Microneedles and methods of making the same

Abstract

The present application relates to a microneedle and a method for manufacturing the same. A microneedle array for administering drugs or other substances into biological tissues is provided. The array includes a base substrate; a primary funnel portion extending from one side of the base substrate; and two or more solid microneedles extending from the primary funnel portion, wherein the two or more microneedles include a substance of interest. A method for manufacturing a microneedle array is also provided. The method may include providing a non-porous and air-permeable mold, the mold having two or more cavities, each cavity defining a microneedle; filling the cavity with a fluid material, the fluid material including a substance of interest and a liquid vehicle; drying the fluid material to remove at least a portion of the liquid vehicle, and forming a plurality of microneedles including the substance of interest, wherein the filling is performed by means of a pressure difference applied between the relative surfaces of the mold.

Description

[0001] This application is a divisional application of an application filed on April 24, 2015, with application number 201580021930.8 and invention name “Microneedle and method for manufacturing the same”. Technical Field

[0002] This application claims priority to U.S. Provisional Patent No. 61 / 983,593, filed April 24, 2014, which is incorporated herein by reference. Background Art

[0003] The present application is generally in the field of microneedles for transporting therapeutic, diagnostic, cosmetic, biological or other molecules into, out of or across the skin or other tissue barriers.

[0004] The small size of microneedles enables them to precisely target superficial tissue layers (e.g., skin) and to do so relatively painlessly. However, their small size may hinder other factors important to their function and / or manufacturing. This is particularly true in the case of microneedle patches produced for transdermal drug delivery.

[0005] For example, because the length of the microneedle is shorter than the base or backing to which the microneedle is formed or attached, it may be difficult to insert the tissue. This is due to the elastic properties of the target tissue (e.g., skin), because when they are applied to the skin, many applied forces are used to deform the skin under the entire microneedle patch so that the microneedle is fully in contact and penetrates the tissue. Therefore, the patch applied force required for successful insertion of the microneedle is greater than the force of inserting the microneedle alone. This has led to the development of a complex and active application device that applies the microneedle patch to the skin by compaction. Thereby increasing cost and complexity, it is undesirable.

[0006] Conventional molding methods are generally not well suited for making microneedle arrays in a simple, rapid, highly reproducible, and accurate manner. For example, the small size of the microneedles limits the amount of material that can be loaded onto them during manufacturing (in the case of drug administration) or the amount of material that can be sampled / extracted (in the case of analyte sampling / monitoring). The volume of the microneedles is limited, similar to the mold cavity in which they are made. This limits the amount of material that can be loaded into the microneedles. Even more challenging is the fact that many molecules of interest have limited solubility in water (one of the preferred carrier solvents during manufacturing) and other solvents.

[0007] The manufacture of small solid microneedles may also result in inaccuracies due to the use of conventional fluid dispensing systems and conventional molds. These inaccuracies may arise from the mismatch between the droplets deposited into the microneedle cavity and the variable fill volume. The small size of the microneedle mold cavity makes it difficult to target with direct deposition techniques, especially during high-volume manufacturing. The target deposition area is defined by the opening of the microneedle cavity in the mold (which is extremely small). The microneedle volume is also extremely small, typically about 10 nanoliters, making it difficult to reproducibly deposit using microliter and nanoliter dispensing systems in a high-volume manufacturing environment. There remains a need for rapid, reproducible, and accurate filling of microneedle molds.

[0008] In summary, there remains a need for improved microneedle designs for better tissue insertion, as well as improved microneedle production methods, particularly such improved designs. Summary of the invention

[0009] Improved microneedle arrays and drug delivery patches, as well as improved methods of making microneedle arrays, have been developed that address one or more of the foregoing needs.

[0010] In one aspect, a microneedle array is provided to administer a substance of interest to a biological tissue. In one embodiment, the array comprises a base substrate having a microneedle side and an opposite back side; at least one primary funnel portion extending from the microneedle side 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 contain a substance of interest. In one embodiment, each of the two or more solid microneedles further comprises a secondary funnel portion extending from at least one primary funnel. In one embodiment, the at least one primary funnel portion comprises a straight tapered sidewall. In one embodiment, the at least one primary funnel portion comprises a hemispherical sidewall. In one embodiment, the at least one primary funnel portion comprises a stepped sidewall. In one embodiment, the substance of interest comprises an active pharmaceutical ingredient. In one embodiment, the two or more solid microneedles are formed by a composition comprising a water-soluble matrix material in which the substance of interest is dispersed. In one embodiment, the at least one primary funnel portion is formed by a composition comprising the water-soluble matrix material. In one embodiment, the water-soluble matrix material comprises polyvinyl alcohol, dextran, carboxymethyl cellulose or maltodextrin and sugar. In one embodiment, the ratio of the height of the at least one primary funnel portion to the height of each of the two or more microneedles is 0.3 to 4. In one embodiment, the two or more microneedles have a length of 200 μm to 1200 μm. In one embodiment, the secondary funnel portion comprises a straight tapered sidewall. In one embodiment, the secondary funnel portion comprises a hemispherical sidewall. In one embodiment, the secondary funnel portion comprises a stepped sidewall. In one embodiment, the secondary funnel portion is formed integrally with the at least one primary funnel portion. In one embodiment, the secondary funnel portion is formed by a composition comprising a water-soluble matrix material.

[0011] In another aspect, a microneedle patch is provided to administer a substance of interest to biological tissue. In one embodiment, the device comprises a base substrate having a microneedle side and an opposite back side; a primary funnel portion extending from the microneedle side of the base substrate; and one or more solid microneedles extending from the primary funnel portion, wherein the one or more solid microneedles contain a substance of interest and one or more matrix materials, and wherein more of the substance of interest is located in the one or more solid microneedles than in the primary funnel portion. In one embodiment, the primary funnel portion comprises 0% to 40% of the substance of interest, which is present in the combination of the one or more solid microneedles and the primary funnel portion from which the one or more solid microneedles extend. In one embodiment, the matrix material comprises polyvinyl alcohol, dextran, carboxymethyl cellulose or maltodextrin and sugar. In one embodiment, two or more of the solid microneedles extend from the primary funnel portion. In one embodiment, each of the two or more solid microneedles further comprises a secondary funnel portion extending from the at least one primary funnel.

[0012] In another aspect, a microneedle patch is provided for administering two or more substances of interest into biological tissue. In one instance, the patch includes a base substrate having a microneedle side and an opposite back side; a first funnel portion extending from the microneedle side of the base substrate, wherein the first funnel portion is elongated in a direction parallel to the base substrate; and a first array of two or more solid microneedles extending from the first funnel portion, wherein the microneedles of the first array contain a first substance of interest; a second funnel portion extending from the microneedle side of the base substrate, wherein the second funnel portion is elongated in a direction parallel to the base substrate; and a second array of two or more solid microneedles extending from the second funnel portion, wherein the microneedles of the second array contain a second substance of interest, the second substance of interest being different from the first substance of interest.

[0013] In another aspect, a microneedle patch is provided, comprising: a microneedle array according to the above; an adhesive layer; and a handling layer attached to a base substrate, wherein the handling layer comprises a tab portion extending from one or more solid microneedles and enabling a person to hold the tab portion by hand to manipulate the patch without contacting the one or more solid microneedles.

[0014] In another aspect, a method for making a microneedle array is provided. In one embodiment, the method comprises (a) providing a mold having an upper surface, an opposite lower surface, and an opening on the upper surface, wherein the opening leads to a first cavity proximal to the upper surface and a second cavity below the first cavity, wherein the first cavity defines a primary funnel portion, and wherein the second cavity defines at least one microneedle; (b) filling at least the second cavity with a first material through the opening of the mold, wherein the first material comprises 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 to form at least a tip portion of a microneedle in the second cavity, wherein the tip portion comprises the substance of interest ; (d) if either the first cavity or the second cavity is not full after steps (b) and (c), fill the opening of the mold with a second material, the second material comprising a matrix material dissolved or suspended in a second liquid vehicle; (e) drying the second material in the mold to remove at least a portion of the second liquid vehicle to form (i) a primary funnel portion, and (ii) any portion of at least one microneedle not formed after steps (b) and (c), wherein the primary funnel portion comprises the matrix material; and (f) removing at least one microneedle from the mold together with the primary funnel portion connected thereto, wherein more of the substance of interest is located in the at least one microneedle than in the primary funnel portion. In one embodiment, the matrix material in step (e) additionally forms a base substrate of the primary funnel portion connected to the distal side of the at least one microneedle. In one embodiment, the mold is a two-part mold, wherein the first part comprises a first cavity and the second part comprises a second cavity. In one embodiment, the first material also comprises a matrix material. In one embodiment, the second material does not comprise the substance of interest. In one embodiment, the first and / or second liquid vehicles comprise water. In one embodiment, the first and second cavities of the mold are defined by a surface having an average surface roughness of less than 10 microns. In one embodiment, the mold is non-porous and breathable. In one embodiment, the mold is made of polydimethylsiloxane or another siloxane. In one embodiment, the filling of step (b) and / or step (d) is carried out by means of a pressure difference applied between the upper surface and the lower surface of the mold. In one embodiment, the mold is breathable and subatmospheric pressure is applied to the lower surface of the mold. In one embodiment, superatmospheric pressure is applied to the upper surface of the mold. In one embodiment, the filling of step (b) and / or step (d) includes applying vibration, ultrasound, centrifugation, electromagnetic field, or a combination thereof to the mold.In one embodiment, the method further comprises a rinsing step after step (c) and before step (d), wherein a certain amount of solvent free of the substance of interest is added to the first cavity to dissolve at least a portion of any residual substance of interest present in the first cavity, and carry such dissolved substance of interest to the second cavity, after which most or all of the solvent is volatilized and removed from the mold. In one embodiment, the filling of step (b) and / or step (d) comprises overfilling, direct droplet deposition, vacuum filling or pressurized filling. In one embodiment, the filling of step (b) and / or step (d) comprises using a filling head comprising a sponge or a roller. In one embodiment, in the filling of step (b), the volume of the first material is less than or equal to the sum of the volumes of the first and second cavities and greater than the volume of the second cavity. In one embodiment, the volume of the second material in step (d) is greater than the volume of the first material in step (b). In one embodiment, the second cavity defines two or more microneedles extending from the primary funnel portion. In one embodiment, the method further comprises attaching an adhesive backing to the base substrate on the back side of the base substrate after step (e) and before step (f). In one embodiment, the mold is elastic and step (f) includes elastically deforming the mold to facilitate separation of the mold from the primary funnel portion and the at least one microneedle. In one embodiment, the drying of step (e) is partial drying, so that the at least one microneedle is in a rubber state at the end of step (e). In one embodiment, the method further includes drying the at least one microneedle after step (f) to convert the at least one microneedle from a rubber state to an operational state. In one embodiment, further drying after step (f) occurs after encapsulating the at least one microneedle. In one embodiment, the drying of step (e) is effective to put the at least one microneedle in an operational state. In one embodiment, the drying of step (c) and / or step (e) includes applying heat to the mold; exposing the first and / or second material to reduced pressure or a dry gas; or a combination thereof. In one embodiment, the at least one microneedle also includes a secondary funnel portion extending from the at least one primary funnel.

[0015] On the other hand, a method for making a microneedle array is provided, the method comprising (a) providing a non-porous and gas-permeable mold, the mold having an upper surface, an opposite lower surface, and a plurality of openings on the upper surface, wherein each opening leads to a cavity defining a microneedle; (b) filling the cavity with a fluid material through the opening, the fluid material comprising a substance of interest dissolved or suspended in a liquid vehicle; (c) drying the fluid material in the mold to remove at least a portion of the liquid vehicle and form a plurality of microneedles comprising the substance of interest; and (d) removing a plurality of microneedles from the mold, wherein the filling of step (b) is performed by means of a pressure difference applied between the upper and lower surfaces of the mold. In one embodiment, a subatmospheric pressure is applied to the lower surface of the mold. In one embodiment, a superatmospheric pressure is applied to the upper surface of the mold. In one embodiment, the mold is made of polydimethylsiloxane or another siloxane. In one embodiment, the method further comprises filling at least a portion of the cavity with a second fluid material, the second fluid material comprising a matrix material dissolved or suspended in a second liquid vehicle. In one embodiment, the matrix material forms a base substrate directly connected to the plurality of microneedles or one or more funnel portions, which in turn are connected to the plurality of microneedles.

[0016] In another aspect, a method for making a microneedle array is provided, the method comprising providing a two-part mold having an upper portion and a lower portion, the upper portion having an upper surface, an opposite lower surface, and an opening therethrough, the opening defining an upper cavity, the lower portion having an upper surface, an opposite lower surface, and an opening on the upper surface, the opening being in fluid communication with the upper cavity and leading to a lower cavity, the lower cavity defining a microneedle, wherein the upper portion and the lower portion are detachably fixed together; filling at least the lower cavity with a first material through the opening on the upper portion, the first material comprising a substance of interest dissolved or suspended in a first liquid vehicle; drying the first material in the mold to remove at least a portion of the first liquid vehicle to form microneedles comprising the substance of interest; and removing the microneedles from the mold. In one embodiment, the upper cavity acts as a funnel during filling of the lower cavity. In one embodiment, the upper portion of the mold is separated from the lower portion of the mold before removing the microneedle from the mold. In one embodiment, it further comprises: filling at least the upper cavity with a second material, the second material comprising a matrix material dissolved or suspended in a second liquid vehicle, wherein the drying further comprises drying the second material to remove at least a portion of the second liquid vehicle from the matrix material to form (i) a distal portion of the microneedle, (ii) a primary funnel, (iii) one or more secondary funnels, (iv) a base substrate, (v) a combination of (i), (ii) and (iv), or (vi) a combination of (i) to (iv). In one embodiment, the method further comprises a rinsing step after filling the lower cavity, wherein an amount of solvent free of a substance of interest is added to the upper cavity to dissolve at least a portion of any residual substance of interest present in the upper cavity and carry such dissolved substance of interest to the lower cavity, after which most or all of the solvent is volatilized and removed from the mold. In one embodiment, the upper cavity acts as a filling cap during filling of the lower cavity. In one embodiment, the lower portion of the mold comprises an array of two or more lower cavities defining microneedles, and the upper cavity leads to two or more cavities. In one embodiment, the upper cavity defines a primary funnel portion, and the drying step results in two or more microneedles extending from the primary funnel portion.

[0017] On the other hand, a method for administering a substance of interest to a patient is provided, the method comprising: providing the microneedle patch described above; grasping the tab portion of the microneedle patch; applying the microneedle patch to the tissue surface of the patient; and manually squeezing the microneedle patch to apply pressure effective to insert the microneedles into the tissue.

