharps waste, and (vi) expectation of easy and painless self-administration by patients. The resulting microneedle patch was studied in vitro and in vivo in rats to assess the ability of the patch to meet these criteria.

[0134] A polydimethylsiloxane (Pdms) mold was used to fabricate the microneedle patch of this example. The microneedles were arranged in a 10x10 array with an area of ​​7x7mm and a center-to-center spacing of 600μm, and each microneedle was cone-shaped with a base radius of 150μm, a height of 600μm, and a tip radius of about 10μm. To demonstrate the feasibility of scaling up to human dosing, a patch containing a 20x20 microneedle array was also fabricated, which could be inserted into and removed from the skin, and contained 1.52±0.08mg of LNG per patch.

[0135] The patch backing contained an array of pedestals (base diameter 600 μm, top diameter 150 μm, height 350 μm) positioned at the base of each microneedle, elevating the microneedles above the base of the backing.

[0136] The microneedles were cast in an organic solvent (dioxane / tetrahydrofuran, 70% / 25%, v / v) to solubilize the polylactic acid (PLA), polylactic-glycolic acid (PLGA), and LNG, with 5% v / v water to retard evaporation during fabrication. The polymer and LNG were filled into the mold cavity by centrifugation to form the microneedles and enhance microneedle strength by minimizing void formation. A PVA / sucrose backing solution was then applied to the mold to trap any air bubbles due to poor wetting of the dried polymer microneedles by the aqueous backing solution. The resulting microneedle patch (i.e., "air bubble microneedle" patch) was a 0.5 cm patch attached to a slightly larger piece of stiff tape. 2 The patch contained a 10 × 10 array of microneedles. The patch was designed to be small enough to simplify shipping / storage, yet large enough for convenient patient handling.

[0137] Microneedle array fabrication involved sequential casting of two solutions into a mold. The first casting solution contained 5% (w / v) of solids dissolved in a mixture of dioxane / tetrahydrofuran / water (70% / 25% / 5%, v / v). The solids consisted of PLGA / PLA / LNG (72% / 8% / 20%, w / w). A formulation containing a 90:10 ratio of PLA:PLA was chosen, such that PLGA provided the primary control over drug release rate, and PLA was added to increase mechanical strength.

[0138] The size of the air bubbles at the base of each microneedle was important to control because the air bubble structure determined, at least in part, the mechanical strength of the microneedle-backing interface. Air bubble size was controlled by adjusting the backing solution volume applied during the second cast, as increasing the weight of a larger amount of backing solution forced more air away from the microneedle-backing interface. Varying backing solution volumes from 30 to 90 µL created air bubble structures with depths of 310 to 105 µm (i.e., height, or distance from the air bubble / microneedle interface and air bubble / backing interface), as shown in Figure 9. The air bubble structures extended into the patch backing base, thereby not altering the size and shape of the microneedles.

[0139] Specifically, the casting solution was prepared by dissolving 0.45 g of PLGA (50 / 50 lactide / glycolide molar ratio, intrinsic viscosity 0.59 dL / g, Durect, Binningham, AL) and 0.05 g of PLA (intrinsic viscosity 1.02 dL / g, Durect) in 2 mL of dioxane (Sigma-Aldrich, St. Louis, MO), then adding a solution of 0.125 g of LNG (Chemo Industriale Chimica SRL, Saronno, Italy) into 3.375 mL of tetrahydrofuran (Thermo Fisher Scientific, Waltham, MA), and finally mixing them with additional dioxane and deionized (DI) water to obtain the final casting solution.

[0140] To fabricate blank microneedle patches, no LNG was added into the polymer solution containing 5% (w / v) solids composed of PLGA / PLA (90% / 10%, vdw) in dioxane / DI water (95% / 5% v / v). To fabricate microneedle patches containing Nile Red (Sigma Aldrich), 20 mg of Nile Red powder was added to the blank casting solution without LNG. 20 microliters of casting solution was applied to the top of the microneedle mold and then centrifuged at 3200 g for 2 minutes to fill the mold. Then, 20 μL of dioxane was applied to the top of the mold and centrifuged at 3200 g for 2 minutes to wash the residual casting solution on the top of the mold into the mold cavity. The loading and washing process was repeated three more times to completely fill the mold, and then the mold was placed in a 60 °C oven with vacuum for 12 hours to dry.

[0141] A second casting solution containing 18% (w / v) PVA (MW 6000 Da, Sigma-Aldrich) and 18% (w / v) sucrose (Sigma-Aldrich) in DI water was lightly applied to the dried PDMS mold surface to form a patch backing. During this casting, air bubbles may be trapped between each of the microneedles and the base of the patch backing, so as to control the bubble size by adjusting the volume of the second casting solution (30 μl, 50 μl, 70 μl, 90 μl). After drying in a chemical hood for 2 h, the mold was placed in a desiccator at room temperature (20-25 °C) for 2 days for complete drying, after which the patch was peeled off from the mold and stored in a desiccator until use.

[0142] The microneedles were made from PLGA, which facilitates controlled LNG release as described in the following examples, and a small amount of PLA, which is used to provide additional mechanical strength to the microneedles. Although virtually all of the LNG was released in vivo within 2 months, in the examples, some biodegradable polymer may remain in the skin. Related literature indicates that PLGA and PLA should biodegrade into oligomers and monomers of lactic acid and glycolic acid, which can be safely removed from the body, on a timescale of several months or a year, respectively. The total amount of PLGA and PLA in the microneedle array here was about 1.1 mg and about 0.1 mg, respectively. For comparison, the amount of PLGA in Lupron Depot, which has been safely administered to patients since FDA approval in 1995, is about 33 mg, and the amount of PLA in Lupron Depot-PED is about 99 mg (Lee, BK et al., Adv. Drug Deliv. Rev. 107, 176-191 (2016)). Therefore, the PLGA / PLA administered by these microneedle arrays / patches should be safely eliminated from the body.

[0143] Example 2 - Mechanical properties of microneedle patches Tests were conducted to investigate whether the bubble microneedle patch of Example 1 has sufficient mechanical strength to penetrate the skin under compression, yet still detach into the skin under mild shear. Microneedle strength during compression was determined to decrease with increasing bubble size, as measured using a 100 microneedle array as shown in Figure 10 and individual microneedles as shown in Figure 11.

[0144] The bubble microneedles of Example 1 were weaker than solid microneedles (no bubbles), but microneedles with the largest bubbles (i.e., 30 μL of backing solution / 310 μm bubble) could withstand a compressive force of 0.05-0.08 N / microneedle, which would be expected to allow skin puncture without fracture (Prausnitz, MR, Adv. Drug Deliv. Rev. 56, 581-87 (2004)).

[0145] In contrast, the air bubble microneedles easily broke under a shear force of 0.05-0.08 N / needle, a force that can easily be applied by hand, as shown in Figure 12. The solid microneedles required a shear of 0.157 ± 0.001 N / needle to deform, and these solid microneedles bent without fracturing, indicating that the shear force would not break the microneedles in the skin without the air bubbles.

[0146] Specifically, the mechanical properties of the solid and rapidly detachable microneedles of Example 1 containing different sized bubble structures were measured by a displacement force testing station (Force Gauge, Mark-10, Copiague, NY).

[0147] To test the microneedle patches under compression, a single patch was positioned vertically (microneedle facing up) on a rigid stainless steel platform and the test station sensor probe was approached vertically to the microneedle at a speed of 0.1 mm / s. The initial distance between the sensor and the microneedle tip was 1 cm, and displacement and force measurements were initiated when the sensor first touched the microneedle tip and continued until the sensor had moved 0.4 mm from the microneedle tip towards the patch backing.

