Method for fabricating microneedles by adjusting the solubility of components in a casting formulation

Abstract

Provided are methods involving the intentional and controlled precipitation of a drug or active agent, or the reduction of the solubility of other film-forming components of a polymer or formulation, or a combination of both methods, to improve the process of making microneedles or other objects by casting into a mold and to improve the final components produced by casting. The selective reduction of the solubility of formulation components addresses many problems associated with casting a polymer formulation into a mold. The methods are preferably adapted for making microneedles of biodegradable polymer and drug composites and can also be used to produce other solid objects formed by casting a composition containing a polymer and an active agent into a mold.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 924,580, filed Oct. 22, 2019, and U.S. Provisional Patent Application No. 62 / 933,739, filed Nov. 11, 2019, which are hereby incorporated by reference.

[0003] Statement Regarding Federally Sponsored Research or Development

[0004] This invention was made with government support under Award No. AID - 0AA - A - 15 - 00045, awarded by the U.S. Agency for International Development. The government has certain rights in this invention. Background of the Invention

[0005] The present invention generally pertains to the field of formulations for casting and associated methods, particularly for making microneedles, for example, in the form of microneedle arrays formed from polymer - drug complexes.

[0006] Microneedles are micron - scale structures that can administer drugs in a minimally invasive manner. Microneedle patches are disclosed in WO 2019 / 075275 of the Georgia Tech Research Corporation, which have a microneedle array that can be inserted into the skin, whereupon the microneedles will dissolve or separate from the remainder of the microneedle patch when the patch is removed, leaving the agent to be delivered in the skin, and this document is hereby incorporated by reference. This can be achieved when the microneedles are made of a water - soluble polymer formulation. In such cases, once the microneedles are inserted into the skin, the tips of the needles begin to dissolve and deposit their contents in the tissue. However, if the microneedle tips are made of a non - water - soluble polymer formulation, this insoluble tip will need to be separated from the remainder of the microneedle patch in order to remain implanted in the tissue when the patch is removed. After the separated needle tips are deposited within the skin, they can begin to release their contents, which typically involves biodegradation of the microneedle tip material. In this way, microneedle patches can deliver drugs or other active agents that are released within the skin over time.

[0007] A desired method of manufacturing such microneedles or an array of such microneedles is to cast a liquid formulation onto / into a mold containing an array of microneedle cavities. However, there is still a need for novel and improved methods of casting microneedles, such as to improve the filling of the mold cavities, reduce loss of drug to undesired or inoperable regions of the molded article, and facilitate separation of the microneedle tips. Summary of the Invention

[0008] In one aspect, a method for fabricating polymer microneedles by casting is provided. According to some embodiments, the method comprises (a) preparing a casting solution comprising at least one organic solvent and a polymer and optionally a substance of interest, wherein the polymer and the substance of interest (if present) are completely dissolved in the casting solution; (b) (i) adding a non-solvent of the polymer to the casting solution, and / or (ii) evaporating at least a portion of the at least one organic solvent, wherein the addition and / or the evaporation effectively reduces the effective molecular volume of the polymer in the casting solution; and (c) casting the casting solution into a mold for the microneedles. In some preferred embodiments, the at least one organic solvent comprises two different organic solvents.

[0009] In a preferred embodiment, the casting solution comprises a substance of interest, wherein adding a non-solvent to the casting solution and / or evaporating at least a portion of the at least one organic solvent effectively precipitates the substance of interest in the casting solution as a colloid or suspension.

[0010] In some embodiments, the step of evaporating at least a portion of the at least one organic solvent is performed before introducing the casting solution into the mold. In some other embodiments, the step of evaporating at least a portion of the at least one organic solvent is performed after introducing the casting solution into the mold.

[0011] In some embodiments, the step of adding a non-solvent to the casting solution is performed before introducing the casting solution into the mold.

[0012] The casting may comprise drying, centrifuging, and / or applying a vacuum to the casting solution in the mold.

[0013] The mold, which may be formed of any suitable material, may comprise one or more cavities, each cavity having a microneedle tip portion and a funnel portion. In a preferred embodiment of the method, the casting solution forms the microneedle tip portion, and the reduction of the effective molecular volume effectively avoids forming a polymer film on the funnel portion.