[0018] In another aspect, a method of administering a substance of interest to a patient is provided, the method comprising: providing the microneedle array described above; applying the microneedle array to a tissue surface of the patient; and applying the microneedles of the array to the tissue without using an application device.

[0019] Other aspects will be described in part in the following description, and in part will be apparent from the description, or may be learned through the practice of the aspects described below. The advantages described below will be realized and achieved through the elements and combinations specifically pointed out in the attached claims. It should be understood that the general description above and the detailed description below are only exemplary and illustrative, and are not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1-Figure 12 Various embodiments of microneedle arrays, microneedle patches, and microneedle structures including a funnel portion are shown.

[0021] Figure 13-Figure 16 , Figure 18-Figure 21 and Figure 25-27 Various methods, molds, and systems for making microneedle arrays as described herein are shown.

[0022] Fig.17 and Figure 22-Figure 24 Some exemplary embodiments of microneedle arrays produced using some of the methods and systems described herein and their properties are shown. DETAILED DESCRIPTION

[0023] Improved microneedle arrays and methods of fabrication have been developed. In some embodiments, the microneedles include an active pharmaceutical ingredient or other substance of interest, and arrays of these microneedles are particularly suitable for use as / in a drug delivery patch, such as for application to a patient's skin.

[0024] In some embodiments, the microneedle array advantageously includes one or more funnel portions between the base substrate and the microneedles themselves. The addition of a funnel portion (sometimes referred to herein as a "funnel," "funnel portion," "primary funnel portion," "secondary funnel portion," or "lead-in") imparts certain advantages to its use, its manufacture, or its use and manufacture.

[0025] First, tissue insertion difficulties can be alleviated by incorporating funnels into the microneedle patch because they lift the microneedles off the base or backing layer, making it easier for the microneedles to contact and penetrate the target tissue—without having to lengthen the microneedles. This increases microneedle insertion efficiency (e.g., microneedle penetration success rate) and reduces the force required to successfully apply the microneedle patch. That is, a greater number of microneedle collections penetrate the tissue (e.g., greater than or equal to 80% or 90% or 95% of the microneedles in the patch) or a greater portion of each microneedle penetrates the skin (e.g., an average of greater than or equal to 50% or 75% or 80% or 90% or 95% of the length or volume of the microneedles in the patch). The end result of any of these microneedle penetration success rate criteria is that a greater portion of the substance of interest administered by the microneedles is delivered to the tissue.

[0026] This microneedle design approach also leaves room for minimal or no insertion of the funnel when the microneedle is inserted after applying a minimum force. That is, the final insertion depth of the microneedle with a funnel is less sensitive to excessive force applied during patch application because the funnel portion rapidly expands to prevent insertion and results in insertion at most to the microneedle-funnel interface. This allows the microneedle to be inserted by simple thumb pressure, thumb pressure with a mechanical device that indicates that the minimum force required has been applied, or a simpler weak active application device that does not rely on compression. For example, if a long microneedle array is pressed against the skin, the microneedles can be only partially inserted, allowing them to still penetrate shallowly. However, the actual depth of microneedle insertion is extremely difficult to control because the minimum force required varies between individuals (e.g., skin type) and application locations (e.g., locations on the patient's body). Therefore, the insertion force for partially inserting a long microneedle array will vary, and improper microneedle insertion depth will result from applying too little or too much force. This problem is alleviated when using microneedles with a funnel introduction because the rapid expansion of the funnel portion limits the insertion depth. If minimal force (or greater) is applied, the insertion depth is consistent.

[0027] Second, by incorporating a funnel into the microneedle device, loading and filling limitations can be significantly reduced because the funnel increases the amount of material of interest that can be loaded into the microneedle during manufacturing. In a molding process that includes a funnel, the amount of material that can be loaded is greater than the volume of the microneedle cavity multiplied by the concentration of the material in the loading solution. The amount loaded can be as large as the microneedle and funnel volumes combined multiplied by the concentration of the filling solution / suspension multiplied by the number of filling steps. The funnel volume is typically many times larger than the microneedle volume, thereby significantly increasing the amount that can be loaded into the microneedle.

[0028] Third, by adding the funnel, the manufacturing challenges can be significantly reduced because the funnel expands from the microneedle cavity during the mold filling step to greatly increase the target area. Compared to a mold without a funnel (where the target area would be the microneedle-base interface), this larger area of ​​the target (i.e., the funnel-base interface) greatly relaxes the accuracy required of the deposition / filling system. In addition, the volume of the microneedle filled with the funnel can be many times larger than the microneedle itself, thereby also reducing this constraint.

[0029] Other advantages and benefits of the microneedle array designs and fabrication methods that have been developed are described in the remainder of this specification. Certain improved fabrication methods are applicable to microneedle arrays that include a funnel portion, as well as microneedle arrays that do not include a funnel portion.

[0030] Unless otherwise defined herein below in the remainder of this specification, all scientific and technological terms used herein have the meanings generally understood by those of ordinary skill in the art to which the present disclosure belongs. It should also be understood that the terms used herein are only used to describe specific embodiments and are not intended to be limiting. When describing and claiming embodiments of the present invention, the following terms will be used according to the definitions listed below.

[0031] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a component" may include a combination of two or more components; reference to "a buffer" may include a buffer mixture, and so forth.

[0032] As used herein, the term "about" indicates that a value of a given amount may include variations within 10% of the stated value, or within 5% of the stated value, or in some embodiments, within 1% of the stated value.

[0033] 1. Microneedle array with funnel portion

[0034] 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 directly or indirectly attached to the base substrate through one or more funnel portions, and a distal tip that is sharp and effective in piercing biological tissue. The microneedle has a tapered sidewall between the proximal end and the distal end.

[0035] The funnel portion may be integrally formed with the microneedle. The outer surface of the funnel portion may be distinguished from the microneedle portion of the protruding structure by a unique change / expansion of the angle of the surface of different portions of the structure, which may be viewed as a rapid expansion in at least one dimension (e.g., radial) when traveling from the distal end of the microneedle toward the proximal end. The base end of the funnel portion is wider than its microneedle end. This expansion may be designed so that little or no funnel portion will be inserted into the target tissue layer or space.

[0036] In a preferred embodiment, a microneedle array is provided for administering a drug or other substance of interest to biological tissue such as skin, wherein the array comprises a base substrate having a microneedle side and an opposite back side; a primary funnel portion extending from the microneedle side of the base substrate; and one or more solid microneedles extending from the primary funnel portion, wherein the one or more solid microneedles contain a substance of interest and a matrix material, and wherein more of the substance of interest is located in the one or more solid microneedles than in the primary funnel portion. For example, the primary funnel portion may include 0% to 20% of the substance of interest, which is present in the combination of the one or more solid microneedles and the primary funnel portion from which the one or more solid microneedles extend. This embodiment advantageously avoids wasting the drug in the funnel portion.

[0037] In one embodiment, a microneedle array is provided to administer drugs or other substances of interest to biological tissues such as skin, wherein the array comprises a base substrate having a microneedle side and an opposite back side; at least one primary funnel portion extending from the microneedle side 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 contain substances of interest. Each of the two or more solid microneedles may also include a secondary funnel portion extending from the at least one primary funnel.

[0038] Figure 1-Figure 2 An example of a microneedle array 105 as a part of a microneedle patch 100 is shown, wherein each microneedle 130 extends from a funnel portion 125. The microneedle array 105 includes a base substrate 110 having a microneedle side 115 and an opposite back side 120. The funnel portion 125 extends from the microneedle side 115 of the base substrate 110. The microneedle array 105 is attached to a handling layer 140 with an adhesive layer 135 disposed therebetween. The handling layer 140 includes a tab portion 145 extending from the microneedle array. The tab portion 145 enables a person to hold and manipulate the microneedle patch 100 by hand without touching the microneedles 130. An adhesive cover 150 is attached to a portion of the tab portion 145 of the adhesive layer 135 that overlaps the handling layer 140. The adhesive cover 150 enables a person to hold and manipulate the microneedle patch 100 by hand without touching the adhesive layer 135.

[0039] Optionally, a mechanical force indicator 155 is disposed between the adhesive layer 135 and the processing layer 140. The mechanical force indicator can be used to indicate to a person the amount of force and / or pressure applied to the patch during use. For example, in one embodiment, the indicator is configured to provide a signal when the force applied to the patch by the person meets or exceeds a predetermined threshold (in the process of applying the patch to the patient's skin to insert one or more microneedles into the patient's skin). The predetermined threshold is the minimum force required for a specific microneedle patch to be effectively applied to the patient's skin or an amount greater than the minimum force. That is, the force required to allow the microneedle to be properly, for example, fully inserted into the patient's skin.

[0040] Structural characteristics of the infundibulum and microneedles

[0041] The funnel portion can be made into a variety of different configurations. The funnel portion can have tapered walls (steep or flat), 'stepped' walls, tapered then vertical walls, hemispherical walls, or a combination thereof. The funnel portion can be symmetrical or asymmetrical. Some of these configurations are shown in Figure 3A-Figure 3F In the cross-sectional view shown in . Figure 3A A tapered funnel portion 310 is shown having straight tapered sidewalls and a microneedle 300 extending therefrom. Figure 3B A funnel portion 320 is shown having stepped sidewalls and a microneedle 300 extending therefrom. Figure 3C A funnel portion 330 is shown having sidewalls with tapered and non-tapered (vertical) portions and a microneedle 300 extending therefrom. Figure 3D An axially asymmetric funnel portion 340 is shown having sidewalls that taper on one side 341 of the funnel portion at a different angle than another (eg, opposite) side 342 of the funnel portion, and a microneedle 301 extending therefrom. Figure 3E A shallowly tapered funnel portion 350 of the microneedle 300 is shown having straight tapered sidewalls and extending therefrom. Figure 3F A hemispherical funnel portion 360 is shown having curved sidewalls and microneedle 300 extending therefrom.

[0042] A single microneedle array or patch may have a funnel portion with two or more different geometries. For example, an array may include a row of microneedles having a funnel portion of a first size or shape and a second row of microneedles having a funnel portion of a second size or shape. For example, the differences may be advantageously designed to deliver two different substances of interest.

[0043] Manufacturing and use considerations also drive the selection of the geometry of the funnel portion. For example, the density (i.e., spacing) of the microneedles and funnels within the array can also be balanced with the microneedle / funnel geometry to allow for simple insertion of the needles, with little or no insertion of the funnels (i.e., because the more closely spaced microneedles are generally more difficult to insert). For another example, during manufacturing, a volume of solution is deposited in the funnel portion of the mold, and upon drying / curing, the solutes generally migrate into the microneedles and their tip portions of the mold. In one embodiment, the funnel shape is designed to promote and maximize this solute migration.

[0044] The length of the microneedle (L MN ) can be between about 50 μm and 2 mm. In most cases, the microneedle is between about 200 μm and 1200 μm, and ideally between about 500 μm and 1000 μm. The length (height) of the funnel (L FUN ) may be between about 10 μm and 1 cm. In most cases, the funnel is between about 200 μm and 2000 μm, and more preferably between about 500 μm and 1500 μm. FUN / L MN The ratio L may be between about 0.1 and 10, more typically between about 0.3 and 4, and more preferably between about 0.5 and 2 or between about 0.5 and 1, but ratios between about 1 and 2 are also possible. FUN / L MN It may be less than about 1 or may be greater than about 1. The sum L MN +L FUN It may be between about 60 um and 1.2 cm, more typically between about 300 um and 1.5 mm, and more preferably between about 700 um and 1.2 mm. MN +L FUN It may be greater than about 1 mm, or greater than about 1.2 mm, or greater than about 1.5 mm.

[0045] Microneedle volume (V MN ) can be between about 1 nl and 100 nl. In most cases, the microneedle volume is between about 5 nl and 20 nl. The funnel volume (V FUN ) may be between about 1 nl and 20,000 nl, more typically between about 5 nl and 1000 nl, and more preferably between about 10 nl and 200 nl. Ratio V FUN / V MN It may be between about 0.1 and 100, more typically between about 0.5 and 20, more preferably between about 1 and 10 or between about 2 and 5.

[0046] The cross-sectional area of ​​the microneedle and the funnel contact (A MN-FUN ) at about 300 μm 2 With 800,000μm 2In most cases, the cross-sectional area is about 10,000 μm 2 With 500,000μm 2 and more preferably about 50,000 μm 2 200,000μm 2 The cross-sectional area of ​​the funnel-base interface (A FUN-BASE ) at about 301 μm 2 With 8x10 7 μm 2 between 10,000 μm and 20,000 μm, more typically between 10,000 μm and 20,000 μm. 2 With 5x10 6 μm 2 between 100,000 μm and more preferably between 100,000 μm and about 100,000 μm. 2 With 2x10 6 μm 2 Ratio A FUN-BASE / A MN-FUN Always greater than 1 because the funnel expands from the microneedle. Ratio A FUN-BASE / A MN-FUN Between about 1.1 and 2500, more typically between about 1.5 and 100, and more preferably between about 2 and 10.

[0047] One or more microneedles can be arranged on the base substrate at any suitable density. For example, a plurality of microneedles can be arranged in an array in uniform or staggered rows, wherein each microneedle is separated from its nearest neighbor by a distance approximately equal to the height of the microneedle.

[0048] Width of microneedle-funnel interface (W MN-FUN ) is between about 20 μm and 1000 μm. In most cases, the width is between about 100 μm and 500 μm, and more preferably between about 200 μm and 400 μm. The width at the funnel-base interface (W FUN-BASE ) is between about 30 μm and 1 cm, more typically between about 300 μm and 1500 μm, and more preferably between about 500 μm and 1000 μm. FUN-BASE / W MN-FUN Always greater than 1 because the funnel expands from the microneedle. FUN-BASE / W MN-FUN It may be between about 1.1 and 50, more typically between about 1.5 and 10, and more preferably between about 2 and 5.

[0049] The funnel portion extends in at least one dimension from the point where it connects to the microneedle. In most cases, it extends radially. The small angle α is between a line extending from the funnel-microneedle interface to the point where the funnel portion contacts the base and a line extending from the same point and perpendicular to the mid-axis of the microneedle, such as Figure 4A-4CAs shown in . 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°.

[0050] Each microneedle can be associated with a funnel, and each funnel can be associated with a microneedle. Alternatively, a microneedle can be associated with more than one funnel. Alternatively, a funnel can be associated with more than one microneedle. Generally speaking, the number of microneedles ≥ the number of funnels per patch. However, when the funnels are used in series, the number of funnels can exceed the number of microneedles. The number of microneedles per patch is typically between 1 and 10,000, and in most cases between about 20 and 1000, more preferably between about 50 and 500. The number of funnels per patch is typically between about 1 and 10,000, and in most cases between about 5 and 500, more preferably between about 10 and 500. The ratio of funnels to microneedles is between about 0.01 and 10, more typically between about 0.05 and 4, and more preferably between 0.1 and 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, multiple microneedles all in a row are associated with the same funnel. In some cases, some microneedles are associated with a funnel and other microneedles are not associated with a funnel. In some cases, the number of funnels associated with each microneedle in the patch is not the same for all microneedles or all funnels.