[0148] To test the microneedle patches under shear, a single microneedle patch was mounted on a rigid platform positioned horizontally (with the microneedle patch facing to the side). The starting position was 1 cm away from the top of the microneedle, and the sensor approached the microneedle vertically at a speed of 0.1 mm / s, initiating displacement and force when the sensor first touched the microneedle and continuing until the sensor had moved 2.1 mm parallel to the patch backing.

[0149] Example 3 - Ex vivo microneedle patch skin insertion To determine whether the microneedles could be rapidly detached from the base when applied to the skin, foam microneedle patches were pressed against pigskin. The microneedles were loaded with Nile red dye for visualization. The microneedles penetrated the skin, and after applying a gentle shear (-0.07 N / needle) with a thumb 5 seconds after patch application, the microneedles detached from the patch backing and remained embedded within the skin. After microneedle detachment, very little red dye remained within the patch, further demonstrating efficient delivery of the microneedles into the skin. Histological sections showed that the microneedles detached completely within the skin below the skin surface. Light repeated scraping of the microneedle patch treatment site with a swab showed that the microneedles were not removed from the skin, as shown in Figure 13. Figure 13 shows quantification of the microneedle detachment efficiency before and after the scraping test. There was no substantial difference between the two data points (Student's t-test, p>0.05). The data showed that detached microneedles within the skin were not substantially removed by scraping the skin surface with a swab. Each point represents the mean ± SD (n=5).

[0150] Although approximately 100% of the microneedles penetrated the skin, more than 95% of the air bubble microneedles detached from the patch backing and more than 90% of the encapsulated dye (simulating encapsulated hormone) was delivered into the skin (Figure 14). In contrast, only 15% of the solid microneedles detached and less than 10% of the dye was delivered into the skin. These results demonstrated the rapid and efficient detachment and high delivery efficiency of the air bubble microneedle patch of this example. Figure 14 shows the quantification of the efficiency of microneedle penetration, microneedle detachment, and microneedle delivery of dye from microneedle patches with and without air bubble structure. Each bar represents the mean ± SD (n = 5), *p > 0.05.

[0151] Specifically, to evaluate the penetration, detachment, retention and delivery efficiency of the patches of Examples 1 and 2, patches loaded with a fluorescent dye (Nile Red) were inserted into ex vivo stretched pigskin by applying pressure with a thumb for 5 seconds, and then gently slid along one side along the skin surface to apply shear force and separate the microneedles from the patch backing.

[0152] After separation, the skin containing the detached microneedles was examined by optical microscopy (Olympus, Tokyo, Japan) to identify any detached microneedles embedded in the skin. In some cases, the swab was gently and repeatedly scraped for 10 seconds over the site of microneedle patch treatment to remove any detached microneedles partially protruding above the skin surface.

[0153] To evaluate the penetration of the microneedle patch, the patch was applied to the skin using normal force only and immediately removed. The skin was covered with gentian violet solution (Humco, Linden, TX) for 10 minutes to stain the microneedle penetration site, and then washed with an alcohol swab to remove residual dye on the skin surface. The penetration, separation, and retention efficiency were calculated by dividing the number of colored spots (i.e., due to gentian violet staining or the presence of fluorescent Mn in the skin) by the number of microneedles in the patch (i.e., 100 microneedles).

[0154] To better simulate actual use, the microneedle patch was applied to the skin by hand. To estimate the forces applied during insertion and detachment, the investigator pressed their thumb against a force gauge with a force similar to that applied to the microneedle patch. The compression force during microneedle patch insertion and the shear force during microneedle detachment were estimated to be approximately 0.25 N / needle and approximately 0.07 N / needle, respectively.

[0155] To evaluate the delivery efficiency of the microneedle patch, the fluorescence intensity from the dye in the microneedle patch before and after skin insertion, as well as the fluorescence from the dye on the skin surface, were measured by quantitative image analysis (Microplate Reader, Bio-Rad, Hercules, CA). The dye delivered into the skin was quantified by subtracting the amount of dye on the residual backing and skin surface from that in the microneedle patch before insertion. The delivery efficiency was calculated by dividing the dye delivered into the skin by the amount of dye in the microneedle patch before insertion. Finally, the skin was frozen and then cut into 10 μm sections for histological analysis.

[0156] Example 4 - Levonorgestrel release from microneedle patches in vitro LNG release from the bubble microneedle patch of Example 1 was performed in vivo using saline release medium containing 0-25% ethanol added to better simulate in vivo release kinetics and was often faster than in vitro release. LNG release did not show an initial burst release on day 1 (Figure 15) and LNG release kinetics was fairly constant over time (ranging from about 0.3% to about 2.2% of LNG released per day depending on ethanol concentration). Using 25% ethanol, all LNG was released within 45 days. These data demonstrated that sustained release of LNG from the bubble microneedle patch is possible and that a targeted delivery timeframe of at least one month can be achieved.

[0157] In addition, microneedle patches were fabricated by encapsulating LNG in microneedles fabricated from highly water-soluble PVA / sucrose. These microneedles demonstrated a burst release of 60-90% of LNG, with all LNG released within 6-12 days. Not all LNG was released immediately, likely due to the modest slow dissolution of water-soluble LNG as opposed to resistance from the highly water-soluble PVA / sucrose microneedle matrix.

[0158] Specifically, to evaluate the in vitro release of LNG from the microneedle patches and predict the in vivo release of LNG, PBST was used as the release medium along with different concentrations of ethanol. Specifically, one microneedle patch was placed in 1 L of PBST (with various concentrations of ethanol) in a glass container.

[0159] The PBST solution contains 137 mM NaCl, 2.68 mM KCl, 10.14 mM Na 2 HPO 4 , 1.76 mM KH 2 PO 4, and 0.02% (w / v) Tween-80, and ethanol was added to PBST to a final concentration of 0%, 2%, 10%, or 25% (v / v) ethanol. The glass vessels were incubated in a shaker water bath at 37°C and shaken at 80 rpm. At the designated time points (0, 1, 3, 6, 12, 18, 24, 30, 36, 43, 49, 54, 60 days), 1 mL of release medium was collected and replaced with the same amount of fresh medium.

[0160] The collected samples were analyzed by UPLC-MS (Waters, Milford, MA) to quantify the LNG concentration. 18 Separation was performed on a column (100 mm x 2.1 mm inner diameter, 1.7 μm particle size) at 50 °C. The mobile phase was a mixture of acetonitrile containing 0.1% formic acid and water containing 0.1% formic acid (8:2 ratio, v / v). The flow rate was 0.3 mL / min and the injection volume was 10 μL. Detection of LNG was performed by electrospray ionization mass spectrometry in positive ion mode. LNG (M+H + ; m / z = 313.4) was used for quantification.

[0161] Example 5 - Levonorgestrel pharmacokinetics after release from microneedles in vivo The bubble microneedle patch of the previous example achieved sustained release of LNG in rats that maintained LNG concentrations above human therapeutic levels (200 pg / ml) for one month. The mean LNG plasma concentration was up to about 1 ng / ml, but the therapeutic window of LNG is relatively large, with commercially available LNG-releasing products producing LNG plasma levels of up to 1.5 ng / mL (Sivin, I., et al., Contraception 56, 317-321 (1997)), indicating that elevated LNG plasma concentrations are acceptable. The microneedle patch of the previous example can be reformulated to release over a shorter (week) or longer (half a year) time period to address different user needs. The dosage can be increased by increasing the drug loading, the size of the microneedles, the number of microneedles, or other parameters (for longer delivery times or to load doses suitable for human use).