[0014] On the other hand, a method for fabricating microneedles is provided, the method comprising: (a) preparing a casting solution comprising at least one organic solvent, a polymer, and a substance of interest, wherein the polymer and the substance of interest are completely dissolved in the casting solution; (b) (i) adding a non-solvent to the casting solution, and / or (ii) evaporating at least a portion of the at least one organic solvent, wherein the addition and / or the evaporation effectively causes the substance of interest to precipitate as a colloid or suspension in the casting solution; and (c) casting the casting solution into a mold for the microneedles. In some preferred embodiments, the at least one organic solvent comprises two different organic solvents.

[0015] In some embodiments of the method, the step of evaporating at least a portion of the at least one organic solvent is carried out before introducing the casting solution into the mold. In some other embodiments, the step of evaporating at least a portion of the at least one organic solvent is carried out after introducing the casting solution into the mold.

[0016] In some embodiments, the step of adding the non-solvent to the casting solution is carried out before introducing the casting solution into the mold.

[0017] The casting may include drying, centrifuging, and / or applying a vacuum to the casting solution in the mold.

[0018] The mold, which may be formed of any suitable material, may include one or more cavities, each cavity having a microneedle tip portion and a funnel portion. In a preferred embodiment of the method, the casting solution forms the microneedle tip portion, and the effective reduction in the molecular volume effectively avoids the formation of a polymer film on the funnel portion.

[0019] In some preferred embodiments of any of these methods, the mold is formed of silicone or another elastomer.

[0020] In another aspect, a microneedle array is provided, which is configured to administer a substance of interest to the biological tissue of a patient. In some embodiments, the microneedle array is manufactured by a process including one of the above methods. In some embodiments, the microneedle array includes: (a) a base; and (b) two or more microneedles extending from the base, wherein each of the two or more microneedles has (i) a tip portion mainly formed of a first material including a polymer and a substance of interest, and (ii) a funnel portion mainly formed of a second material, the funnel portion extending between the base and the tip portion, wherein the first material is formed by a first casting, the second material is formed by a second casting, and the interface between the first material and the second material is flat. In some preferred embodiments, the polymer includes PLGA, PLA or another biodegradable polymer.

[0021] The funnel portion may include a water-soluble matrix material, and the two or more solid microneedles may be configured to penetrate into the biological tissue of the patient under pressure, wherein the tip portion is configured to separate from the funnel portion when at least a part of the water-soluble matrix material in the funnel portion is dissolved. The funnel portion may further include an effervescent material.

[0022] The substance of interest may include an active pharmaceutical ingredient, such as a contraceptive hormone.

[0023] The substance of interest may be in the form of particles from 1 nm to 1 μm dispersed in the polymer. For example, the particles may be from 10 nm to 900 nm, from 50 nm to 800 nm, from 100 nm to 1 μm, or from 500 nm to 1 μm. The particles may be formed by casting a polymer solution in which the substance of interest has been precipitated as a colloid or suspension before casting.

[0024] In yet another aspect, a method for administering a substance of interest to a patient is provided. The method includes: (a) inserting the microneedles of the microneedle array as described above into the biological tissue of the patient (e.g., the skin of the patient); (b) separating the tip portion of the inserted microneedles from the funnel portion; and (c) releasing the substance of interest from the separated tip portion of the microneedles into the biological tissue. The separation may include the dissolution of a water-soluble polymer forming a part of the microneedle array (e.g., forming the funnel portion). Description of the Drawings

[0025] Figure 1 is a cross-sectional view depicting an embodiment of microneedles extending from the base or backing of a microneedle patch.

[0026] Figure 2 A cross-sectional view comparing microneedle tips formed in a mold, where the left view shows poor tip formation (obtained using a conventional process) due to the formation of a thin film in the upper region of the mold, and the right view shows good tip formation where the casting formulation has migrated into the tips of the mold (obtained using the process described herein).

[0027] Figure 3 Shows two embodiments of adjusting the casting liquid for forming microneedle tips as described herein.