[0051] The funnels can also be used in series, i.e., a stack of funnels, where the first funnel (i.e., the primary funnel portion) (base end) feeds several other funnels (i.e., the secondary funnel portion). For example, each microneedle can have its own funnel, and a row or a portion of the microneedles and funnels of the patch can be connected to a larger, elongated funnel. This is particularly beneficial when the microneedle patch is filled with multiple active substances for some reason (e.g., the active substances are incompatible with each other, and are formulated differently for stability and / or release kinetics). For example, some microneedles can release active substances quickly, thereby providing an immediate surge, quickly raising the blood level of the active substance to the therapeutic range, and other microneedles can be designed to slowly release the active substance to maintain the blood level of the active substance within the therapeutic range for a long time. Alternatively, a single large funnel can be connected to the entire patch of microneedles (they have or do not have their own independent funnels). This is useful for filling a single active substance.

[0052] Figure 5-Figure 8 Various embodiments of microneedle arrays comprising a plurality of microneedles having a funnel portion are shown.

[0053] In one embodiment, if Figure 5 and Figure 6As shown in , the microneedle array 505 includes a base substrate 510 having a microneedle side 515 and an opposite back side 520. The microneedle array 505 also includes three groups of microneedles 530, each group having a funnel portion 525 extending from the microneedle side 515 of the base substrate 510. As shown, the microneedle tip portion includes a substance of interest, but the funnel portion 525 and the base substrate portion 510 contain little or no substance of interest. Each funnel portion 425 is elongated in a direction (D) parallel to the base substrate 510. In this embodiment, the microneedles 530 of all three elongated funnel portions 525 contain the same substance of interest.

[0054] In other embodiments, different portions of the microneedle array may contain different substances of interest and / or excipients, e.g. Figure 7 and Figure 8 . The microneedle array 705 includes a base substrate 710 having a microneedle side 715 and an opposite back side 720. The microneedle array 705 also includes three groups of microneedles 730a containing a first substance of interest and three groups of other microneedles 730b containing a second substance of interest, wherein each group has a funnel portion 725 extending from the microneedle side 715 of the base substrate 710. Each funnel portion 725 is elongated in a direction (D) parallel to the base substrate 710.

[0055] Figure 9-12 Various embodiments of a microneedle array including a plurality of microneedles having two funnel portions (a primary funnel portion and a secondary funnel portion) are shown.

[0056] In one embodiment, if Fig. 9 and Fig.10 As shown in , the microneedle array 905 includes a base substrate 910 having a microneedle side 915 and an opposing back side 920. The microneedle array 905 also includes three groups of microneedles 930, each group having a primary funnel portion 925 extending from the microneedle side 915 of the base substrate 910 and a secondary funnel portion 935 extending from the primary funnel portion 925. Each primary funnel portion 925 is elongated in a direction (D) parallel to the base substrate 910. In this embodiment, the microneedles 930 and the funnel portions 925, 935 respectively contain the same substance of interest and excipients.

[0057] In other embodiments, different portions of the microneedle array contain different substances of interest and / or excipients, e.g. Fig.11 and Fig.12. The microneedle array 1105 includes a base substrate 1110 having a microneedle side 1115 and an opposite back side 1120. The microneedle array 1105 also includes three groups of microneedles 1130a containing a first substance of interest and three groups of other microneedles 1130b containing a second substance of interest, each group having a primary funnel portion 925 extending from the microneedle side 1115 of the base substrate 1110 and a secondary funnel portion 1135 extending from the primary funnel portion 1125. Each funnel portion 1125, 1135 is elongated in a direction (D) parallel to the base substrate 1110.

[0058] Microneedle patches as described above can also be made by automated pick-and-place manufacturing, where each individual region of the patch containing a different formulation is molded separately and then assembled on an adhesive pad or backing.

[0059] The microneedle patch may include, for example, different microneedles containing different material compositions, the compositions comprising different active substances and / or excipients and / or other materials. Microneedles containing the same material composition may be connected to a common funnel. In addition to different microneedles, rows, or areas loaded with different materials, the microneedles and the funnel themselves may have discontinuous material layers. The discontinuous layers may be as follows: Fig.15 As shown in FIG. 1 , the stack or strip form may be shown, or the discontinuous layers may be as shown in FIG. Fig.16 The shell layer forms starting from the side wall of the cavity in the mold as shown in FIG.

[0060] Substance of interest / Active pharmaceutical ingredient

[0061] Numerous substances can be formulated for delivery to biological tissues by means of the microneedles and methods of the present invention. As used herein, the term "substance of interest" includes active pharmaceutical ingredients, allergens, vitamins, cosmetics, cosmeceuticals, diagnostic agents, markers (e.g., colored dyes or radioactive dyes or markers), and other materials that are desired to be introduced into biological tissues. "Substances of interest" are sometimes referred to herein as "active substances." In a preferred embodiment, the biological tissue is human or other mammalian tissue, including (but not limited to) human or other mammalian skin. In an alternative embodiment, the biological tissue is plant tissue.

[0062] In one embodiment, the substance of interest is a preventive, therapeutic or diagnostic agent that can be used in medical or veterinary applications. In one embodiment, the substance of interest is a preventive or therapeutic substance, which may be referred to herein as an API. In certain embodiments, the API is selected from suitable proteins, peptides and fragments thereof, which may be naturally occurring, synthetic or recombinantly produced. Representative examples of the types of APIs for delivery include antibodies, antivirals, analgesics, anesthetics, antihistamines, anti-inflammatory agents, anticoagulants, allergens, vitamins, anti-tumor agents.

[0063] In one embodiment, the substance of interest includes a vaccine. Examples of vaccines include vaccines for infectious diseases, therapeutic vaccines for cancer, neuropathy, allergies, and smoking cessation or other addictions. Some examples of vaccines currently and in the future for preventing the following: anthrax, cervical cancer (human papillomavirus), dengue fever, diphtheria, Ebola virus, hepatitis A, hepatitis B, hepatitis C, type b Haemophilus influenzae (Hib), HIV / AIDS, human papillomavirus (HPV), influenza (seasonal and pandemic), Japanese encephalitis (JE), Lyme disease, malaria, measles, meningitis, monkeypox, mumps, pertussis, pneumococcus, polio, rabies, rotavirus, rubella, herpes zoster, smallpox, tetanus, typhoid, tuberculosis (TB), chickenpox, West Nile virus, and yellow fever.

[0064] In another embodiment, the substance of interest comprises a therapeutic agent. The therapeutic agent can be selected from small molecules and larger molecules produced or purified by biotechnology (e.g., peptides, proteins, DNA, RNA). Examples of therapeutic agents (which may include their analogs and antagonists) include (but are not limited to) 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, beta-glucocerebrosidase, alglucosidase-alpha, laronidase, idursulphase, galsulphase, agalsidase-beta, alpha-1 proteinase inhibitor, lactase, pancreatic enzymes, adenosine deaminase, pooled immunoglobulin, human serum albumin, erythropoietin, darbepoietin-alpha, filgrastim, pegfilgrastim, sargramostim, oprelleukin, human follicle-stimulating hormone, human chorionic gonadotropin, luteinizing hormone-alpha, interferon (alpha, beta, γ), aldesleukin, alteplase, reteplase, tenecteplase, urokinase, factor VIIa, drotrexone-alpha, salmon calcitonin, exenatide, octreotide, daptomycin-alpha, recombinant human bone morphogenic protein 7, dapoxetine 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, indole Filiximab, afacept, efalizumab, natalizumab, eculizumab, antithymocyte globulin, basiliximab, daclizumab, muromonab-CD3, omalizumab, parivizumab, enfuvirtide, abciximab, pegvisomant, monocrotaline multivalent fab (sheep), digoxin immune serum fab (sheep), ranibizumab, denileukin, tentanisbetumomab, gemtuzumab ozogamicin, tositumomab, I-tositumomab, anti-rhesus (rh) immunoglobulin G, desmopressin, vasopressin, desamino [Val4, D-Arg8] arginine vasopressin, growth hormone inhibitor, growth hormone, bradykinin, bleomycin sulfate, chymopapain, glucagon, epoprostenol, cholecystokinin, oxytocin, adrenocorticotropic hormone, prostaglandins, pentigitide, thymosin alfa-1, alpha-1 antitrypsin, fentanyl, lidocaine, epinephrine, sumatriptan, benztropine mesylate, liraglutide, dalparin, heparin, hydromorphone, homoharringtonine, praslinide acetate, thyrotropin-alpha glycopyrrolate, dihydroergotoxin mesylate, bortezomib, triptorelin pamoate, teduglutide, methylnaltrexone bromide, pasireotide, ondansetron hydrochloride, droperidol, triamcinolone (hex) acetonide, aripiprazole, estradiol valerate, morphine sulfate, olanzapine, methadone hydrochloride, and methotrexate.

[0065] In yet another embodiment, the substance of interest is a vitamin, a herb, or a dietary supplement known in the art. Non-limiting examples include 5-HTP (5-hydroxytryptophan), acai berry, acetyl-L-carnitine, activated carbon, aloe vera juice, alpha-lipoic acid, apple cider vinegar, arginine, ashitaba, ashwagandha, astaxanthin, barley, bee pollen, beta-alanine, beta-carotene, beta-glucan, biotin, bitter melon, black cherry, black cohosh, black currant, black tea, branched chain amino acids, bromelin, calcium, camphor, chamomile, holy Berries, chitosan, chlorella, chlorophyll, choline, chondroitin, chromium, cinnamon bark, citicoline, coconut water, coenzyme Q10, conjugated linoleic acid, cordyceps, cranberry, creatine, D-mannose, damiana, deer antler, DHEA, DMSO, echinacea, EDTA, elderberry, ostrich oil, evening primrose oil, fenugreek, wild chamomile, folic acid, forskolin, GABA (gamma-aminobutyric acid), gelatin, ginger, ginkgo, Korean ginseng, glycine, glucose Glucosamine, glucosamine sulfate, glutathione, gotu kola, grape seed extract, green coffee, guarana, Indian artemisia, gymnema, hawthorn, hibiscus, holy basil, epimedium, inulin, iron, krill oil, L-carnitine, L-citrulline, L-tryptophan, lactobacillus, magnesium, magnolia, milk thistle, MSM (dimethyl sulfone), niacin, olive, omega-3 fatty acids, oolong tea, oregano, passion fruit, pectin, phenylalanine, phosphatidylserine, potassium, prebiotics , progesterone, quercetin, ribose, red yeast rice, reishi, resveratrol, rose hips, saffron, SAM-e, saw palmetto, schisandra, sea buckthorn, selenium, senna, slippery elm, St. John's wort, 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, safflower, xanthan gum, xylitol, yohimbe, and zinc.

[0066] The microneedle patch may include a single substance of interest or may include two or more substances of interest. In the latter case, different substances may be provided together in one of the microneedles, or some microneedles in the microneedle array may include one substance of interest, while other microneedles may include another substance of interest.

[0067] The API is preferably provided in a stable formulation or composition (i.e., a formulation or composition in which the biologically active material substantially retains its physical stability and / or chemical stability and / or biological activity upon storage). Stability can be measured at a selected temperature for a selected time. Trend analysis can be used to estimate the expected shelf life before the material is actually stored for that time.

[0068] In some embodiments, a solid substance of interest is provided that is "dried" or has been "dried" to form one or more microneedles and dissolves in vivo after the microneedles are inserted into a patient's biological tissue. As used herein, the term "dried" or "dried" refers to a composition from which a substantial portion of water has been removed to produce a solid phase of the composition. The term does not require complete absence of moisture (e.g., an API may have a moisture content of between about 0.1% by weight and about 25% by weight).

[0069] The substance of interest may be included in a formulation together with one or more excipients and other additives, as described in detail below.

[0070] Matrix material / excipient

[0071] The matrix material forms the body of microneedle, funnel portion and backing layer. The matrix material usually only includes biocompatible polymeric materials or its combination with other materials. In some embodiments, at least the matrix material of microneedle is water-soluble. In certain preferred embodiments, the matrix material includes one or a combination of polyvinyl alcohol, dextran, carboxymethyl cellulose, maltodextrin, sucrose and other sugars. As used herein, when referring to any excipient that is not volatile during drying and forming microneedle, funnel and basic substrate, the terms "matrix material" and "excipient" are used interchangeably.

[0072] Fluid solution used in mold filling process as described herein may include any of various excipients. Excipient may be those excipients widely used in pharmaceutical preparations or novel excipients. In a preferred embodiment, excipient is an excipient in the medicine approved by FDA (referring to Inactive Ingredient Search for Approved Drug Products at http: / / www.accessdata.fda.gov / scripts / cder / iig / index.Cfm). Can use zero, one or more than one from the following excipient category: stabilizer, buffer, swelling agent or filler, adjuvant, surfactant, disintegrant, antioxidant, solubilizer, lyophilization protectant, antimicrobial agent, antitack agent, pigment, lubricant, viscosity promoter, glidant, preservative, for extending or controlling the material (for example, biodegradable polymer, gel, storage formation material etc.) that sends. And single excipient can play more than a kind of preparation effect. For example, sugar can be used as stabilizer and swelling agent, or buffer can be used for buffering pH and preventing active substance oxidation.Some examples of excipients include, but are not limited to, 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, polyvinyl pyrrolidone, 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 4000), cellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, gum arabic, 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, citrate buffer, 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, sodium acetone bisulfate, ascorbyl citrate, ascorbate, castor oil, cottonseed oil, alum, aluminum hydroxide, aluminum phosphate, bone meal, paraffin oil, squalene, Quil A, IL-1, IL-2, IL-12, Freund's complete adjuvant, Freund's incomplete adjuvant, killed Bordetella pertussis pertussis), Mycoobacterium bovis, and toxoid. One or more selected excipients may be selected to improve the stability of the substance of interest during drying and storage of the microneedle device, as well as to provide bulk and / or mechanical properties to the microneedle array.

[0073] 2. Microneedle patch

[0074] The microneedle arrays described above can be combined with one or more components to produce a microneedle patch, such as a patch that can be manually applied to a patient's skin. For example, the microneedle array can be combined with an adhesive layer that can be used to help secure the patch to the patient's skin during application of the substance of interest. A backing or handling layer can additionally be included to facilitate handling as described above and Figure 1 and Figure 2 The patch shown in .