[0162] As demonstrated by this and the previous examples, no burst release of LNG from the bubble microneedle patch was observed in vitro or in vivo, although burst release is commonly seen in other biodegradable polymer controlled release systems (Huang, X., et al., J. Control Release 73, 121-136 (2001); Wang, J. et al., J. Control Release 82, 289-307). It is believed that no burst release occurred in the bubble microneedle patch of the examples herein due to the formation of a film of mostly drug-free polymer on the microneedle surface, possibly due to solvent migration into the mold, which concentrates / precipitates PLGA / PLA at the microneedle mold interface, possibly due to faster LNG redistribution within the mold due to its small molecular size, and / or possibly due to phase separation into polymer-rich and polymer-poor phases.

[0163] The foam microneedle patch of Example 1 (encapsulating hydrophobic Nile Red dye) was applied by hand to rat skin in vivo and after 5 seconds of gentle shearing, the microneedles penetrated the skin, detached from the patch backing, and became fully embedded beneath the skin surface. Fluorescence imaging of the skin surface demonstrated the dye release kinetics during microneedle biodegradation within the skin.

[0164] An array of fluorescent spots corresponding to the microneedles embedded within the skin was initially seen, which then gradually dimmed over time. The variable fluorescence intensity at the site of each microneedle may be due to different depths of insertion of the microneedles into the skin, resulting in different amounts of skin between each embedded microneedle and the skin surface that absorbed and scattered light. Quantitative analysis also showed a steady decay of fluorescence, corresponding to a slow and continuous release kinetics, with most of the fluorescence disappearing after 45 days, as shown in Figure 16. These release kinetics mirrored those of the Lng release shown in Figure 18.

[0165] Furthermore, application of a water-soluble microneedle patch made of PVA / sucrose loaded with a red dye also produced an array of bright fluorescent spots on the skin, which disappeared within 18 hours. This rapid disappearance demonstrated that the dye could be cleared from the skin within a day, whereas encapsulation in detachable PLGA / PLA microneedles extended the release for at least one month (see Figure 16).

[0166] To evaluate the LNG pharmacokinetics from the bubble microneedle patch of this example, rats were administered (i) an LNG-loaded bubble microneedle patch, (ii) a blank bubble microneedle patch containing no LNG, or (iii) no treatment ( FIG. 17 ). Rats administered the LNG-loaded microneedle patch showed no significant difference in time (T) 6.0±1.9 days after application. max ) with a peak concentration (C max ) showed increased LNG plasma concentrations. Table 1: S1 Mean ± SD levonorgestrel pharmacokinetic parameters following intravenous injection or LNG-loaded microneedle patch administration. [Table 1] C max :Maximum plasma concentration T max :C max Time AUC (0-t) : Area under the concentration-time curve from time 0 to the last detection time AUC (0-inf) : Area under concentration-time hardening from time 0 to infinity LNG removal rate constant (K e ) was estimated using the terminal phase of the plasma concentration versus time profile after intravenous LNG injection in the control group, and the data was fitted by log-linear regression to obtain the slope (K e ) was estimated. Half-life = 0.693 / Ke%F(bioavailability) = 100*[AUC MIN *dose IV ] / [AUC IV *dose MIN ]IV injection dose = 0.006 mg / each 200 g rat Microneedle dose = 0.3 mg / each 200 g rat NA: Not applicable

[0167] LNG levels then declined slowly, remaining above 200 pg / ml (which is the therapeutic level in humans) for 30 days, then hovering near therapeutic levels until 45 days, after which LNG concentrations declined to insignificant levels by 60 days.

[0168] Pharmacokinetic analysis showed relatively fast LNG absorption over the first 30 days, followed by slower absorption with >95% absorption after 45 days (Figure 18). The slow continuous LNG absorption profile in vivo was similar to the LNG release kinetics in vitro (using 25% ethanol release medium, Figure 15) and dye release in vivo (Figure 16). The LNG release profile in vivo was also similar to the target kinetics for the once-monthly contraceptive patch. The area under the curve for LNG delivery from the bubble microneedle (AUC) of 598 ± 141 ng·h / mL (Figure 17, Table 1) indicated 70% bioavailability compared to intravenous LNG injection (Table 1). Rats receiving blank microneedle patches or no treatment did not achieve Lng concentrations above background noise.

[0169] Bubble microneedle patch administration of LNG was well tolerated by the rats without erythema, edema, or other signs of irritation during the 60-day study. Histological analysis after completion of the study showed no evidence of changes in skin structure, inflammatory cells, or other signs of tissue damage.

[0170] Specifically, LNG pharmacokinetics was evaluated in adult female Sprague Dawley rats (200±12 g) by applying an LNG-loaded microneedle patch to each rat under isoflurane anesthesia. The skin on the back of the rat was shaved before applying the microneedle patch, taking care not to damage the skin during shaving.

[0171] To investigate polymer biodegradation and dye release from PLGA / PLA microneedles in rats, microneedle patches containing Nile Red were administered to rats using the method described above for ex vivo microneedle patch application to pigskin, and then the rats were imaged by fluorescence microscopy (Olympus) using consistent imaging settings (e.g., fluorescence excitation light intensity, image capture exposure time) for all rats on different days after microneedle application (0, 1, 7, 15, 30, 45, and 60 days).

[0172] The fluorescence intensity of microneedles implanted in rat skin was quantified by analyzing the fluorescence images using ImageJ (National Institute of Health, Bethesda, MD). As a control group, a water-soluble microneedle patch containing Nile red was applied to rat skin in vivo and kept on the skin for 15 min to allow the microneedles to completely dissolve. The rat skin was then imaged at 0, 4, 8, 12, and 18 h after administration, and the fluorescence intensity was quantified using the same method. As an additional control, a solution containing 10 mg / mL Nile red in dioxane was exposed to ambient light for 18 h. There was no significant difference in the fluorescence intensity of the solution between the exposed samples and (i) freshly prepared samples or (ii) similar samples left in the dark for 18 h.

[0173] To study the pharmacokinetics of LNG release from detachable microneedles, rats were randomly divided into three groups: the first group received an LNG-loaded microneedle patch, the second group received a blank microneedle patch (without LNG), and the third group did not receive any microneedle patch. Power analysis indicated that a sample size of 8 rats per group would be sufficient to distinguish the pharmacokinetic profile in animals receiving LNG from animals receiving a blank microneedle patch (without LNG) with 95% confidence.

[0174] The primary endpoint of the animal study was LNG plasma concentrations above human therapeutic levels over a one-month period. The secondary endpoint was inflammation at the microneedle patch application site. All data collected in this study was retained and outliers were not excluded. Blood samples (-500 μL) were taken from the tail vein at different times after microneedle patch application: 0 hours, 12 hours, 24 hours, 3 days, 7 days, 10 days, 14 days, 17 days, 21 days, 24 days, 28 days, 31 days, 35 days, 38 days, 42 days, 45 days, 49 days, 52 days, 55 days, and 60 days.

[0175] Plasma was then separated by centrifugation of blood samples at 2000 g for 15 min at 4°C, followed by analysis by enzyme-linked immunosorbent assay (ELISA, Thermo Fisher Scientific) according to the manufacturer's instructions to determine LNG concentrations. To evaluate the biocompatibility of Lng delivery from the detachable microneedle patch, rats were treated with CO 2 Mice were euthanized by asphyxiation and the tissue surrounding the patching site was excised, fixed in 10% neutral buffered formalin at 4° C. for 2 days, then embedded in paraffin after complete dehydration, cut into 5 μm thick sections, and stained with hematoxylin and eosin for histological analysis.

[0176] Example 6 - Pharmacokinetic Analysis Pharmacokinetic parameters were calculated using non-compartmental pharmacokinetic analysis. The parameters included: C max is the maximum observed plasma concentration and T max is C max is achieved, and K e is the elimination rate constant of LNG, and is the slope (K e ) and AUC (o-t) is the area under the plasma concentration-time curve from time 0 to the time of last detection using the linear trapezoidal rule, AUC (o-inf) is the area under the curve from time 0 to infinity. The bioavailability of LNG delivered from the microneedle was calculated from the ratio of dose-normalized AUC values ​​after microneedle patch administration and intravenous LNG injection. The Wagner-Nelson method was used to estimate the percent of LNG absorbed in vivo, and numerical deconvolution was applied to the LNG plasma concentration versus time profiles.