[0028] Figure 4 Shows an embodiment of adjusting the casting liquid for forming microneedle tips as described herein.

[0029] Figure 5 Is a schematic diagram of a manufacturing process for one embodiment of producing a microneedle patch.

[0030] Figures 6A to 6B Is a micrograph showing an example of a cast microneedle tip formed in a mold, where a thin film left in the funnel region by a standard process using a soluble polymer / drug formulation in an organic solvent is shown above, and the tip cast by an improved method using a polymer and drug with reduced solubility according to the present invention is shown below.

[0031] Figure 7 Is a schematic diagram comparing a conventional process with one embodiment of the currently disclosed process for forming microneedle tips in a mold by casting. Detailed Description

[0032] Improved methods have been developed that include casting a solvent-based formulation into a mold, particularly a silicone or other elastomeric mold, which reduce or eliminate problems associated with conventional casting methods.

[0033] These improved methods can be applied to the manufacture of microneedles or other microscale medical devices or other three-dimensional articles. In a preferred embodiment, the methods are used to fabricate a microneedle array for a microneedle patch configured to administer a therapeutic or prophylactic agent into the skin.

[0034] Identify the problem to be solved

[0035] A common method of fabricating microneedle patches is to cast a liquid formulation onto a silicone mold containing an array of microneedle cavities. Once on the mold, the formulation is manipulated into the microneedle cavities using a variety of methods, including vacuum aspiration, centrifugation, and pressure. These processes remove or displace the air trapped beneath the liquid formulation, allowing the liquid to fill the tiny tips of the microneedles in the mold. Once the formulation has filled the microneedle cavities, the solvent in the formulation is evaporated, leaving behind a solid formulation that forms the microneedle tips. One problem associated with this microneedle casting method is that the solids in the formulation tend to accumulate at the interface with the silicone mold (or a mold made of other materials) as the solvent swells the silicone and diffuses into the silicone mold. This can create a thin film of material where the formulation contacts the mold, rather than having all of the solid material migrate towards the tip portion of the microneedles where solid material is needed. The result is a concave center in the microneedle tips and a thin film of the formulation in the upper region of the mold, where the thin film is not desired. See Figure 2 , left side. This problem is greatest when using formulation solvents that have the greatest swelling effect on silicone and least when using aqueous formulations, which are slightly repelled by the hydrophobic silicone surface.

[0036] The thin film formed above the tips of the solid formulation in the silicone microneedle mold after casting can be problematic because, when using a polymer that is not water-soluble, this thin film can prevent the separation of the needle tips located beneath the skin after insertion. Microneedles composed of, for example, biodegradable polymers can be covered with a water-soluble backing material that forms the main structure of the microneedle patch. Once the patch is inserted into the skin, interstitial fluid contacts the water-soluble backing, causing the water-soluble backing to dissolve and release the biodegradable polymer tips to deposit them in the skin. If a biodegradable polymer thin film is present in the region where the water-soluble polymer is supposed to reside above the needle tips, this water-insoluble thin film can prevent interstitial fluid from migrating into the water-soluble backing, thereby preventing tip separation. This can cause some of the microneedle tips to remain on the patch when the patch is removed, reducing the amount of drug or active agent intended to be delivered to the skin through the microneedle tips. When the drug / polymer thin film forms above the microneedle tips in the mold cavity, the thin film reduces the amount of active agent in the tips, thereby reducing the amount of drug or active agent delivered to the skin through the tips.

[0037] Another problem encountered in manufacturing microneedles is the difficulty of casting a formulation containing suspended particles of an active agent. When insoluble particles must be suspended in a microneedle casting formulation, it is difficult to produce a stable suspension of sufficiently small particles that will not aggregate and accumulate in the upper region of the mold during casting. Another problem with suspended particle formulations is that the particles tend to settle, causing them to concentrate in the dispensing device before casting can be completed and also causing the particles to settle in the storage container (if not stirred). Settling of the drug particles can cause variations in the drug concentration within the cast microneedles of a given batch. These are commonly observed limitations to using formulations in which the active agent is suspended from a powder, and thus an improved method for suspending insoluble particles of an active agent in a castable polymer / drug formulation is needed. By the method of the present invention, the active agent can be directly precipitated in situ within the castable formulation, thereby producing a stable colloidal suspension of the active agent having a much smaller particle size than can typically be achieved by suspending dry particles of the same active agent. The resulting colloidal suspension is less likely to settle out of solution, adhere to the surface of a silicone mold, and aggregate into particle clusters. The smaller particle size of the in situ formed colloidal particles also allows them to fill deeper regions of the pointed tip cavities, thereby producing a much higher drug concentration in the tip than can typically be achieved with a dry powder suspension of the same active agent.