[0075] The backing layer can be made of various materials and can be the same or different from the tab portion. In some embodiments, the backing layer can be a composite material or a multilayer material comprising a material with various properties to provide desired properties and functions. For example, the backing material can be flexible, semi-rigid or rigid, depending on the specific application. For example, the backing layer can be substantially impermeable, protecting one or more microneedles (or other components) from moisture, gas and pollutants. Alternatively, the backing layer can have other permeability and / or porosity based on the desired protection level. Non-limiting examples of materials that can be used for the backing layer include various polymers, elastomers, foams, paper-based materials, foil-based materials, metallized films, nonwoven materials and woven materials.

[0076] Before use, the microneedle patch can be stored in a protective package. In one case, the microneedle patch is combined with a storage tray. One or more trays can be placed in a flexible container (e.g., a pouch) and / or a rigid container (e.g., a box). In some embodiments, a lid can be placed on the tray to protect the microneedle patch before use. Such a lid can be the same or different material as the tray, and the periphery of the tray can be sealed (i.e., using heat seals, cold seals or pressure-sensitive adhesives). In one embodiment, a desiccant can be provided in a recessed area or a flexible or rigid container in which a tray is placed. Alternatively or in addition, a desiccant can be a part of the tray itself. For example, a desiccant material can be incorporated into (e.g., dispersed in or coated on) a material forming a tray structure. For example, a tray can be formed by a desiccant polymer known in the art. The desiccant can be completely dried after the microneedle is removed from the production mold.

[0077] In one embodiment, the microneedle patch includes several microneedles, for example, an array of 10 to 1000 microneedles. In a preferred embodiment, the microneedle is a solid microneedle containing a substance of interest, such as an active pharmaceutical ingredient (API), which dissolves in vivo after the microneedle is inserted into a biological tissue, for example, into the patient's skin. For example, the substance of interest can be mixed into a water-soluble matrix material to form a solid microneedle extending from a base substrate. The substance of interest referred to herein as "soluble" is provided in a preparation. In an embodiment in which the substance of interest and the matrix material in which the substance of interest is dispersed form a microneedle structure, the matrix material is also preferably dissolvable in vivo so that the entire microneedle dissolves in vivo.

[0078] In one embodiment, the microneedles in a given patch all contain the same active substance and excipients. However, the active substance and / or excipients in each microneedle, microneedles in different rows, or portions / regions of the microneedle array may be different. Possible reasons for designing a microneedle patch with such separations are: i) different active substances are incompatible with each other, ii) different active substances require different stabilizing excipients, and iii) a single active substance or different active substances are desired to have different release profiles (e.g., a combination of a rapid large dose followed by a sustained release). Figure 5-Figure 12 Examples of different arrays and patches are described in .

[0079] 3. Methods for Fabricating Microneedle Arrays

[0080] Embodiments of the manufacturing methods described herein are used to manufacture a generally described microneedle array comprising a base substrate and one or more microneedles extending from the base substrate. In general, the method comprises a molding process, which is advantageously highly scalable. The process requires providing a suitable mold; filling the mold with a suitable fluidized material; drying the fluidized material to form microneedles, a funnel portion (if included), and a base substrate; and then removing the formed component from the mold. These filling and drying steps may be referred to herein as "casting."

[0081] Fig.13 An embodiment of a molding process including two injections is shown. In this embodiment, a mold 1301 is provided, and then filled with a first fluidized material 1302, and then the first fluidized material 1302 is dried to form the microneedles of the microneedle array 1306. Thereafter, the mold 1301 is filled with a second fluidized material 1304, and then the second fluidized material 1304 is dried to form a corresponding funnel portion of each microneedle of the microneedle array 1306. The microneedle array 1306 is then removed from the mold 1301. In a preferred embodiment, the first fluidized material 1302 includes a drug or other substance of interest, and the second fluidized material 1304 does not include a drug or other substance of interest. Fig.25 A process flow chart of a method for manufacturing a microneedle array as described herein is shown in a block flow chart.

[0082] In a preferred embodiment, a method for manufacturing a microneedle array is provided, the method comprising: (a) providing a mold having an upper surface, an opposite lower surface, and an opening in the upper surface, wherein the opening leads to a first cavity proximal to the upper surface and a second cavity below the first cavity, wherein the first cavity defines a primary funnel portion, and wherein the second cavity defines at least one microneedle; (b) filling at least the second cavity with a first material through the opening of the mold, wherein the first material comprises 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 to form at least a tip portion of the microneedle in the second cavity, wherein the tip portion comprises the substance of interest; (d) if any of the first cavity and the second cavity is not full after steps (b) and (c), fill the first cavity and the second cavity with a second material through the opening on the mold, the second material comprising a matrix material dissolved or suspended in a second liquid vehicle; (e) drying the second material in the mold to remove at least a portion of the second liquid vehicle to form (i) a primary funnel portion, and (ii) any portion of at least one microneedle not formed after steps (b) and (c), wherein the primary funnel portion comprises the matrix material; and (f) removing at least one microneedle from the mold together with the primary funnel portion connected thereto, wherein more of the substance of interest is located in the at least one microneedle than in the primary funnel portion. The matrix material in step (e) may additionally form a base substrate of the primary funnel portion connected to the distal side of at least one microneedle. In a preferred embodiment, the percentage of the substance of interest located in at least one microneedle is at least 50%, more preferably 60%, more preferably 70%, more preferably 80%, and more preferably 90%. Typically, this percentage represents the average percentage between microneedles loaded with the substance of interest within the microneedle patch.

[0083] In another preferred embodiment, a method for making a microneedle array is provided, the method comprising (a) providing a non-porous and gas-permeable mold, the mold having an upper surface, an opposite lower surface, and a plurality of openings on the upper surface, wherein each opening leads to a cavity defining a microneedle; (b) filling the cavity with a fluid material through the opening, the fluid material comprising a substance of interest dissolved or suspended in a liquid vehicle; (c) drying the fluid material in the mold to remove at least a portion of the liquid vehicle and form a plurality of microneedles comprising a substance of interest; and (d) removing a plurality of microneedles from the mold, wherein the filling of step (b) is performed by means of a pressure difference applied between the upper and lower surfaces of the mold. This can advantageously fill particularly viscous materials at an effective rate. For example, a pressure greater than atmospheric pressure can be applied to the upper surface, a pressure less than atmospheric pressure can be applied to the lower surface, or a combination of both to achieve a pressure difference.

[0084] In another embodiment, a method for manufacturing a microneedle array is provided, the method comprising providing a two-part mold having an upper portion and a lower portion, the upper portion having an upper surface, an opposite lower surface, and an opening therethrough, the opening defining an upper cavity, the lower portion having an upper surface, an opposite lower surface, and an opening on the upper surface, the opening being in fluid communication with the upper cavity and leading to a lower cavity, the lower cavity defining microneedles, wherein the upper portion and the lower portion are detachably fixed together; filling at least the lower cavity with a first material through the opening in the upper portion, the first material comprising a substance of interest dissolved or suspended in a first liquid vehicle; drying the first material in the mold to remove at least a portion of the first liquid vehicle to form microneedles comprising the substance of interest; and

[0085] The microneedles are removed from the mold.

[0086] The method of making the microneedle array and patch is preferably carried out under a minimum ISO 5 (100) process, an ISO 7 process, or an ISO 8 process. Terminal sterilization may be utilized when compatibility of the sterilization method with the active substance has been demonstrated.

[0087] Mould

[0088] In some embodiments, the mold for making a microneedle array includes a cavity that is the negative phase of the microneedles to be produced and any funnel portion. In some embodiments, the mold includes a funnel portion that is only used to increase the internal load of the microneedles and then removed before processing the entire microneedle array. In those embodiments, the mold can be a two-part mold or include a separate filling template. Some novel methods for making microneedles described herein can be used to make microneedles that extend from a base substrate and do not include a funnel portion.

[0089] The mold can be formed by a single part or multiple parts. In one embodiment, the two-part mold is composed of an upper mold part with one or more cavities defining the funnel part and a lower mold part with one or more cavities defining one or more microneedles. The mold parts can be permanently or reversibly fixed to each other. The mold consisting of two or more parts can be aligned with each other and reversibly or irreversibly connected to each other by applying pressure (e.g., pneumatic, mechanical force or clamping), adhesive, magnetic charge / electric charge, surface tension, chemical bonding (i.e., covalent, non-covalent) or vacuum.

[0090] Figure 14-16 Examples of various molds are shown in the cross-sectional views of FIG. Fig.14 An embodiment of a one-part mold 1400 is shown having an upper surface 1405 and a lower surface 1410. The upper surface 1405 has openings 1415, wherein each opening 1415 leads to a first cavity 1420 proximate to the upper surface 1405 and a second cavity 1425 extending from the first cavity 1420 in a direction away from the upper surface 1405. The first cavity 1420 defines a primary funnel portion 1430, and the second cavity 1425 defines a microneedle 1435. Fig.15 and Fig.16 A two-part mold embodiment is shown. Fig.15 One embodiment of a two-part mold 1500 is shown having an upper portion 1501 detachably secured to a lower portion 1502. The upper portion 1501 includes an upper surface 1505, an opposing lower surface 1506, and an opening 1515 therethrough, wherein the opening 1515 defines an upper cavity 1520. The lower portion 1502 includes an upper surface 1509, an opposing surface 1510, and openings 1522 on the upper surface 1509. The openings 1522 are in fluid communication with the upper cavity 1520, and each opening 1522 leads to a lower cavity 1525 defining a microneedle 1535.

[0091] Fig.16 Another embodiment of a two-part mold 1600 is shown having an upper portion 1601 detachably secured to a lower portion 1602. The upper portion 1601 includes an upper surface 1605, an opposing lower surface 1606, and openings 1615 therethrough, wherein each opening 1615 defines an upper cavity 1620. The lower portion 1602 includes an upper surface 1609, an opposing surface 1610, and openings 1622 on the upper surface 1609. Each opening 1622 is in fluid communication with a corresponding upper cavity 1620 and leads to a lower cavity 1625 defining a microneedle 1635.

[0092] In one embodiment, the upper cavity acts as a filling cap during filling of the lower cavity. That is, the upper cavity is not configured as a funnel, but rather as a structure that can be used to maintain the liquid material in place above the opening during the drying process, at least until the material is sufficiently solidified so as not to flow away. The filling cap can be discarded after the microneedles are formed.

[0093] The molds can be reusable or disposable. For traditional molding processes, molds are expensive and are usually made of hardened steel and can be used again and again to produce, for example, millions of parts. Because the mold / tool ​​costs are spread over many parts, the process is still economical. However, low-cost disposable molds are also of interest. For example, molds made of elastomers manufactured by casting or direct processing techniques (e.g., laser ablation) are cheap to make. In addition, their elastic properties allow the microneedle array to be removed from the mold more gently relative to rigid mold materials. Disposable manufacturing tools are generally preferred in pharmaceutical and / or aseptic manufacturing because they are advantageous from the perspective of sterility and cleanliness (e.g., there are no strict cleaning methods or cleaning validation to ensure that active substances are completely removed between manufacturing batches).

[0094] The geometry of the mold is typically the inverse of the microneedle array to be produced. The mold has essentially the same geometry (in inverse form) as described above for the microneedles and funnel.

[0095] In general, the molds can be open (i.e., without a top portion) for casting or similar types of filling processes, or they can have a separate top portion that is compatible with pressure-driven or injection-molding-type filling processes. The mold size can be adjusted to produce individual microneedles (i.e., a single cavity), sheet or plate arrays of more than one microneedle (i.e., multiple cavities), or multiple microneedle arrays that can then be assembled into a patch. In one case, the mold can be in the form of a flexible roll fed by a continuous roll-to-roll process, an embodiment of which is shown in Fig.19 middle.

[0096] Fig.191 is a cross-sectional view of an example of a system for a continuous filling process. The figure shows a portion of a ring of a flexible mold 1901 including a spaced array of microneedle cavities 1902. The mold 1901 is fed by a roller or reel 1907 through a fixed filling station including a pressure / filling head 1904. The pressure / filling head 1904 includes a reservoir 1904 containing a fluid 1905, which enters the cavity of the array 1902 under pressure. A fixed plate 1906 contacts the back ("lower") side of the mold 1901 and fixes / stabilizes the mold near the filled cavity array 1902, providing an opposing force acting on the mold to provide a fluid-tight interface between the pressure / filling head 1904 and the mold 1901. In some embodiments, the fixed plate 1906 can be a vacuum plate, providing a pulling force at the bottom of the mold to supplement the thrust at the top of the mold. The filled microneedle array is then moved to other locations downstream for further processing.

[0097] The mold can be made of a variety of materials, including but not limited to metals, polymers, ceramics, elastomers, composites, etc., or combinations of these materials or other materials. The mold can be solid, can contain discrete pores / voids, and / or can be permeable to gases but have very low or no permeability to liquids such as the processing solvent (liquid vehicle) of interest. Examples of suitable processing solvents include water and organic solvents, such as volatile organic solvents known in the art of polymer molding.

[0098] In one embodiment, the mold is made of siloxane (e.g., polydimethylsiloxane, PDMS), which is permeable to air, but not too permeable to water and other solvents. This allows air to pass through the mold wall, and is removed from the microneedle / funnel cavity of the mold via a pressure gradient from the inside of the mold cavity (high) to the outside of the mold (low). Advantageously, this process is more scalable and suitable for a sterile environment than applying a vacuum around the entire system, for example as described in the literature. Advantageously, PDMS does not contain interconnected discrete holes like porous metal or porous ceramic molds. These discrete holes can be closed by blocking with a dry excipient, and are replaced and / or actively cleaned. The PDMS mold is also elastic, and unlike rigid mold materials, this advantageously provides an extremely gentle demoulding process, and does not require a release agent / coating. When a rigid mold is utilized, the microneedle tip may break in the mold during the demoulding process. This will produce poor quality microneedles, and will require active cleaning of the mold before reuse. With suitable elastic (eg, PDMS) molds, the probability of microneedles breaking is low, and the molds can be manufactured cheaply, making them disposable if desired.

[0099] In certain embodiments, the molds are more permeable to air than to water or other liquid solvents (so that they are configured / effective to remove air from the molds during microneedle fabrication by a pressure gradient across the mold walls), and lack interconnected porous structures. In certain embodiments, the molds are made of flexible / elastic materials (so that they are configured / effective to be molded and demolded without the use of release agents / coatings, to achieve demolding by deforming the molds, and / or to enable cost-effective disposable molds).

[0100] The mold is preferably made of a material that produces no or minimal leaching or dust. The material of construction of the mold is selected to be compatible with the substance of interest, excipients, disinfectants (e.g., ethanol, isopropanol), one or more common sterilization methods (e.g., heat, steam, ethylene oxide, irradiation, chemicals, UV light), and other processing materials used to form the microneedle array.