[0177] Example 7 - Fabrication of a microneedle patch with a foam backing In this example, when designing a rapidly detachable microneedle patch with a foam backing, PLGA was selected as the microneedle material because the biodegradable polymer is biocompatible, mechanically strong, and can be formulated for controlled release over weeks to months, however, other materials that may possess one or more of these characteristics may also be used and are envisioned.

[0178] Polyvinylpyrrolidone (PVP) was chosen as the backing because of its rapid solubility in water, good mechanical strength, and biocompatibility, however, other backings that may have one or more of these characteristics may be used and are envisioned.

[0179] To further increase the dissolution rate of the backing plate and realize rapid separation of the microneedles, a foaming agent (citric acid and sodium bicarbonate) was also formulated with PVP in the backing plate portion (Figure 19). When inserted into the skin tissue and contacted with biological tissues, such as interstitial fluid (ISF), under the skin tissue, sodium bicarbonate and citric acid quickly dissolved and reacted with each other immediately, producing CO2. 2 and water were produced. 2 made the backing plate more porous, and the water produced could dissolve more PVP polymer, citric acid, and sodium bicarbonate, and continuously stimulate the reaction between citric acid and sodium bicarbonate, further accelerating the dissolution of the backing plate polymer and facilitating the rapid separation of the microneedles.

[0180] As shown in FIG. 20, microneedle patches with foam backing were fabricated by casting a PLGA solution in diglyme / water (95% / 5%, v / v) with suspended LNG crystals. The polymer and LNG were filled into the mold cavity by centrifugation to form the microneedles and enhance microneedle strength by minimizing void formation. After drying the mold, 80 μL of foam backing polymer was pipetted onto the top of the mold surface, then dried in a chemical hood for 1 hour and then demolded. The resulting patch was a 0.5 cm2 microneedle patch attached to a slightly larger piece of stiff tape. 2 The patch consisted of a 10 × 10 array of sharp microneedles of 150 μm each, with each microneedle being cone-shaped with a base radius of 150 μm, a height of 600 μm, and a tip radius of approximately 10 μm. Mechanical strength measurements using a force gauge showed a failure force of 0.07 N / needle for the PLGA / LNG patch with a foam backing, indicating that the fabricated patch had sufficient strength to penetrate the skin without fracture.

[0181] Specifically, microneedle patches were fabricated using polydimethylsiloxane (PDMS) (Dow Corning, Midland, MI) molds. The microneedles were arranged in a 10 x 10 array with an area of ​​7 x 7 mm and 600 μm center-to-center spacing, and each microneedle was cone-shaped with a base radius of 150 μm, height of 600 μm, and tip radius of approximately 10 μm. The patch backing contained an array of pedestals (base diameter 600 μm, top diameter 150 μm, height 350 μm) positioned at the base of each microneedle, elevating the microneedles above the base of the backing.

[0182] Microneedle patch fabrication involved sequential casting of two solutions into a mold. The first casting solution contained 10% (w / v) solids dissolved in a mixture of diglyme / THF / water (70% / 25% / 5%, v / v). The solids consisted of PLGA / LNG (60% / 40%, w / w).

[0183] To fabricate microneedle patches containing Nile Red (Sigma-Aldrich), 20 mg of Nile Red powder was added to the casting solution. Seven microliters of the casting solution was applied to the top of the microneedle mold, then centrifuged at 3200 g for 20 minutes, and the mold was filled after waiting for 5 minutes. Then, 20 μL of diglyme / water (95% / 5%) was pipetted onto the top of the mold, followed by centrifugation at 3200 g for 20 minutes to wash the residual casting solution on top of the mold into the mold cavity. The mold was then placed in a 60° C. oven under vacuum for 12 hours to dry.

[0184] After the first casting on the mold, 80 μL of a second casting solution containing 13% (w / v) PVP with molecular weight 2 (360k / 55k, 50% / 50%, Sigma-Aldrich), 4% (w / v) citric acid (Sigma-Aldrich), and 5% (w / v) sodium bicarbonate (Sigma-Aldrich) in pure ethanol was lightly applied to the dried PDMS mold surface to form a patch foam backing. For the control group, the second casting solution contained 13% (w / v) PVA (Sigma-Aldrich) / 13% (w / v) sucrose (Sigma-Aldrich) in water or 13% (w / v) PVP (360k / 55k, 50% / 50%) in ethanol. After drying in a chemical hood for 1 h, the molds with foam or regular backings were placed in a desiccator at room temperature (20–25°C) overnight or for 2 days, respectively, for complete drying, after which the patches were peeled off from the molds and stored in a desiccator until use.

[0185] Example 8 - Mechanical properties of microneedle patches The mechanical properties of the rapidly detachable microneedle patches with foam backing were measured by a displacement force test station (Force Gauge, Mark-10, Copiague, NY). Briefly, a single patch was mounted on a rigid stainless steel platform positioned vertically (microneedle pointing up) and the test station sensor probe was moved vertically towards the microneedle at a speed of 0.1 mm / s. The initial distance between the sensor and the microneedle tip was 1 cm, and displacement and force measurements were initiated when the sensor first touched the microneedle tip and continued until the sensor had moved 0.4 mm from the microneedle tip towards the patch backing.

[0186] Example 9 - Microneedle patch detachment test To investigate whether the microneedle patch with foam backing of the previous examples can achieve rapid detachment of the microneedles, the patch was immersed in phosphate buffered saline (PBS), which was used to mimic the in vivo environment. The microneedles were filled with the fluorescent dye Nile Red for better visualization. Light field microscopy images showed that after the patch was immersed in the PBS buffer, the backing portion of the patch immediately generated a huge number of air bubbles, rapidly detaching the microneedles from the patch, at least in part due to the reaction of citric acid with sodium bicarbonate and the rapid dissolution of the backing polymer. As shown in Figure 21, the microneedle patch with foam backing took 10.7 ± 1.2 seconds to detach, compared to 94.0 ± 6.6 seconds for the patch with PVP backing and 53.3 ± 3.1 seconds for the patch with PVA / sucrose backing, demonstrating the rapid detachment of the microneedles with the foam backing.

[0187] Specifically, to evaluate the rapid detachment of microneedle patches with foam backing, a single patch facing up was mounted on a holder and then immersed in phosphate-buffered saline (PBS) solution. A camera was used to capture the detachment process of the microneedles in the PBS solution on the side until all the microneedles were detached from the patch. In the control group, the detachment of microneedle patches with PVP or PVA / sucrose backing was also recorded in PBS solution.

[0188] Example 10 - Ex vivo microneedle patch skin insertion To determine whether the microneedle patch with foam backing of the above embodiment can also be rapidly separated in skin, the patch is applied to pigskin in vivo.The microneedle is filled with Nile Red dye to improve visualization.The microneedle patch is pressed against the skin for 3 seconds, allowing the microneedle to enter the skin, and then the patch is placed on the skin for another 50 seconds, allowing the reaction of the foam backing formulation in ISF and the subsequent separation of the fluorescent microneedle in the skin.

[0189] After separation, almost no fluorescent dye remained in the residual patch, and only dissolved backing polymer could be observed. Histological sections showed that the separated microneedles were fully embedded. Based on the quantification shown in FIG. 22, 100% or close to 100% of the microneedles penetrated the skin, about 96% of the microneedles were delivered into the skin after separation from the patch with foam backing, and about 90.4% of the encapsulated fluorescent dye (simulating encapsulated hormone) was delivered into the skin. However, the microneedle patches with PVP backing or PVA / sucrose backing only showed less than 45% microneedle detachment efficiency and less than 35% dye delivery efficiency within such a short application time on the skin. Together, these results demonstrated the successful rapid detachment of microneedles with foam backing within the skin and high delivery efficiency of the patch in a very short period of time.

[0190] Specifically, to evaluate the penetration, detachment, retention and delivery efficiency of the microneedle patch, a patch loaded with a fluorescent dye (Nile Red) was inserted into ex vivo stretched pigskin by pressing with a thumb for 10 seconds, and then the patch attached to the skin was left for 50 seconds to allow complete dissolution of the foam backing and detachment of the microneedles. After detachment, the skin containing the detached microneedles was examined by optical microscopy (Olympus, Tokyo, Japan) to identify the detached microneedles embedded in the skin.

[0191] In some cases, the swab was gently scraped repeatedly over the site of the microneedle patch treatment for 10 seconds to remove detached microneedles that partially protruded above the skin surface. To evaluate the penetration of the microneedle patch, the patch was applied to the skin with only 5 seconds of pressure and immediately removed. The skin was covered with gentian violet solution (Humco, Linden, TX) for 10 minutes to stain the microneedle penetration site and then washed with an alcohol swab to remove residual dye on the skin surface. The penetration, separation and retention 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., 100 microneedles).

[0192] Specifically, to evaluate the delivery efficiency of the microneedle patch, the fluorescence intensity from the dye in the microneedle patch before and after skin insertion, as well as the fluorescence from the dye on the skin surface, were measured by quantitative image analysis (Microplate Reader, Bio-Rad, Hercules, CA). The dye delivered into the skin was quantified by subtracting the amount of dye on the residual backing and skin surface from that in the microneedle patch before insertion. The delivery efficiency was calculated by dividing the dye delivered into the skin by the amount of dye in the microneedle patch before insertion. Finally, the skin was frozen and then cut into 10 μm sections for histological analysis.

[0193] Example 11 - Levonorgestrel release from microneedle patches in vitro The microneedle patch with foam backing of the previous example was further tested for release of LNG by using a release medium of saline containing 0-25% ethanol, which was added to better simulate the release kinetics in vivo. Approximately 25% of the LNG was released on day 1 in the medium containing 25% ethanol, as shown in Figure 23, while there was no initial burst release of LNG in the other release media (i.e., media containing 0%, 15%, 20% ethanol). The Lng release kinetics was fairly constant over time. Even though the release medium with 25% ethanol showed the fastest LNG release at a rate of about 2.8% per day, it took as long as 35 days for all of the LNG to be released from the microneedle patch, indicating that sustained release of LNG from the microneedle patch is possible, with a targeted delivery term frame of at least one month being achievable.

[0194] Specifically, to evaluate the in vitro release of LNG from the microneedle patches and predict the release of LNG in vivo, PBST was used as the release medium with different concentrations of ethanol. Specifically, one microneedle patch was placed in 1 L of PBST (with various concentrations of ethanol) in a glass container.

[0195] The PBST solution contains 137 mM NaCl, 268 mM KCl, 10.14 mM Na 2 HPO 4 , 1.76 mM KH 2 PO 4, and 0.02% (w / v) Tween-80, and ethanol was added to PBST to a final concentration of 0%, 2%, 10%, or 25% (v / v) ethanol. The glass vessels were incubated in a shaker water bath at 37 °C and shaken at 80 rpm. At the designated time points (0, 1, 3, 6, 12, 18, 24, 30, 36, 43, 49, 54, and 60 days), 1 mL of release medium was collected and replaced with the same amount of fresh medium. The collected samples were analyzed by UPLC-MS (Waters, Milford, MA) to quantify LNG concentration. LNG was analyzed by Acquity UPLC BEH C 18 Separation was performed on a column (100 mm x 2.1 mm inner diameter, 1.7 μm particle size) at 50 °C. The mobile phase was a mixture of acetonitrile containing 0.1% formic acid and water containing 0.1% formic acid (8:2 ratio, v / v). The flow rate was 0.3 mL / min and the injection volume was 10 μL. Detection of LNG was performed by electrospray ionization mass spectrometry in positive ion mode. LNG (M+H + ; m / z=313.4) was used for quantification.

[0196] Example 12 - Levonorgestrel pharmacokinetics after release from microneedles in vivo To test the rapid detachment of microneedles and LNG pharmacokinetics from the microneedle patch with foam backing in vivo, a microneedle patch with foam backing (containing hydrophobic Nile Red dye) of the previous example was manually pressed against shaved rat skin in vivo for 3 seconds, and then the patch was left attached to the rat skin surface for an additional 50 seconds for dissolution of the foam backing and subsequent detachment of the microneedles. After application of the patch to the rat skin, the fluorescent microneedles detached from the patch in less than 1 minute (i.e., 3 seconds for pressing and 50 seconds for attachment), and histological sections showed that these microneedles were completely embedded in the rat skin. Figure 24 shows rat plasma concentrations of LNG after administration of LNG-loaded microneedle patches. Therapeutic LNG levels in humans are indicated by the blue dashed line. Each point represents the mean ± SD (n=10).

[0197] Specifically, LNG pharmacokinetics was evaluated in adult female Sprague Dawley rats (200±12 g) by applying an LNG-loaded microneedle patch to each rat under isoflurane anesthesia. The skin on the back of the rat was shaved before applying the microneedle patch, taking care not to damage the skin during shaving.

[0198] To investigate the detachment of PLGA / LNG MNs in rats, microneedle patches containing Nile red were administered to rats using the method described above for ex vivo microneedle patching of pigskin, and then the administration sites in the rats were imaged by fluorescence microscopy (Olympus).

[0199] To study the pharmacokinetics of LNG release from detachable microneedles, groups of 10 rats received LNG-loaded microneedle patches. Power analysis indicated that a sample size of 10 rats per group would be sufficient to distinguish the pharmacokinetic profile in animals receiving LNG from those not applying any patch with 95% confidence. The primary endpoint of the animal study was LNG plasma concentrations above human therapeutic levels over a one-month period. A secondary endpoint was inflammation at the microneedle patch administration site. All data collected in this study were retained and outliers were not excluded.

[0200] Blood samples (approximately 500 μL) were collected from the tail vein at different times after microneedle patch application: 0 h, 12 h, 24 h, 3 days, 7 days, 10 days, 14 days, 17 days, 21 days, 24 days, 28 days, 31 days, 35 days, 38 days, 42 days, 45 days, 49 days, 52 days, 55 days, and 60 days. Plasma was then separated by centrifugation of blood samples at 2000 g for 15 min at 4°C, after which analysis was performed by enzyme-linked immunosorbent assay (ELISA, Thermo Fisher Scientific) according to the manufacturer's instructions to determine LNG concentration.

[0201] To evaluate the biocompatibility of LNG delivery from the detachable microneedle patch, rats were monitored with CO at the end of the study (i.e., 60 days after microneedle patch application). 2 Mice were euthanized by asphyxiation and the tissue surrounding the patching site was excised, fixed in 10% neutral buffered formalin at 4° C. for 2 days, then embedded in paraffin after complete dehydration, cut into 5 μm thick sections, and stained with hematoxylin and eosin for histological analysis.

[0202] Example 13 - Microneedle Patch with Foam Backing in Human Trials To be eligible, participants had to be healthy, non-pregnant, female adults with normal skin, no known problems with pain perception, and no known allergies to the materials used in the study. Ten subjects between the ages of 21 and 36 were recruited.