[0101] In an optional embodiment, the mold is coated with a material that acts as a release agent, making the microneedle array / patch easier to remove from the mold. The mold may have a demolding pin or similar mechanical structure to help remove the microneedle array / patch.

[0102] In a preferred embodiment, the mold surface, e.g., that of the cavity that contacts and defines the microneedles and funnel, should be smooth. Minimum surface roughness facilitates a cleaner filling process (i.e., more active material is transferred to the microneedle and its tip compared to the sidewalls of the funnel), allows the microneedle patch to be released from the mold, and reduces friction during insertion of the microneedles (i.e., a smooth-walled mold produces smooth-walled microneedles that have less frictional losses during insertion than microneedles with rough surfaces). The surface roughness average (Ra) should be less than 10 microns, preferably less than 1 micron, and more preferably less than 0.1 micron.

[0103] The mold can be made by grinding, milling (e.g., conventional milling, micro-milling, nano-milling), drilling, laser processing (e.g., ablation, drilling), electrical discharge machining (e.g., EDM, microEDM), wet and / or dry etching, 3D printing, electroforming, lithography (e.g., UV, stereolithography), etc. In a preferred embodiment, the mold is formed by making a casting of the main structure. The main structure can be processed using the techniques described herein or techniques known in the art for making molds. The geometry of the main structure can be the same as that described herein for the microneedles.

[0104] Although the above mold and molding process can be described with reference to manufacturing a single microneedle patch, the mold can be configured to form multiple microneedle patches. For example, in an embodiment, the mold can be configured to produce 6 or more patches, 12 or more patches, etc.

[0105] filling

[0106] The composition of the filling solution generally reflects the desired material of the final microneedle array, except for the solvent, which can be substantially removed during processing.

[0107] In a preferred embodiment, the substance of interest is preferably loaded into the microneedles and their tips, rather than the funnel portion. The substance of interest is a part of the filling material transferred to the mold. The filling material may also include a liquid vehicle. The filling material may be in the form of a solution, slurry, suspension, melt, powder or particle of particles or any combination of these forms. One or more of these forms can be used in a multi-step filling process. This "filling material" may be referred to as a "solution" or "fluid material" herein.

[0108] In various filling steps, the filling material may include a liquid vehicle. The term "liquid vehicle" may be referred to herein as a "solvent" or "carrier fluid". In various embodiments, the filling material may include (1) only a solvent, (2) no solvent, (3) only a host material, (4) a combination of a solvent and a host material without a substance of interest, (5) only a combination of a solvent and a substance of interest, or (6) a combination of a solvent, a substance of interest, and a host material. The solvent may be water, an organic solvent such as a volatile organic solvent, or a combination thereof. Some examples are Class 3 solvents, including acetic acid, heptane, acetone, isobutyl acetate, anisole, isopropyl acetate, 1-butanol, methyl acetate, 2-butanol, 3-methyl-1-butanol, butyl acetate, methyl ethyl ketone, methyl tert-butyl ether, 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.

[0109] The microneedles and funnel cavities can be completely filled, partially filled, or overfilled. After the filling step occurs, a drying or curing step is usually followed. The drying step can be achieved by heating or reducing pressure (e.g., evaporating the solvent), by cooling or increasing pressure (curing the matrix material), exposing to light (e.g., polymerizing due to exposure to ultraviolet light), or a combination thereof. This drying or curing step can cause the deposited material to be completely, substantially, or only partially dried or cured. In general, when the viscosity is low, the solution transfers more active substances to the microneedles and their tips, the solution has a high surface energy in the funnel, and the active substances are not saturated (i.e., the active substances are highly soluble in the solvent). However, none of these three characteristics are required, and they are usually just more preferably loaded microneedles and their tips.

[0110] In a preferred embodiment, a two-step filling process is used, wherein the first filling step contains the substance of interest, which migrates substantially to 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 contains a matrix material that imparts mechanical structure to the microneedles and funnels and can be overfilled to produce a base substrate or a component of a base substrate.

[0111] In other embodiments, a single filling step or more than two filling steps may be used. For example, if the active material is cheap and the excess active material in the funnel and the base can be wasted, a single filling step is suitable. More than two filling steps may be needed to further increase the load of the active material in the microneedle, the increase is greater than and far exceeds the increase in the funnel, further target the active material in the microneedle and their tips, deposit a variety of active materials or excipients in a discontinuous layer in the microneedle, deposit a variety of active materials or excipients in different needles or needle segments in a given microneedle patch and / or give the microneedle patch further functionality (for example, insert a fast dissolving or breakable layer, the microneedle contacts the funnel at the layer to allow rapid separation of the microneedle, thereby significantly reducing the required application time).

[0112] One embodiment of a process comprising more than two filling steps is as follows: The mold can be filled with a first solution containing the active substance (and possibly excipients) and then dried. The mold is filled again with the same solution and dried. This operation can be repeated until the desired amount of active substance is loaded into the microneedles. 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 operation) without active substances, which, once dried, will provide the mechanical structure for the microneedles.

[0113] Another embodiment of a process comprising more than two filling steps is as follows: While the funnel allows the microneedles to be preferentially filled with active material (and possibly excipients), some of the active material may be deposited on the side walls of the funnel. This is more pronounced when the solution becomes more viscous and / or supersaturated during the drying process. Therefore, one or more 'rinsing' steps can be inserted into the process, which will bring the active material further down into the microneedles (i.e., towards the microneedle tips). The rinsing steps will contain a solvent or carrier (and possibly excipients) for the active material, but no active material. When the solvent or carrier fills the funnel, it redissolves or 'stirs up' the active material and transfers the active material to the microneedles as it migrates into the microneedle cavities. This is followed by a final filling step, in which the mold is filled with excipients (which may be the same or different excipients as in the previous filling operation) without the active material, which once dried will provide the mechanical structure for the microneedles.

[0114] In one embodiment, the filling process includes a first filling using a solution having a volume substantially equal to or less than the volume of the microneedles plus the funnel cavity and preferably greater than the volume of the microneedle cavity. This filling process is best suited for filling droplets of a specified volume. The volume of the microneedles + funnel is the sum of the volume of all filled microneedle cavities and the volume of the funnels connected to these filled microneedle cavities at the time of the filling process. In one embodiment, the filling process includes a second filling using a solution having a volume substantially equal to or greater than the volume of the microneedles + funnel cavity. The filling process can combine the first and second filling steps as described above in this paragraph.

[0115] In some embodiments, the filling step includes one or more features or sub-steps that enhance preferential loading of the fluid or substance of interest into the microneedles relative to the funnel portion.Combinations of the following embodiments are contemplated.

[0116] In one embodiment, the funnel portion has a relatively steep funnel angle. With a steeper funnel angle, gravity (or an applied pressure gradient) is allowed to further influence the solution to flow downward (i.e., toward the microneedle tip) to the mold sidewalls as it dries. To this end, the microneedle and mold geometry may include a steep funnel angle. References here and elsewhere in this disclosure to movement "downward" do not necessarily refer to orientation relative to gravity, but rather to orientation relative to the mold, so "downward" refers to movement toward the microneedle tip.

[0117] In one embodiment, at least the funnel portion of the mold cavity has smooth sidewalls. With smooth sidewalls, the solution is facilitated to migrate into the microneedles as they dry. The solution is less likely to get stuck in cracks and crevices, and will have less frictional resistance to flow driven by gravity, surface tension, pressure-driven convection, vibration, electrophoresis / electroosmosis, and other forces.

[0118] In one embodiment, the microneedle portion of the mold has a lower surface tension than in the funnel portion. With the relatively high surface tension in the funnel portion and the relatively low surface tension in the microneedle portion, the solution will migrate more easily and cleanly from the funnel down and into the microneedle portion of the mold. The surface tension can be affected by the properties of the solution and the surface of the mold. Therefore, the surface tension can be changed by selecting and using surfactants, oils, mold surface roughness, coatings, etc.

[0119] In one embodiment, a filling solution with low viscosity is provided. A filling solution with relatively low viscosity flows more easily and can flow down into the microneedles more easily when dried. In embodiments where the solution comprises an active substance, it is generally preferred that the solution viscosity 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.

[0120] In one particularly effective and preferred embodiment, the filling process includes a rinsing step. This "rinsedown" or "rinse" step can be used to further preferentially load the microneedles and their tips. In the rinsing step, after filling with the active substance and drying / curing, the mold can be refilled with a solvent / carrier to redissolve or arouse the active substance and bring it down to the microneedle cavity, where the active substance can be re-precipitated. The rinsing step rinses off the active substance on the funnel wall and transfers it to the microneedles. Therefore, in one embodiment, the molding process includes at least three casting processes in the following order: a casting process to deposit the active substance in the mold, a process to further "rinse" the active substance downward into the mold (i.e., the purpose is to remove the active substance from the funnel portion of the mold and move it to the microneedle portion and / or the tip of the microneedle portion of the mold), and a casting process to deposit the excipient that provides the mechanical structure for the microneedles after drying.

[0121] In one embodiment, vibration or ultrasound is applied to the mold to promote the movement of the active material from the funnel down and toward the microneedles during drying. The vibration will help more solution / active material find the lowest energy point in the mold (i.e., the microneedles and their tips).

[0122] In one embodiment, the filling step comprises applying an electromagnetic field or a combination thereof to the filling material. For example, electrophoresis, electroosmosis, magneto-introduction or other mechanisms mediated by electric and magnetic fields may be used.

[0123] In one embodiment, pressure is applied to the fluid to further aid in the migration of the solution toward and into the microneedle cavities. Pressure in the form of flowing sterile air / nitrogen (ie, a blower) or similar methods can be applied to create a pressure gradient to help drive the solution downward during drying.

[0124] In one embodiment, a vacuum is applied to the bottom side of the mold, where the mold includes discrete holes, or where the mold is permeable to air. Such a vacuum can help pull the solution down into the microneedle cavities as it dries.

[0125] In one embodiment, positive pressure is applied to the top side of the mold, where the mold includes discrete holes, or where the mold is permeable to air. Such positive pressure can help push the solution down into the microneedle cavities as it dries.

[0126] In one embodiment, the mold can be rotated using a centrifuge or similar device to generate a normal force into the mold, thereby generating a gravity force that drives the solution down into the microneedles during drying / curing. This process can also help drive larger molecules (e.g., active substances) down into the microneedles and their tips while the fill fluid is still in solution. The term "larger molecules" is used to refer to molecules that are larger than molecules of the liquid vehicle or solvent, and can also include nanoparticles, microparticles, and other particles composed of many molecules.

[0127] In various embodiments, the microneedle molding process includes one or more of the following steps before, during, and / or after any or all mold filling steps: applying vibration, ultrasound, pressure, vacuum, electromagnetic field, and centrifugation.

[0128] In one embodiment, the active substance is controlled to precipitate in the microneedles, but not in the funnel portion. By maintaining the active substance in solution while the solution is still in the funnel, less active substance will be deposited on the side walls of the funnel. To this end, the mold needs to be filled with a solution that is not saturated with the active substance. The solution should be saturated when it is dried to occupy only the volume of the microneedle cavity. At this time, the active substance will precipitate out of the solution and further migrate into the microneedle cavity.

[0129] Various methods can be used to fill the mold. Examples include covering the entire area of ​​the microneedle patch and / or filling individual funnels directly.

[0130] The tips of the microneedle cavities within the mold are closed. If the solution is poured onto the top of the entire mold or funnel, etc., air will be trapped in the microneedle / funnel cavities. This air needs to be removed to fill the mold with material and properly replicate the microneedles. Various methods can be used to remove this air, including (but not limited to): 1) filling the solution under vacuum (i.e., there is no air in the microneedle / funnel cavity to begin with), 2) applying a vacuum after depositing the solution, which will cause the entrapped air to expand and rise through and out of the solution, 3) applying a pressure gradient across the air-permeable mold (e.g., applying a vacuum from the underside of the mold, applying pressure to the top side of the mold, or both) so that the air expels itself from the mold, 4) subjecting the mold to centrifugation to drive the solution into the mold, 5) using ultrasonic treatment or other physical methods from the bottom or top side of the mold to evacuate bubbles from the mold cavity, and / or 5) a combination of these methods.

[0131] Microneedle-by-microneedle filling using conventional microneedle molds is difficult because of the small target size that needs to be deposited (e.g., resulting in misalignment and missing individual microneedle reservoirs in the mold) and small volume (e.g., very small deposition volumes will result in increased volume variation of deposition). This becomes increasingly difficult in high-volume manufacturing. However, funnel-by-funnel (i.e., depositing fill material in individual funnel mold cavities) and 'blanket' filling (i.e., covering the mold surface area, including multiple individual microneedles / funnel mold cavities) are much simpler because the target area is many times larger than the open area of ​​an individual microneedle cavity. With funnel-by-funnel filling, the filling 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 filling volume and target area of ​​the microneedle alone, so this can greatly reduce the variation in deposited volume (e.g., 5nl±1nl is 5nl±20%, and 100nl±1nl is 100nl±1% - an absolute variation of 20 times difference under this assumption) and droplet-target misalignment. With coverage filling, the entire area is covered with solution, further reducing volume and position constraints. The volume deposited by the coverage method can be less than, equal to, or greater than the combined volume of the microneedle and funnel. Once the microneedle and funnel cavities are filled, any excess solution is removed (e.g., wiped, air purged).

[0132] The volume of solution deposited into the microneedle mold can be controlled by the volume of the cavity within the mold (i.e., completely filling the cavity with solution and then cleaning the surface) or the filler (i.e., dispensing or loading to control volume, mass, etc.). For microneedle arrays produced by multiple filling steps, these volume control methods can be used simultaneously. For example, a solution containing an active substance is coated onto the entire surface, the microneedles and funnel cavities are filled, the solution is cleared from the mold surface, the solution is dried, a second solution is deposited in an amount controlled by the filler, the second solution is dried, and the like.

[0133] When filling a microneedle mold without a funnel, the amount of active material deposited in the microneedle is equal to the volume of the microneedle mold cavity multiplied by the concentration of the active material in the filling solution. The amount of active material in the microneedle can be increased by increasing the concentration of the active material in the filling solution. This will be affected by solubility, suspension and other factors. The amount of active material in the microneedle can be increased by increasing the volume of the microneedle mold cavity. This will be limited by the size of the microneedle, which can still achieve its intended function, such as insertion into the skin or other tissues, painless application, etc. Adding a funnel to the microneedle mold design effectively increases the volume of the microneedle mold during filling without changing the volume of the microneedle itself during use. This is because, due to the manufacturing process design, the microneedle and funnel portions of the mold can be filled together, and materials that are dissolved, suspended or otherwise associated with the filling solution can be preferentially deposited in the microneedle portion of the mold when drying. However, when the microneedle patch is applied to the skin or other tissues, only the microneedle portion generally penetrates the skin, while the funnel portion generally does not insert into the skin, thereby effectively becoming part of the base portion of the patch.

[0134] Thus, provided herein are microneedle arrays that contain an amount of active material in the microneedles (referred to as amount A) (and / or an amount of active material applied from the microneedles, referred to as amount A') that is greater than the total volume of the microneedles in the patch multiplied by the average concentration of the active material in each of the filling steps employed during one or more manufacturing processes of the filling solution multiplied by the number of filling steps employed during manufacturing (referred to as amount B). Conventional microneedle mold filling (without a funnel) is not able to achieve this amount of active material (i.e., typically A or A' ≤ B). Use of a funnel allows this amount of active material to be achieved (A or A' ≥ B). For example, A or A' ≥ 1.5B; or A or A' ≥ 2B; or A or A' ≥ 3B; or A or A' ≥ 5B.

[0135] During overfilling or other methods that do not overfill the mold cavity, the filling solution remaining on the mold surface may be lost. During methods that overfill the mold cavity, the filling solution remaining on the mold surface may be lost because the filling process is not accurate and the filling solution is not successfully overfilled in the mold cavity. Having a larger area at the top of the mold cavity makes it easier to overfill the mold cavity because the deposition method will be able to more easily selectively deposit the material in the mold cavity with a larger opening. The use of a funnel allows the mold cavity opening to be larger than the base of the microneedle. The base of the microneedle using a conventional mold that does not include a funnel is at the interface of the microneedle and the mold base. Therefore, the base of the microneedle defines the size of the opening of the mold cavity. In contrast, the base of the microneedle using a mold that includes a funnel is at the interface of the microneedle and the funnel, and the size of the opening of the mold cavity is at the interface of the funnel and the mold base. In this way, the size of the microneedle base and the size of the mold cavity opening can be at least partially separated. The geometry of these interfaces is described above in the section on the geometry of the microneedle and the mold.

[0136] In another embodiment, a method of making a microneedle array is provided wherein one or more filling solutions are applied to a mold such that substantially all of the filling solution is deposited in the mold cavity (i.e., in the funnel and microneedle portion of the mold) and almost no filling solvent is deposited on the mold surface. The ability of the filling solution to have such selective deposition is achieved by having a large mold cavity opening, which is achieved by using a funnel. More specifically, incorporating a funnel portion can result in a method wherein the amount of one or more active substances deposited in the mold cavity (i.e., in the funnel and microneedle portion of the mold) is in a ratio of ≥80%, more preferably ≥90%, more preferably ≥95%, more preferably ≥98%, more preferably ≥99%. In some embodiments, the amount of one or more active substances within the funnel and microneedle portion of the patch is in a ratio of ≥80%, more preferably ≥90%, more preferably ≥95%, more preferably ≥98%, more preferably ≥99% to the amount found in the entire patch (i.e., including the backing).

[0137] In some embodiments, a method for manufacturing a microneedle patch is provided, wherein each microneedle cavity is filled (in parallel and / or in series) by a separate filling solution droplet, and wherein the volume of the droplet is greater than the volume of the microneedle (i.e., the microneedle portion of the mold). The absolute volume of the filling solution droplet may be the same as the volume determined above for the combined volume of the microneedle and funnel portion of the microneedle patch and the mold. The ratio of the microneedle volume (i.e., the volume of the microneedle in the microneedle patch or the volume of the microneedle portion of the mold) to the droplet volume may be equal to the ratio of the microneedle volume to the sum of the above-mentioned microneedle and funnel volumes (or the sum of the microneedle and funnel portions of the mold). More specifically, the ratio of the droplet volume to the microneedle volume may be>1, more preferably ≥1.5, more preferably ≥2, more preferably ≥3, more preferably ≥5. "Droplet volume" can be considered as the sum of the volumes of multiple droplets applied to the same mold cavity before substantially drying, because it is possible to fill each mold cavity with multiple droplets instead of a single droplet.

[0138] Other filling methods can be used to provide selective filling within the patch and needles, including: applying a local selective pressure gradient to fill only the desired locations, changing the surface properties of the mold (e.g., surface tension, specific and nonspecific binding sites) to selectively fill the desired locations, if filling with microchannels, the microchannels can be separated to cover and fill only the desired portions of the patch, or multiple solutions can be used that are immiscible or miscible but flow at low Reynolds number (little or no mixing) to fill only the desired locations.

[0139] In one embodiment, a fluid handling / dispensing technique / system known in the art that can deposit a solution onto a mold is used. Some of these are suitable for 'covering' coating (partial or full patch), targeted deposition, or both. Some examples of fluid handling / dispensing systems are: a syringe or a pump coupled to a dispensing head (Tecan / Cavro, Gilson, Hamilton), an automatic pipetting system (Tecan, Biotek, Eppendorf), screen printing or other mask and cleaning systems, slit coating or similar systems, inkjet printing systems (MicroFab), needle or capillary array dispensing technology, active capillary systems (Nanodrop made by Innovadyne), systems based on aerosols or spraying, dipping, brushing, stamping, surface chemical controlled deposition (PRINT-non-wetting template particle replication technology), acoustic-based systems (Picoliter, Inc.), and any combination of these deposition techniques (e.g., BioJet made by BioDot, a syringe pump-inkjet hybrid). The filling head may be automated and move, the mold may move, or both may move, to deposit the solution at the desired location. This may be in the form of a single cavity mold, a multi-cavity mold template, or a continuous reel-to-reel process. We disclose methods of filling microneedle molds, wherein all microneedle cavities and funnels are filled substantially simultaneously, or wherein different microneedle cavities and funnels are filled at different times. This may be accomplished with droplets of filling solution selectively applied to individual microneedle cavities and funnels, or subsets thereof. This may be accomplished by "capping" selected areas of the filling mold.

[0140] In one embodiment, vacuum filling is used. Vacuum can be applied before the solution is deposited on the mold. This removes most of the air before filling the mold. Vacuum can also be applied after the solution is deposited on the mold. This removes the air in the cavity by expanding and rising the air through the deposited solution and leaving the mold. The vacuum can be applied to the entire mold or to selected areas of the mold to flow through the air permeable / porous mold or both. Such as, the top side or bottom side or a subset of the microneedle cavity and funnel, such as selectively filling those microneedle cavities and molds with filling solution.

[0141] In a particularly preferred embodiment, the mold is filled by applying a vacuum through the gas permeable mold. For example, a vacuum may be applied only to the underside of the mold to create a pressure differential across the mold (e.g., between the upper open surface of the mold and the lower closed surface of the mold). An example of a vacuum device for achieving such vacuum filling is shown in Fig.18, the figure shows a vacuum plate 1800 having an upper surface, on the bottom side of which is placed a gas permeable mold 1802 that mates with the gas permeable / porous surface of the vacuum plate, thereby evacuating the mold. The upper surface of the mold has an array of openings into the microneedle-shaped cavities. By using a mold with discrete holes / openings or a mold that is solid but highly permeable to gas (air, nitrogen, etc.), the microneedle / funnel reservoir can be filled with solution simply by covering the openings of a funnel, multiple funnels, or the entire mold, and then applying a vacuum from the underside of the mold. This draws air out of the mold and creates a pressure gradient to draw the solution into the cavity. See Figure 8 Such a process can advantageously eliminate the transfer step of placing the entire mold into a vacuum chamber.

[0142] The mold used in this process can be made of any suitable gas permeable material that is substantially impermeable to liquids. Preferably, it is a non-porous material without interconnecting pores that can be blocked. In a preferred embodiment, the mold is made of an elastomeric material, such as a silicone, for example, polydimethylsiloxane.

[0143] It has been found that the time to remove the air and fill the mold with the solution is not strongly affected by the viscosity of the solution, so it is suitable for both low-viscosity solutions and high-viscosity solutions. Using this method, the filling time can be, for example, two minutes to four minutes. Advantageously, the vacuum process is highly scalable because the process can be completed in parallel.

[0144] In another particularly preferred embodiment that can be optionally used in combination with the aforementioned vacuum filling embodiment, filling the air-permeable mold is performed by applying an overpressure to the upper side of the solution (the cavity opening side of the mold). By injecting the solution into the mold or mold cavity by pressure, the air can be forced to leave the mold by itself, if the mold has discrete holes / voids or is a solid mold made of a material that is breathable or highly breathable but not too permeable to liquids (e.g., siloxane / PDMS). For example, it has been shown that applying an appropriate amount of pressure (65psi, i.e., a pressure difference of about 50psi) to the solution forces the solution to enter the cavity downward and forces the air to leave the PDMS mold or enter the solution itself within 20 seconds. The time to fill the mold with the solution is not strongly affected by viscosity. See Example 9. This can be done by pressurizing the chamber on the mold. This chamber can be directly pressurized by air, or pressurized by gas moving a barrier material (e.g., a piston or a film) to directly pressurize the solution. Pressure can also be applied similar to a conventional injection molding process. Pressure can be applied mechanically by extruding a movable barrier (e.g., a piston or a film) or directly extruding the solution itself in the form of a plate or roller.

[0145] Thus, in certain embodiments, filling the mold by applying pressure to the top side of the mold may include applying pressure only to the top side of the mold. In other embodiments, the mold is filled by applying vacuum only to the underside of the mold. In other embodiments, the mold is filled by a combination of applying pressure to the top side of the mold and applying vacuum to the underside of the mold. The pressure gradient applied may be between 1 and 1000 psi, and preferably between 10 and 100 psi.

[0146] The terms 'pressure differential' and 'pressure gradient' are used interchangeably herein. The terms refer to the pressure differential used to generate a driving force through at least a portion of the thickness of the mold by, for example, using a pump to generate subatmospheric or superatmospheric pressure on the upper or lower side of the mold. This "pressure differential" does not include the inherent small differences in atmospheric pressure or fluid pressure caused by gravity by virtue of the upper surface of the mold being located on the lower surface of the mold or the head of fluid (e.g., casting solution) being on top of the mold.

[0147] In one embodiment, direct droplet deposition is used to fill the mold. Small droplets can be deposited by inkjet or other techniques, aerosols or narrow fluid streams to directly fill microneedles and funnels without the need to supply external pressure or vacuum because they can fill the microneedle / funnel cavity from bottom to top (i.e., the microneedle tip passes through the funnel-base interface and exceeds the funnel-base interface). The size scale of the droplets or streams is significantly smaller than the size scale of the microneedle / funnel cavity (i.e., the droplet / stream width is greater than the cavity width), and all of them are significantly smaller than the size of the mold cavity. If there is no funnel, it may be difficult to apply droplets to the microneedle mold because the droplets from the deposition device may be larger than the microneedle-base interface width. This is an advantage of using a funnel, where the width of the funnel-base interface is greater than the width of the microneedle-funnel interface. Using a funnel allows the use of larger droplets. Therefore, in one embodiment, the manufacturing process includes filling the mold with droplets having a width less than the width of the funnel-mold interface, and may be greater than the funnel-microneedle interface width, or having a width less than the funnel-microneedle interface width.

[0148] In another embodiment, the filling method includes placing discrete capping structures, thin film microcapillaries and / or semi-continuous surface microchannels on a mold, filling with a solution, and then filling the microneedle / funnel cavity by using a pressure gradient. The pressure gradient can be applied as described (i.e., applying a vacuum from the lower side of the mold and / or pressurizing the solution in the lid / channel). Referring to Example 6. The solution can also flow through these structures by other mechanisms, such as capillary flow, electroosmosis and / or other mechanisms known in the field of microfluidics. In such embodiments, the microneedle mold cavity is filled with a filling solution applied from the mold side, and the filling solution flows in a direction substantially perpendicular to the central axis of the cavity. This is in contrast to conventional filling methods, which are applied from above the mold, and flow (through air) in a direction substantially parallel to the central axis of the cavity. The filling solution fills the microneedle mold cavity.

[0149] In one embodiment, a custom filling head is contacted with the open side of the mold and fluid-tight with it, thereby adding a pressure gradient to force the solution into and / or be pulled into the mold. The filling head comprises a solution reservoir, which may comprise a volume equal to, greater than, and preferably much greater than the volume of the microneedle / funnel mold cavity to be filled. The reservoir may also be refilled during processing, refilled (e.g., removed, filled, reinstalled) outside the processing process, or disposable, wherein the reservoir or the reservoir and the filling head are replaced with a new full unit. The filling head may be a tube with fine and / or rounded edges, or may have an O-ring, gasket, or other sealing material, so that it can fully contact the mold to form a fluid seal. The front of the filling head may also have a porous material, wherein the porosity (pore size and number) and surface chemistry are controlled so that it does not dispense solution without an applied pressure gradient. The filling head can be slid to the next microneedle array (e.g., to maintain its fluid seal, face seal), or the solution can be retracted and the filling head can be removed from the mold and repositioned to the next microneedle array. The filling system and method can use more than one filling head. The filling head can be an elongated slot or some other geometric shape that is different from tubular and is more suitable for filling the solution into many microneedle patch cavities at the same time. In one embodiment, the face seal filling head is beneficial to remove excess solution from the mold surface on the filled cavity.

[0150] Fig. 27An embodiment of a system and a filling method including the use of a filling head is shown. System 2700 includes a gas permeable mold 2704 having three microneedle cavity arrays 2708a, 2708b, and 2708c (each array is shown with three microneedle cavities), wherein each array has an opening on the upper surface 2705 of the mold 2704. Filling head 2702 contains filling material 2706 and is engaged with the upper surface 2705 of the mold 2704 and is shown in a position to fill the microneedle cavity array 2708b. The horizontal arrows show the movement of the filling head 2702 across the upper surface 2705 of the mold 2704 to sequentially fill the cavity array with filling material 2706, which is typically assisted by a pressure difference across the mold (i.e., pressure-assisted and / or vacuum-assisted).

[0151] Another method of venting the air from the mold cavity and allowing the deposition solution to enter is to apply physical energy to the mold to force the bubbles to pass upward or into the solution to be vented. For example, ultrasonic treatment can be applied from the bottom side of the mold to vent the air from the cavity, or ultrasonic treatment can be applied to the top side of the mold and the solution used to fill the cavity. Moreover, impact can be applied from the bottom side of the mold to vent the air from the cavity. Alternatively, the air can be vented by stretching an elastomeric mold. By stretching the elastomeric mold, the cavity can be closed to vent the air, and the solution can be applied to allow the mold to return to its original state and fill the cavity with the solution.