[0203] Subjects received a microneedle patch on the dorsal surface of the hand. Three subjects received two patches on both hands, and the other subjects received only one patch on the left hand. The patch was applied to the subject's hand for approximately one minute, and the skin morphology was photographed by a camera at 0, 1, and 24 hours after patch application. For subjects who received two microneedle patches, the application site on the right hand was stained with gentian violet and then imaged 5 minutes after staining. All subjects were required to complete a short questionnaire to solicit information regarding pain of microneedle patch administration and acceptability of the microneedle patch for delivery of medications (e.g., contraceptives).

[0204] Figure 25 shows the normalized erythema intensity of the skin sites to which the microneedle patch was applied over time (n=10). Figure 26 shows the efficiency of the microneedle patch of this example in penetrating and detaching from the skin of subjects (n=4).

[0205] Example 14 - Statistical Analysis All results presented in this study were means ± standard deviations. Statistical analysis was performed using two-sided Student's t test or ANOVA test using Origin software. Probability values ​​less than 0.05 were considered significant.

Claims

1. 1. A microneedle array for administering a substance of interest into biological tissue of a patient, comprising: a base substrate having a microneedle surface and an opposite back surface; at least one primary funnel portion extending from the microneedle surface of the base substrate; and two or more solid microneedles extending from said at least one primary funnel portion, said two or more solid microneedles containing a substance of interest and a secondary funnel portion extending from said at least one primary funnel portion; the two or more solid microneedles are constructed to penetrate under pressure into biological tissue of the patient and then detach from the secondary funnel portion under shear after said penetration; A microneedle array, wherein the two or more solid microneedles comprise an air bubble structure at or near a base end of each microneedle, the air bubble structure facilitating the separation of the microneedles from the secondary funnel portion.

2. The microneedle array of claim 1 , wherein the bubble structure is at each interface of the two or more microneedles and the secondary funnel portion.

3. The microneedle array of claim 1 , wherein the substance of interest comprises a contraceptive hormone.

4. The microneedle array of claim 3 , wherein the contraceptive hormone comprises progestin.

5. The microneedle array of claim 1 , wherein the substance of interest comprises an active pharmaceutical ingredient.

6. The microneedle array of any one of claims 3 to 5, wherein the microneedle array is configured to release a therapeutically or prophylactically effective amount of the substance of interest to the patient for a sustained period of at least two weeks.

7. The microneedle array of any one of claims 3 to 5, wherein the microneedle array is configured to release a therapeutically or prophylactically effective amount of the substance of interest in the patient for a sustained period of at least four weeks.

8. The microneedle array of claim 1 , wherein the two or more solid microneedles are formed from a composition comprising a first matrix material in which the substance of interest is dispersed.

9. The microneedle array of claim 8 , wherein the first matrix material comprises polylactic acid, polylactic-glycolic acid, or a combination thereof.

10. The microneedle array of claim 8 , wherein the secondary funnel portion comprises a second matrix material.

11. The microneedle array of claim 10 , wherein the second matrix material comprises polyvinylpyrrolidone, polyvinyl alcohol, a carbohydrate, or a combination thereof.

12. The microneedle array of claim 11 , wherein the carbohydrate comprises sucrose.

13. The microneedle array of claim 1 , wherein the two or more microneedles have a length of about 200 μm to about 1200 μm.

14. The microneedle array of claim 1 , wherein the secondary funnel portion includes a straight tapered sidewall.

15. A microneedle patch, The microneedle array according to any one of claims 1 to 5, An adhesive layer; a handle layer attached to the base substrate, the handle layer including a tab portion extending laterally away from a single face of the two or more solid microneedles, the tab portion enabling a person to hold the tab portion in their hand and manipulate the patch without touching the two or more solid microneedles.

16. 1. A microneedle array for administering a substance of interest into biological tissue of a patient, comprising: a base substrate having a microneedle surface and an opposite back surface; at least one primary funnel portion extending from the microneedle surface of the base substrate; and two or more solid microneedles extending from said at least one primary funnel portion, said two or more solid microneedles containing a substance of interest and a secondary funnel portion extending from said at least one primary funnel portion; the secondary funnel portion comprises a first water soluble matrix material and a foam material; The two or more solid microneedles are constructed to penetrate into biological tissue of the patient under pressure and then detach from the secondary funnel portion upon at least partial dissolution of the secondary funnel portion.

17. The microneedle array of claim 16 , wherein the foam material comprises a salt of an acid and a base.

18. The microneedle array of claim 17 , wherein the acid comprises citric acid and the base salt comprises sodium bicarbonate.

19. The microneedle array of any one of claims 16 to 18, wherein the foam material and the first water-soluble matrix material are present in the secondary funnel portion in a weight ratio of about 0.2:1 to about 1:0.

2.

20. The microneedle array of claim 16 , wherein the substance of interest comprises a contraceptive hormone.

21. The microneedle array of claim 20 , wherein the contraceptive hormone comprises progestin.

22. The microneedle array of claim 16 , wherein the substance of interest comprises an active pharmaceutical ingredient.

23. The microneedle array of any one of claims 20 to 22, wherein the microneedle array is configured to release a therapeutically or prophylactically effective amount of the substance of interest in the patient for a sustained period of at least two weeks.

24. The microneedle array of any one of claims 20 to 22, wherein the microneedle array is configured to release a therapeutically or prophylactically effective amount of the substance of interest in the patient for a sustained period of at least four weeks.

25. 17. The microneedle array of claim 16, wherein the two or more solid microneedles are formed from a composition comprising a second matrix material in which the substance of interest is dispersed.

26. 26. The microneedle array of claim 25, wherein the second matrix material comprises polylactic acid, polylactic-glycolic acid, or a combination thereof.

27. The microneedle array of claim 16 , wherein the first water-soluble matrix material comprises polyvinylpyrrolidone, polyvinyl alcohol, sucrose, or a combination thereof.

28. The microneedle array of claim 16, wherein the two or more microneedles have a length of about 200 μm to about 1200 μm.

29. The microneedle array of claim 16 , wherein the secondary funnel portion includes a straight tapered sidewall.

30. A microneedle patch, The microneedle array according to any one of claims 16 to 18 or 20 to 22, An adhesive layer; a handle layer attached to the base substrate, the handle layer including a tab portion extending laterally away from the two or more solid microneedles to enable a person to hold the tab portion in their hand and operate the patch without touching the two or more solid microneedles.

31. 1. A microneedle array for administering a substance of interest into biological tissue of a patient, comprising: a base substrate having a microneedle surface and an opposite back surface; at least one primary funnel portion extending from the microneedle surface of the base substrate; and two or more solid microneedles extending from said at least one primary funnel portion, said two or more solid microneedles containing a substance of interest and a secondary funnel portion extending from said at least one primary funnel portion; the two or more solid microneedles are configured to (i) penetrate under pressure into biological tissue of the patient and then detach from the secondary infundibulum portion, and (ii) release a therapeutically or prophylactically effective amount of the substance of interest to the patient for a sustained period of at least two weeks; A microneedle array, wherein the substance of interest comprises a contraceptive hormone.

32. The microneedle array of claim 31 , wherein the contraceptive hormone comprises progestin.

33. 33. The microneedle array of claim 31 or 32, wherein the two or more solid microneedles comprise an air bubble structure at or near a base end of each microneedle, the air bubble structure facilitating the separation of the microneedles from the secondary funnel portion.

34. 34. The microneedle array of claim 33, wherein the bubble structure is at each interface of the two or more solid microneedles and the secondary funnel portion.

35. 33. The microneedle patch of claim 31 or 32, wherein the secondary funnel portion comprises a first water soluble matrix material and a foam material configured to increase the rate at which the first matrix material dissolves upon contact with biological fluid beneath the biological tissue, thereby facilitating the separation of the microneedles from the secondary funnel portion.