[0152] A sponge (e.g., foam, fabric, or other absorbent material) filling head can be used to fill the mold by pressing a saturated or partially saturated (with filling solution) filling head against the microneedle / funnel cavity. The filling head can be pressed against the mold and held in place one or more times. When the sponge containing the deposition solution is pressed against the mold, the sponge deforms and expels the solution, forcing (e.g., by pressure) the solution into the microneedle / funnel cavity, thereby filling the cavity and forcing air out of the cavity through the mold wall. After filling, the force is released, the sponge relaxes, and can then be used to 'wipe dry' or clean any residual solution from the surface. There can be more than one sponge filling head. The sponge filling heads can also be presented in the form of rollers. The sponge filling heads can replenish the solution during processing by dispensing the solution to them. Or some of the sponges can be in contact with the supply reservoir at all times so that the solution saturation level of the sponge remains relatively constant.

[0153] dry

[0154] A variety of drying and / or curing methods can be used during the entire manufacturing process. Heat can be applied in a batch process, but is preferably integrated into a semi-batch or continuous process. Some drying methods (solvent removal by evaporation hardens the solution) include applying: 1) heat - by convection, conduction (i.e., hot plate or heated surface), and / or radiation (heat lamp, IR or NIR light), 2) convection-drying (dry), drying (desiccated), sterile air or nitrogen blower, 3) vacuum - exposed to reduced pressure, 4) atmospheric drying, 5) drying, 6) freeze drying or freeze drying, 7) dielectric drying (e.g., rf or microwave), 8) supercritical drying, and 7) a combination of one or more drying methods.

[0155] Various curing methods (hardening of a material by polymerization / crosslinking or reversible polymerization / crosslinking of polymer chains) are induced by electron beam, heat, or chemical additives / reactions. Curing triggers may include time, ultraviolet radiation (eg, UV light), pressure, heating, etc.

[0156] In one embodiment, the aqueous solution can be dried at ambient temperature for a period of about 30 minutes to about one week to form dry solid microneedles (e.g., about 45 minutes to about one week, about one hour to about one week, about one hour to about one day, etc.). In one embodiment, the aqueous solution can be vacuum dried using a backside vacuum for about 3 minutes to about 6 hours, about 3 minutes to about 3 hours, about 3 minutes to about 1 hour, or about 3 minutes to about 30 minutes. Although various temperatures and humidity levels can be used to dry the aqueous solution, the formulation is preferably dried at 1°C to 60°C (e.g., 15°C to about 45°C, about 25°C to about 45°C, or at about ambient temperature) and 0 to 40%, 0 to 20%, 0 to 10%, or at ambient relative humidity.

[0157] As used herein, the terms "drying", "dried" or "dry" when referring to a material (e.g., a matrix material and / or a substance of interest) in a mold means that the material becomes at least partially hardened. In some embodiments, the microneedles may be removed from the mold before they are completely dried. In one embodiment, the microneedles are removed from the mold after the microneedles are dried to an operational state. However, in a preferred embodiment, the microneedles are removed from the mold when the microneedles are in a rubbery state but are strong enough to be pulled or peeled out of the mold. It has been found that this can improve demolding without breaking the microneedles. As used herein, the term "operating state" means that the microneedles are rigid enough for their intended use, for example, piercing the skin. As used herein, the term "rubbery state" means that the microneedles are not in an operational state because they are too soft and flexible to penetrate their intended target tissue, such as the skin. For example, a microneedle (such as a microneedle composed of a matrix / matrix material (including polyvinyl alcohol and sugar)) will enter a rubbery state when undergoing a drying process because its water content is reduced, and then enter an operational state.

[0158] Demolding and casting products

[0159] The microneedle patch can be removed from the mold using a variety of methods. Non-limiting examples include 1) adhering an adhesive pad or backing to the back side of the microneedle array and demolding the assembled microneedle patch from the mold, 2) removing the microneedle array from the mold and adhering it to an adhesive pad or backing using pick-and-place automation (picked up by suction cups or small clamps), 3) ejecting from the mold using an ejector pin or other mechanical techniques similar to traditional injection molding processes.

[0160] Additional process steps

[0161] In some embodiments, the microneedle patch is composed of a first portion of a patch manufactured using a mold filling method and a second portion that is not manufactured using the same mold filling method. Specifically, the second portion of the patch can be manufactured before the first portion of the patch is manufactured. The second portion of the patch can be combined with the first portion of the patch during or at a certain time afterwards for the mold filling process of the first portion of the patch. The first portion of the patch can be a microneedle, a funnel, and a base, and comprises one or more active substances. The second portion of the patch can be a backing attached to the top side of the molded base.

[0162] Microneedle patches can be inspected prior to packaging to ensure they meet specifications. The machine vision industry has developed a number of technologies suitable for this purpose. A number of inline and non-contact automated inspection systems are available (digital inspection mirrors (Keyence), color confocal imaging (Nanovea), and reflectance-based systems).

[0163] The patch that meets the specification is then packaged. In a preferred embodiment, packaging protects the microneedle patch and its content (that is, active ingredient) from mechanical damage, moisture, light, oxygen and / or pollution (for example, particulate, microorganism). A single microneedle patch can be attached to a lid, or a plurality of microneedle patches can be attached to a tray. The lid or tray can be formed by plastic material, metal material (aluminum), metallized plastic material or other materials. The example description of this type of microneedle patch lid and tray is in the PCT patent application disclosure WO / 2015 / 048777 of GeorgiaTech Research Corporation.

[0164] 4. Methods of using microneedle arrays

[0165] The microneedle arrays and patches provided herein can be applied by oneself or with the aid of another individual (e.g., a parent, guardian, minimally trained health care worker, skilled trained health care worker, and / or other personnel). Unlike the microneedle systems of the prior art, the microneedle patches provided herein can be directly handled and applied by a person applying the patch without the need to use an application device to apply the required force / pressure, thereby allowing for extremely simple low-profile (i.e., thin and patch-like) microneedle patches (e.g., total patch thickness (including any application aid) not exceeding 2 cm, more preferably 1.5 cm, more preferably 1 cm, and more preferably 0.5 cm).

[0166] Therefore, the embodiments provided herein additionally include a simple and effective method for applying a substance of interest by means of a microneedle patch. The method may include identifying the application site, and preferably disinfecting the region (e.g., using alcohol cotton), and then applying the microneedle patch. If necessary, the application site may be allowed to dry first, and then the microneedle patch may be applied. The patch is then applied to the patient's skin / tissue, and the patient's skin / tissue is manually pressed into the patient's skin / tissue (e.g., using a thumb or finger) by applying a pressure sufficient to insert one or more microneedles into the patient's skin / tissue. After application is complete, the patch of the patient's skin / tissue may be removed as follows: by manually grasping the tab portion (e.g., between the thumb and the finger), the patch is peeled off from the patient's skin / tissue, and the patch is discarded.

[0167] In some embodiments, the microneedle patch described herein is used to deliver one or more substances of interest (e.g., vaccines, therapeutic agents, vitamins) to the body, tissues, cells and / or organs. In one embodiment, the active substance is delivered to the skin by microneedles, which are inserted into the stratum corneum (10 to 20 microns outside the skin, a barrier for transdermal transport), and enter the active epidermis and dermis. The small size of the microneedles makes them cause little or no pain and target the intradermal space. The intradermal space is highly vascularized and rich in immune cells, and provides an attractive path for administering vaccines and therapeutic agents. The microneedles are preferably soluble, and once they enter the intradermal space, they dissolve in the interstitial fluid and release the active substance into the skin. Once the microneedles are completely dissolved (usually taking a few minutes (e.g., <20 minutes)), the patch can be removed and discarded as non-sharp waste because the microneedles are dissolved. The microneedles can be changed to provide a faster release or faster separation from the patch. They can also be formulated to release active substances over a long period of time. Alternatively, the microneedles can be designed to detach quickly from the patch, but then dissolve slowly. A combination of these release features can be incorporated into a single microneedle patch to provide a desired release profile for the agent.

[0168] In one embodiment, a method for administering a substance of interest to a patient is provided, the method comprising providing a microneedle array as described herein; and applying the microneedles of the array to a patient's tissue surface, wherein the microneedles of the array are manually inserted into the skin without the use of a separate or internal application device. In this particular context, the term "application device" is a mechanical device that provides its own force, for example, through spring action, etc., which acts as a motive force to drive the microneedle array toward the tissue surface, which is different from any force imparted by the user when holding the device and / or pressing the microneedles against the tissue surface.

[0169] 5. Examples

[0170] The present invention may be further understood with reference to the following non-limiting examples.

[0171] Example 1: Fabrication of a microneedle array mold

[0172] Laser engineered funnels based on polydimethylsiloxane (PDMS, Sylgard 184, Dow Corning, Midland, MI) microneedle array molds were prepared using a Universal Laser Systems (VLS3.50) on a 2.0-mm thick PDMS sheet. The microneedle array mold includes a plurality of cavities, each of which includes a first cavity and a second cavity. The first cavity defines a primary funnel portion with a height of 300-700 μm and a diameter of 500-1000 μm at its widest point. The second cavity defines a conical microneedle with a height of 600-900 μm, a diameter of 250-300 μm at its widest point, and a terminal radius of about 10 μm.

[0173] Example 2: Fabrication of a microneedle array mold

[0174] A polylactic acid (PLA) microneedle master structure was fabricated by casting molten PLA pellets (L-PLA, 1.0 dL / g, Birmingham Polymer, Pelham, AL) onto the PDMS multi-cavity mold fabricated in Example 1 for 1 h under vacuum, -91 kPa, and 195° C. Thereafter, a PDMS multi-cavity mold replica was fabricated by curing the PDMS on top of the PLA master structure at 37° C.

[0175] Example 3: Fabrication of microneedle arrays

[0176] Microneedle matrix material was prepared with polyvinyl alcohol (PVA) (MW 2000, ACROS Organics, Geel, Belgium) and sucrose (Sigma-Aldrich, St Louis, MO) in a 1:1 mass ratio. Eight grams of PVA were distributed into 15 ml of DI water at 25°C and then heated to 90°C for 1 hour to dissolve to form a PVA solution. Thereafter, 6.0 g of sucrose was added and uniformly mixed with the PVA solution. The resulting mixture was then heated for 2 hours and then centrifuged at 2000 x g for 30 minutes to remove bubbles in the mixture to form a microneedle matrix material. The microneedle matrix material was then cooled to 4°C before use.

[0177] The model drug solution was prepared with sulforhodamine B (MW 559Da, Molecular Probes Eugene, OR) in deionized water, and the sulforhodamine B is a water-soluble red fluorescent dye with an excitation / emission peak of 565 / 586nm. The model drug solution was then moved to the upper surface of the PDMS multi-cavity mold to cover all cavities, and then evacuated to -91kPa at room temperature for 3 minutes. After evacuation, the residual drug solution on the upper surface of the PDMS multi-cavity mold was removed and recovered for reuse. The PDMS multi-cavity mold was then dried at room temperature under 3000x g centrifugation for 5 minutes. Thereafter, the dry sulforhodamine B attached to the upper surface of the PDMS multi-cavity mold was removed by Scotch tape (3M, St.Paul, MN).

[0178] Then about 200 μL of microneedle matrix material was applied to the upper surface of the PDMS multi-cavity mold to cover all cavities. Thereafter, the PDMS multi-cavity mold was evacuated to -91 kPa for 3 minutes at room temperature, and then centrifuged at 3000Xg for 5 minutes at room temperature to remove bubbles.

[0179] The PDMS multi-cavity mold filled with sulforhodamine B and microneedle matrix material was then freeze-dried with a freeze dryer (VirTis Wizerd 2.0 freeze dryer, Gardiner, NY) for about 24 hours. The freeze drying step was performed as follows: the mold was frozen to -40°C for 1 hour, and then vacuumed at 2.67Pa and -40°C for 10 hours. When the pressure remained constant (2.67Pa), the temperature was gradually ramped up to 0°C for 1 hour, up to 20°C for 1 hour, and up to 25°C for another 10 hours. After freeze drying, double-sided tape (444 double-sided polyester film tape, 3M, St.Paul, MN) was used to remove the final microneedle array from the PDMS mold. Various microneedle arrays were prepared as disclosed in the examples. The following table summarizes the structural parameters of each microneedle array.

[0180]

[0181] Fig.17 Microscopic image of a microneedle array prepared as disclosed in this Example. Fig.17 As shown in , the model drug sulforhodamine B is primarily located in the microneedles of the final microneedle array (ie, more of the substance of interest is located in the microneedles rather than in the funnel portion).

[0182] Example 4: Drug loading capacity and efficiency in microneedle arrays

[0183] Six different microneedle arrays prepared as described in Example 2 were dissolved in 10 mL of deionized water for 1 hour in different containers at room temperature, each array containing different drug concentrations (i.e., 0.1 mg / mL, 1.0 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, and 20 mg / mL). Each dissolved microneedle array was then transferred to a 96-well plate and analyzed by scanning in a microplate reader (multimode microplate synergy TM MX, Biotek) and Gen5 TM Software (Biotek). The basis of this experiment is to measure the emission / excitation spectrum of sulforhodamine B, which is linearly proportional to the concentration of sulforhodamine B in the range of 0.001 μg / mL to 1 μg / mL. The total amount of drug encapsulated in the microneedles and funnel of the microneedle array (A) is determined using the average value of the signal of each microneedle array. MN+F ). Fig. 22 The drug loading of each of the six microneedle arrays is shown in FIG. Fig.23 The drug loading efficiency of each drug in the six microneedle arrays is shown in FIG.

[0184] Example 5: Evaluation of drug delivery efficiency of microneedle arrays

[0185] Studies were conducted to measure the drug delivery efficiency of the microneedle arrays by using porcine cadaver skin (Pel-Freez, Rogers, AR) for in vitro testing. The initially frozen porcine cadaver skin was first thawed to room temperature and then shaved to remove all hair using a disposable razor (Dynarex, Orangeburg, NY). Subcutaneous fat was then removed from the porcine cadaver skin using a scalpel (Feather, Osaka, Japan).

[0186] The microneedle arrays prepared as described in Example 2 were manually inserted into the skin of pig cadavers for 5 seconds, 30 seconds, 1 minute, 2 minutes, 10 minutes and 20 minutes, respectively, each microneedle array having a cavity of different sizes (primary funnel portion and microneedles containing sulforhodamine B). For each insertion time, each microneedle array subgroup had 6 parallel determinations. After each microneedle insertion, the microneedle array was microscopically imaged under a microscope (Olympus SZX16, Pittsburgh, PA) to determine whether the microneedle failed to insert (bend) or inserted, the amount of microneedles dissolved in the skin of pig cadavers, and whether the primary funnel portion was dissolved in the pig cadavers. The insertion site on the skin of pig cadavers was also observed under a microscope to determine whether the drug was delivered in the pig cadavers. Then an adhesive tape (3M, St.Paul, MN) was applied to the insertion site of the skin of the pig cadavers to remove the residual drug left on the skin surface.