36. 36. The microneedle array of claim 35, wherein the first water-soluble matrix material comprises polyvinylpyrrolidone, polyvinyl alcohol, sucrose, or a combination thereof.

37. The microneedle array of claim 35 or 36, wherein the foam material comprises a salt of an acid and a base.

38. 33. The microneedle array of claim 31 or 32, wherein the microneedle array is configured to release a therapeutically or prophylactically effective amount of the substance of interest in the patient for a sustained period of at least four weeks.

39. 33. The microneedle array of claim 31 or 32, wherein the two or more solid microneedles are formed from a composition comprising a second matrix material in which the contraceptive hormone is dispersed.

40. 40. The microneedle array of claim 39, wherein the second matrix material comprises polylactic acid, polylactic-glycolic acid, or a combination thereof.

41. The microneedle array of claim 31 or 32, wherein the two or more microneedles have a length of about 200 μm to about 1200 μm.

42. The microneedle array of claim 31 or 32, wherein the secondary funnel portion comprises a straight tapered sidewall.

43. A microneedle patch, The microneedle array according to claim 31 or 32, An adhesive layer; a handle layer attached to the base substrate, the handle layer including a tab portion extending laterally away from a single face of the two or more solid microneedles, the tab portion enabling a person to hold the tab portion in their hand and manipulate the patch without touching the two or more solid microneedles.

44. 1. A method for fabricating an array of microneedles, comprising: (a) providing a mold having an upper surface, an opposing lower surface, and an opening in the upper surface, the opening leading to a first cavity proximal to the upper surface and a second cavity below the first cavity, the first cavity defining at least one funnel portion, and the second cavity defining at least one microneedle; (b) filling at least the second cavity with a first material through the opening in the mold, the first material including a first matrix material and a substance of interest dissolved or suspended in a first liquid vehicle; (c) drying the first material in the mold to remove at least a portion of the first liquid vehicle and form at least a tip portion of a microneedle in the second cavity, the tip portion comprising the substance of interest; and (d) filling the first cavities and, if any, the second cavities unoccupied after steps (b) and (c), with a second material through the opening in the mold and trapping gas bubbles between the first material and the second material to form a cellular structure at or near a base end of each of the at least one microneedle, wherein the second material comprises a second matrix material dissolved or suspended in a second liquid vehicle; (e) removing at least a portion of the second liquid vehicle to dry the second material in the mold to form (i) the at least one funnel portion and (ii) any portion of the at least one microneedle not formed after steps (b) and (c), wherein the at least one funnel portion comprises the second matrix material; and (f) removing the at least one microneedle together with the at least one funnel portion attached thereto from the mold; wherein the substance of interest is located more within the at least one microneedle than within the at least one funnel portion.

45. 45. The method of claim 44, wherein the second cavity defines two or more microneedles and the first cavity defines two or more funnel portions such that each of the two or more microneedles includes one of the two or more funnel portions.

46. 45. The method of claim 44, wherein the mold is an elastomer, and step (f) comprises elastically deforming the mold to facilitate separation of the mold from the at least one funnel portion and the at least one microneedle.

47. 45. The method of claim 44, wherein the drying of step (e) comprises partially drying such that the at least one microneedle is in a rubbery state at the end of step (e).

48. 45. The method of claim 44, further comprising the step of drying the at least one microneedle after step (f) to transform the at least one microneedle from a rubbery state to an operational state.

49. 49. The method of claim 48, wherein the further drying after step (f) occurs after packaging of the at least one microneedle.

50. 45. The method of claim 44, wherein the substance of interest comprises a contraceptive hormone.

51. 51. The method of claim 50, wherein the contraceptive hormone comprises a progestin.

52. 45. The method of claim 44, wherein the substance of interest comprises an active pharmaceutical ingredient.

53. 45. The method of claim 44, wherein the first matrix material comprises polylactic acid, polylactic acid, polylactic acid, glycolic acid, or a combination thereof.

54. 54. The method of claim 53, wherein the second matrix material comprises polyvinylpyrrolidone, polyvinyl alcohol, a carbohydrate, or a combination thereof.

55. 55. The method of claim 54, wherein the carbohydrate comprises sucrose.

56. 1. A method for fabricating an array of microneedles, comprising: (a) providing a mold having an upper surface, an opposing lower surface, and an opening in the upper surface, the opening leading to a first cavity proximal to the upper surface and a second cavity below the first cavity, the first cavity defining at least one funnel portion, and the second cavity defining at least one microneedle; (b) filling at least the second cavity with a first material through the opening in the mold, the first material including a first matrix material and a substance of interest dissolved or suspended in a first liquid vehicle; (c) drying the first material in the mold to remove at least a portion of the first liquid vehicle and form at least a tip portion of a microneedle in the second cavity, the tip portion comprising the substance of interest; and (d) filling the first cavity and, if any, the second cavity unoccupied after steps (b) and (c), with a second material through the opening in the mold, the second material comprising a foamed material and a second water-soluble matrix material dissolved or suspended in a non-aqueous second liquid vehicle; (e) removing at least a portion of the second liquid vehicle to dry the second material in the mold to form (i) the at least one funnel portion and (ii) any portion of the at least one microneedle not formed after steps (b) and (c), wherein the at least one funnel portion comprises the foam material and the second water soluble matrix material; (f) removing the at least one microneedle together with the at least one funnel portion attached thereto from the mold; The method of claim 1, wherein the substance of interest is located in greater amount within the at least one microneedle than within the at least one funnel.

57. 57. The method of claim 56, wherein the second cavity defines two or more microneedles and the first cavity defines two or more funnel portions such that each of the two or more microneedles includes one of the two or more funnel portions.

58. 57. The method of claim 56, wherein the mold is an elastomer, and step (f) comprises elastically deforming the mold to facilitate separation of the mold from the at least one funnel portion and the at least one microneedle.

59. 57. The method of claim 56, wherein the drying of step (e) comprises partially drying such that the at least one microneedle is in a rubbery state at the end of step (e).

60. 57. The method of claim 56, further comprising the step of drying the at least one microneedle after step (f) to transform the at least one microneedle from a rubbery state to an operational state.

61. 61. The method of claim 60, wherein the further drying after step (f) occurs after packaging of the at least one microneedle.

62. 57. The method of claim 56, wherein the substance of interest comprises a contraceptive hormone.

63. 63. The method of claim 62, wherein the contraceptive hormone comprises a progestin.

64. 57. The method of claim 56, wherein the substance of interest comprises an active pharmaceutical ingredient.

65. 57. The method of claim 56, wherein the first matrix material comprises polylactic acid, polylactic acid, polylactic acid, polylactic acid, glycolic acid, or a combination thereof.

66. 57. The method of claim 56, wherein the second matrix material comprises polyvinylpyrrolidone, polyvinyl alcohol, sucrose, or a combination thereof.

67. 57. The method of claim 56, wherein the non-aqueous second liquid vehicle comprises an organic liquid.

68. 68. The method of claim 67, wherein the organic liquid comprises ethanol.

69. 1. A microneedle array for administering a substance of interest into biological tissue of a patient, comprising: a base substrate having a microneedle surface and an opposite back surface; a primary funnel portion extending from the microneedle surface of the base substrate; one or more solid microneedles extending from the primary funnel portion, at least a tip portion of each microneedle containing a substance of interest; a foam material is disposed within the primary funnel portion and / or the base end of each microneedle in an amount effective to separate the microneedles from the primary funnel portion after insertion of the one or more microneedles into the biological tissue and thereafter at least partially dissolving the primary funnel portion and / or the base end of the microneedles.

70. 70. The microneedle array of claim 69, configured to provide said separation of said microneedles from said primary funnel portion within 60 seconds after insertion of said microneedles into a patient's skin.

71. 71. The microneedle array of claim 70, wherein the inserted and separated microneedles provide a controlled release of the substance of interest for at least two weeks after said insertion.

72. The microneedle array of any one of claims 69 to 71, wherein the substance of interest comprises a contraceptive hormone.

73. 73. The microneedle array of claim 72, wherein the contraceptive hormone comprises progestin.

74. 70. The microneedle array of claim 69, wherein the substance of interest comprises an active pharmaceutical ingredient.

75. 75. The microneedle array of claim 74, wherein the microneedle array is configured to release a therapeutically or prophylactically effective amount of the substance of interest in the patient for a sustained period of 2 to 4 weeks.

76. 76. The microneedle array of claim 75, wherein the substance of interest comprises a contraceptive hormone.

77. 77. The microneedle array of claim 76, wherein the contraceptive hormone comprises progestin.

78. 1. A microneedle array for administering a substance of interest into biological tissue of a patient, comprising: a base substrate having a microneedle surface and an opposite back surface; a primary funnel portion extending from the microneedle surface of the base substrate; one or more solid microneedles extending from the primary funnel portion, at least a tip portion of each microneedle containing a substance of interest; A microneedle array, wherein a bubble structure is disposed at the interface of the primary funnel portion and a base end of each microneedle, and wherein the one or more solid microneedles are configured to penetrate into biological tissue of the patient under compression and then detach from the primary funnel portion under shear by fracturing at the bubble structure.

79. 80. The microneedle array of claim 78, wherein the inserted and separated microneedles provide a controlled release of the substance of interest for at least two weeks after said insertion.

80. 80. The microneedle array of claim 78 or 79, wherein the substance of interest comprises a contraceptive hormone.

81. The microneedle array of claim 80, wherein the contraceptive hormone comprises progestin.

82. 79. The microneedle array of claim 78, wherein the substance of interest comprises an active pharmaceutical ingredient.

83. 83. The microneedle array of claim 82, wherein the microneedle array is configured to release a therapeutically or prophylactically effective amount of the substance of interest in the patient for a sustained period of 2 to 4 weeks.

84. 84. The microneedle array of claim 83, wherein the substance of interest comprises a contraceptive hormone.

85. 85. The microneedle array of claim 84, wherein the contraceptive hormone comprises progestin.

86. 1. A method for administering a substance of interest to a patient, comprising: Inserting the microneedles of a microneedle array according to any one of claims 1 to 14, 16 to 29, 31 to 42 and 69 to 85 into biological tissue of the patient; Separating the inserted microneedle from the primary funnel portion or the secondary funnel portion; and releasing the substance of interest from the separated and inserted microneedle into the biological tissue.

87. 87. The method of claim 86, wherein the biological tissue comprises skin.

88. 88. The method of claim 87, wherein the substance of interest comprises a contraceptive hormone.

89. 89. The method of claim 88, wherein the contraceptive hormone comprises a progestin.

90. 88. The method of claim 87, wherein the substance of interest comprises an active pharmaceutical ingredient.

91. 91. The method of claim 90, wherein the inserted microneedles release a therapeutically or prophylactically effective amount of the drug substance to the patient for a sustained period of at least two weeks.

92. 92. The method of claim 91, wherein the active pharmaceutical ingredient comprises a contraceptive hormone.

93. 93. The method of claim 92, wherein the contraceptive hormone comprises a progestin.

94. 91. The method of claim 90, wherein the inserted microneedles release a therapeutically or prophylactically effective amount of the active pharmaceutical ingredient to the patient for a sustained period of at least four weeks.

95. 95. The method of claim 94, wherein the active pharmaceutical ingredient comprises a contraceptive hormone.

96. 96. The method of claim 95, wherein the contraceptive hormone comprises a progestin.

97. 88. The method of claim 87, wherein the separating comprises disrupting a bubble structure by applying a shear force to the microneedle array.

98. 98. The method of claim 97, wherein the shear force is applied from 1 second to 60 seconds after the insertion of the microneedles.

99. 88. The method of claim 87, wherein the separation comprises wetting of a foam material with a biological fluid followed by dissolution of material forming part of the microneedles, the primary funnel portion, and / or the secondary funnel portion.

100. 100. The method of claim 99, wherein the detachment occurs between 10 seconds and 60 seconds after the insertion of the microneedle.

101. 1. A microneedle array for administering a substance of interest into biological tissue of a patient, comprising: a base substrate having a microneedle surface and an opposite back surface; and two or more solid microneedles extending from the base substrate, wherein at least a tip portion of each microneedle contains a substance of interest; a cellular structure is at least partially disposed on each of said two or more solid microneedles, said two or more solid microneedles being configured to penetrate into biological tissue of said patient under pressure and then fracture at said cellular structure, separating said at least a tip portion of each microneedle from said base substrate.

102. 102. The microneedle array of claim 101, further comprising a primary funnel portion, wherein the bubble structure of each of the two or more microneedles is located at an interface of each of the microneedles and the primary funnel portion.

103. 1. A method for administering a substance of interest to a patient, comprising: Inserting the microneedles of the microneedle array of claim 101 or 102 into biological tissue of the patient; applying a shear force to the microneedle array effective to separate the tip portions of the inserted microneedles from the base substrate; and releasing the substance of interest from the inserted and separated microneedle into the biological tissue.

104. 104. The method of claim 103, wherein the biological tissue comprises skin.

105. 105. The method of claim 103 or 104, wherein the shear force is applied from 1 second to 60 seconds after the insertion of the microneedle.

106. 106. The method of any one of claims 103-105, wherein the substance of interest comprises a pharmaceutical agent and the inserted and separated microneedles release a therapeutically or prophylactically effective amount of the pharmaceutical agent to the patient for a sustained period of at least four weeks.

107. 1. A microneedle array for administering a substance of interest into biological tissue of a patient, comprising: a base substrate having a microneedle surface and an opposite back surface; and two or more solid microneedles extending from the base substrate, wherein at least a tip portion of each microneedle contains a substance of interest; a foam material is disposed on a portion of each of the two or more solid microneedles, on at least a portion of the base substrate, or a combination thereof; a microneedle array configured to penetrate into biological tissue of the patient under pressure and then separate at least the tip portion of each microneedle from the base substrate upon at least partial dissolution of the at least a portion of the base substrate on which the foam material is disposed and / or the portion of each of the two or more microneedles.

108. 108. The microneedle array of claim 107, further comprising a primary funnel portion, the foam material being disposed in at least a portion of the primary funnel portion.

109. 1. A method for administering a substance of interest to a patient, comprising: Inserting the microneedles of the microneedle array of claim 107 or 108 into biological tissue of the patient; wetting the foam material with an aqueous fluid, thereafter dissolving material forming part of the microneedles and / or the base substrate; Separating the inserted microneedles from the base substrate; and releasing the substance of interest from the inserted and separated microneedle into the biological tissue.

110. 110. The method of claim 109, wherein the biological tissue comprises skin.

111. 111. The method of claim 109 or 110, wherein the separation of the inserted microneedle from the base substrate occurs within 60 seconds after the insertion of the microneedle into the biological tissue.

112. 111. The method of claim 109 or 110, wherein the substance of interest comprises a pharmaceutical agent and the inserted and separated microneedles release a therapeutically or prophylactically effective amount of the pharmaceutical agent to the patient for a sustained period of at least four weeks.

113. 13. The method of any one of claims 101-106 or 109-112, wherein the release of the substance of interest comprises biodegradation, bioerosion, and / or bioabsorption of a biodegradable, bioerodible or bioabsorbable polymer or material that forms the microneedles and encapsulates the substance of interest.

114. 111. The method of claim 109 or 110, wherein the aqueous fluid comprises a biological fluid.

115. 111. The method of claim 109 or 110, wherein the aqueous fluid is applied to the biological tissue, the microneedle array, or a combination thereof.

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