[0187] After each insertion time, the tape and the inserted microneedle array were placed in separate containers with 10 mL of deionized water for 1 hour at room temperature to dissolve. Samples of dissolved tape and dissolved microneedle array were then transferred to a 96-well plate and read by scanning in a microplate reader (Multimode Microplate Synergy TM MX, Biotek) and Gen5 TM Software (Biotek). The basis of this experiment is to measure the emission / excitation spectrum of sulforhodamine B, which is linearly proportional to the concentration of sulforhodamine B in the range of 0.001 μg / mL to 1 μg / mL. The average of the signal of each dissolved tape sample was used to determine the total amount of drug left on the skin (AF), and the average of the signal of each dissolved microneedle array was used to determine the total amount of drug encapsulated in the microneedles and funnel of the microneedle array sample (A MN+F ).

[0188] Fig.24 The amount of drug delivered to the skin per insertion time using two microneedle arrays containing 1.0 mg / mL of drug and having the following structural parameters is depicted: the microneedle array of each cavity has a total volume of 275 nL, the first cavity defines a primary funnel portion with a height of 650 μm, a diameter of 1050 μm at the widest point, a volume of 257 nL, and a base angle of 60 degrees, and the second cavity defines a base diameter of 750 μm, a base diameter of 300 μm, and a volume of 18 nL. The amount of drug delivered to the skin (A) was determined using the following equation MN ):

[0189] A MN =A F -A MN+F

[0190] Among them: A F = amount of drug left on the skin and in the funnel

[0191] A MN+F = the total amount of drug contained in the microneedle array

[0192] The drug delivery efficiency of each microneedle array is defined as:

[0193]

[0194] Among them: A MN = amount of drug delivered to the skin

[0195] A MN+F = the total amount of drug contained in the microneedle array

[0196] Example 6: Fabrication of microneedle array using microchannel structure

[0197] A microneedle array is formed, wherein mold filling is accomplished using a microchannel structure. Fig.26 A cross-sectional view of a multi-cavity PDMS mold 2602 coupled to a thin film unit microchannel structure 2604 and closed on top by a thin polymer cover 2606 is shown. The microchannel structure 2604 is made of a thin adhesive layer and includes microchannels 2608 connecting multiple microneedle cavity arrays spaced apart on the mold 2602 surface. Fig.26 Only one microneedle cavity array 2610 is shown in the figure. A model drug solution (sulforhodamine) is supplied (via a syringe acting as a pump) through channel 2608 (as shown on the left side of the figure), and a vacuum is applied (via a vacuum plate) to the lower side of mold 2602 for 10 minutes (27 in Hg vacuum), causing the dye solution to be pulled into the cavity of mold 2602 (as shown on the right side of the figure). The direction of the dye solution flowing through the channel will be visualized and enter / exit the page. Then, the dye solution left in channel 2608 is purged with air to form the microneedles of the microneedle array.

[0198] The dye was dried and then the fish gelatin and sucrose solution was cast on the mold. Vacuum was applied for 30 minutes as before and the microneedle array was dried and then demolded. The patch was dissolved in deionized water and analyzed for fluorescence. The results confirmed that the dye was loaded onto the microneedles.

[0199] Example 7: Fabrication of microneedle arrays

[0200] The microneedle multi-cavity mold was formed by 3D printing. Some parts of the microneedle mold were 3D printed into tapered truncated cones (stepped sidewalls), each with a height of 1.0 mm and a diameter of 2.0 mm at the widest point to form a funnel portion (positive phase). The 3D printed structure was then cast with PDMS to produce a mold for the base of the funnel. A universal laser system (VLS3.50) was then used to form a microneedle portion (negative phase) in the center of the funnel portion (negative phase) of PDMS to produce a microneedle multi-cavity mold.

[0201] The model drug solution is then deposited onto the top surface of the resulting microneedle multi-cavity mold and then dried. The molten incremental polymer is then poured onto the resulting microneedle multi-cavity mold and then cooled / solidified. The resulting microneedle array is then removed from the microneedle cavity mold.

[0202] Example 8: Vacuum Assisted Filling of Molds

[0203] Design, build and evaluate vacuum plates to receive multi-cavity molds. Fig.18 The vacuum plate and the mold are shown in FIG.

[0204] A mold made of polydimethylsiloxane (PDMS) (DC Sylgard 184) was used in conjunction with a vacuum plate. The mold was 2 mm thick. Solutions of various viscosities were prepared and applied as a thin layer on the top surface of the mold. The solution was water and 0.4% dye, 40 wt % polyvinyl pyrrolidone (PVP) solution, 60 wt % PVP solution, and a solution (25% solid) of sodium carboxymethyl cellulose (CMC) and trehalose (1:1). A vacuum pressure of -13.8 psi was applied to the lower side of the mold for various time periods. Whether the microneedle cavity filling was achieved was then evaluated.

[0205] The results are shown in the table below and generally demonstrate that the microneedle mold can be filled in 3 minutes by applying a vacuum through the underside of the mold, and that the time to remove the air and fill the mold with solution is not strongly affected by the viscosity of the solution within the range considered.

[0206]

[0207]

[0208] Example 9: Pressure Assisted Filling of a Mold

[0209] The pressure-assisted filling of the microneedle mold was evaluated. The mold was made of PDMS (DC Sylgard 184), and the mold was 2 mm thick. Solutions of various viscosities were prepared and applied as a thin layer on the top surface of the mold. The solution was water and 0.4% dye, 40% by weight polyvinyl pyrrolidone (PVP) solution, and 60% by weight PVP solution. A pressure of 50 psi or 65 psi (for a cross-mold pressure difference of 35 or 50 psi, an atmospheric pressure of about 15 psi was given) was applied to the upper side of the mold for various time periods. Whether the microneedle cavity filling was achieved was then evaluated.

[0210] The results are shown in the table below and generally demonstrate that by applying the right amount of pressure to the solution, it is possible to force the solution down into the cavity and force air out of the mold or into the solution itself within 20 seconds. The results also demonstrate that the time to remove the air and fill the mold with the solution is not strongly affected by the viscosity of the solution under the conditions studied.

[0211] Solution Approximate viscosity (cP) ΔP(psi) Time (seconds) Successfully filled? Water / Dye 1 35 20 no Water / Dye 1 35 30 yes 40% PVP 100 35 30 yes 60% PVP 1000 35 30 yes 40% PVP 100 50 20 yes 60% PVP 1000 50 20 yes

[0212] Although the present invention has been described in detail with reference to specific embodiments of the present invention, it will be appreciated that those skilled in the art can easily conceive of changes, variations and equivalents of these embodiments when understanding the above content. Therefore, the scope of the present invention should be estimated as the scope of the attached claims and any equivalents thereof.

Claims

1. A microneedle array for administering a substance of interest into a biological tissue, the array comprising: a base substrate having a microneedle side and an opposing back side; a primary funnel portion extending from the base substrate; an array of secondary funnel sections extending from the primary funnel section; and a single conical microneedle extending from each secondary infundibulum portion; wherein the base end of the primary funnel portion and each of the secondary funnel portions is wider than the microneedle ends thereof; wherein each of the microneedles comprises a tip portion formed of a dissolvable formulation comprising a substance of interest dispersed in a matrix material; and Each of the secondary funnel portions has a funnel length L between 0.3 and 4 FUN With microneedle length L MN proportion.

2. The microneedle array of claim 1, wherein the substance of interest is substantially absent in the primary funnel portion. 3 . The microneedle array according to claim 1 , wherein the primary funnel portion, the secondary funnel portion and / or the microneedles have straight tapered sidewalls. The microneedle array according to claim 1 , wherein the primary funnel portion is formed integrally with the secondary funnel portion. The microneedle array of claim 1 , wherein the substance of interest comprises an active pharmaceutical ingredient. 6 . The microneedle array according to claim 1 , wherein the matrix material is a water-soluble matrix material.

7. The microneedle array of claim 6, wherein the secondary funnel portion comprises the water-soluble matrix material substantially free of a substance of interest.

8. The microneedle array of claim 7, wherein the primary funnel portion comprises the water-soluble matrix material substantially free of a substance of interest. 9 . The microneedle array of claim 8 , wherein the water-soluble matrix material comprises one or more of polyvinyl alcohol, carboxymethyl cellulose or sugar.

10. The microneedle array according to any one of claims 1 to 5, wherein each of the secondary funnel portions contacts only a single microneedle among the microneedles and the primary funnel portion.

11. The microneedle array according to claim 1, wherein L FUN / L MN The ratio is between 0.5 and 2.

12. The microneedle array according to claim 1, wherein each of the secondary funnel portions has a height of from 300 µm to 700 µm, and / or has a diameter at its widest point of from 500 µm to 1000 µm.

13. The microneedle array of claim 12, wherein each of the microneedles has a length of from 600 µm to 900 µm at the distal end of the secondary funnel.

14. The microneedle array of claim 1, wherein the substance of interest is a vaccine.

15. The microneedle array of claim 1, having between 50 and 500 of the microneedles. The microneedle array according to claim 1 , wherein each of the microneedles has a proximal region and a distal tip portion.

17. The microneedle array according to claim 1, wherein each of the secondary funnel portions is integrally formed with the microneedle to which it is connected.

18. A microneedle patch, comprising: The microneedle array according to any one of claims 1 to 17; an adhesive layer; and A handling layer is attached to the base substrate, wherein the handling layer includes a tab portion extending from the conical microneedles and enabling a person to grasp the tab portion by hand to manipulate the microneedle patch without touching the microneedles.

19. A method for manufacturing a microneedle array, the method comprising: (a) providing a mold having an upper surface, an opposite lower surface, and an opening on the upper surface, wherein the mold includes a first cavity defining a primary funnel portion and a second cavity defining two or more microneedles, wherein the opening leads to the first cavity and the second cavity below the first cavity; (b) partially filling the second cavity through the opening in the mold with a first material comprising 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 to form only the tip portions of two or more microneedles in the cavity; (d) filling the remainder of the first cavity and the second cavity with a second material through the opening in the mold, if not full, the second material comprising a matrix material dissolved or suspended in a second liquid vehicle; (e) drying the second material in the mold to remove at least a portion of the second liquid vehicle to form the primary funnel portion and respective remaining portions of the two or more microneedles; and (f) removing the two or more microneedles together with the primary funnel portion from the mold, wherein at least step (c) and step (e) are performed under centrifugation; wherein the second material does not contain the substance of interest; and Wherein only the respective tip portions of the two or more microneedles substantially contain the substance of interest.

20. The method of claim 19, wherein the matrix material in step (e) additionally forms a base substrate connected to the two or more microneedles.

21. The method of claim 19, wherein the first material further comprises a water-soluble matrix material.

22. The method of claim 19, wherein the tip portion is a dissolvable formulation comprising a water-soluble matrix material in which the substance of interest is dispersed.

23. The method of claim 19, wherein the first liquid vehicle and / or the second liquid vehicle comprises water.

24. The method of claim 19, wherein the primary funnel portion is integrally formed with the two or more microneedles.

25. The method of claim 19, wherein the mold is non-porous and air permeable.

26. The method of claim 25, wherein the mold is made of polydimethylsiloxane.

27. The method according to claim 19, wherein the filling of step (b) and / or step (d) comprises covering filling, direct droplet deposition, vacuum filling or pressurized filling.

28. The method of claim 19, further comprising attaching an adhesive backing to the base substrate on a back side of the base substrate after step (e) and before step (f).

29. The method of claim 19, wherein the mold is elastic, and step (f) comprises elastically deforming the mold to facilitate separation of the mold from the primary funnel portion and the two or more microneedles.

30. The method of claim 19, wherein the drying of step (e) is partial drying, such that the two or more microneedles are in a rubbery state at the end of step (e).

31. The method of claim 30, further comprising drying the two or more microneedles after step (f) to convert the two or more microneedles from a rubber state to an operational state.

32. The method of claim 31, wherein further drying after step (f) occurs after encapsulating the two or more microneedles.

33. The method of claim 19, wherein the drying of step (e) is effective to place the two or more microneedles in an operative state.

34. The method of claim 19, wherein each second cavity further defines a secondary funnel portion, wherein each secondary funnel portion is disposed and connected between (i) a single microneedle of each of the two or more microneedles and (ii) the primary funnel portion.

35. A method for manufacturing a microneedle array, the method comprising: (a) providing a mold having an upper surface, an opposite lower surface, and an opening on the upper surface, wherein the opening leads to a first cavity proximate to the upper surface and a plurality of second cavities below the first cavity, the plurality of second cavities defining two or more microneedles; (b) partially filling each second cavity through the opening in the mold with a first material comprising a substance of interest dissolved or suspended therein; (c) curing the first material in the mold to form tip portions of two or more microneedles on the second cavity, wherein each of the tip portions contains the substance of interest; (d) after step (b) and step (c), filling the first cavity and the unfilled proximal portion of the second cavity with a second material through the opening of the mold, the second material not containing a substance of interest; (e) curing the second material in the mold to form respective remaining portions of the two or more microneedles; and (f) removing the two or more microneedles from the mold, wherein one or more of steps (b) to (c) are performed under centrifugation.

36. The method of claim 35, wherein the first material comprises a dissolvable formulation comprising a water-soluble matrix material in which the substance of interest is dispersed.

37. The method of claim 35, wherein: Step (c) comprises drying the first material in the mold to remove at least a portion of the first liquid vehicle from the first material to form at least a tip portion of the microneedle in each second cavity, wherein the tip portion comprises the substance of interest; The second material in step (d) comprises a matrix material dissolved or suspended in a second liquid vehicle; Step (e) includes drying the second material in the mold to remove at least a portion of the second liquid vehicle to form a primary funnel portion defined by the first cavity and any remaining portions of the two or more microneedles; and Step (f) comprises removing the two or more microneedles together with the primary funnel portion connected thereto; and The at least partial drying of step (c) and / or step (e) is performed under centrifugation.

38. The method of claim 35, wherein the curing in step (c) and / or step (e) comprises curing the first material and / or the second material, respectively.

39. The method of claim 35, wherein the first material and / or the second material comprises a melt, and the solidifying in step (c) and / or step (e) comprises cooling the first material and / or the second material, respectively.

40. The method of claim 35, wherein the first cavity defines a single primary funnel portion, wherein each of the two or more microneedles further comprises a secondary funnel portion, and wherein each secondary funnel portion is disposed and connected between a single one of the microneedles and the single primary funnel portion.

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