[0038] Swelling of the silicone mold material is another problem associated with casting a solvent-based formulation containing a soluble active agent into a silicone or other polymer mold. The solvent used to dissolve the polymer and drug can and typically does diffuse into the silicone mold and cause it to swell. During swelling, the drug dissolved in the formulation can be carried into the silicone by the flux of the diffusing solvent, thereby reducing the amount of active agent remaining in the tip of the formed microneedle. The flux of solvent into the mold also allows the ends of the soluble polymer chains to migrate a short distance into the mold surface, leaving a polymer film where the polymer solution contacts the mold and reducing the migration of polymer into the tip where it is needed. The polymer deposited in this manner will also trap and deposit the active agent, thereby reducing their concentration in the tip.

[0039] Accordingly, there is a great need for new methods of casting microneedles that reduce or eliminate the film formation on the surface of the microneedle mold to improve tip filling and detachment and reduce the amount of drug not deposited in the mold cavities where the drug is needed. There is also a need for improved casting formulations containing a stable suspension of insoluble active agents to reduce soluble drug loss during mold swelling. Although related to the casting of microneedles, these needs also exist when casting many other types of devices into molds of any material that will swell in the solvent of the casting formulation.

[0040] Improvements and solutions to the identified problem

[0041] The presently disclosed method addresses one or more of the aforementioned needs for a wide range of castable devices and materials.

[0042] It has been found experimentally that when an organic solvent is used to cast a polymer into, for example, a silicone mold, the air interface above the deposited film is typically convex and conical rather than flat as desired. This is attributed to the combination of the solvent flux into the silicone material of the mold as the mold swells and the evaporation of the solvent from the formulation after casting, both of which cause the polymer to deposit over the entire contact surface of the silicone. The phenomenon of polymer deposition due to mold swelling can be likened to filtration, where the solvent is drawn out of the solution, leaving behind the solids that cannot follow the solvent. The main part of the present method is the discovery that reducing the polymer solubility in the formulation to be cast reduces the amount of film formed on the silicone mold surface. This can be attributed to two things: reducing mold swelling by increasing the percentage of a lower-swelling polymer nonsolvent in the formulation, and reducing the polymer conformation in the solution when the polymer solubility is reduced by evaporating a good solvent or adding a poor solvent or nonsolvent. The polymer conformation in the solution can be defined as the average distance from one end of the polymer chain to the other, as the polymer exists in a random coil in the solution. The intermolecular interaction between the polymer segments and the coordinated solvent molecules has an associated interaction energy, which can be positive or negative. For a good solvent, the interaction between the polymer segments and the solvent molecules is energetically favorable and will cause the polymer coil to expand. For a poor solvent, polymer-polymer self-interaction is preferred and the polymer coil will contract. The quality of the solvent depends on the chemical composition of the polymer and the solvent molecules as well as the solution temperature. Reducing the polymer conformation in the solution by bringing the polymer closer to the precipitation point via evaporation of a good solvent or addition of a poor solvent reduces the interaction of the polymer molecules with the mold surface, thus allowing the polymer molecules to more easily enter the microcavities of the mold, for example, by centrifugation or suction. This important discovery allows for the generation of improved methods for fabricating microneedles and improves the quality of microneedles by better filling the mold cavities. These methods enable the generation of a substantially flatter (better) interface between the tip and the funnel portion of the microneedle. See Figure 2 , right side.

[0043] Figure 7 An example of the improved results obtainable with the presently described method is also shown, showing a better microneedle tip structure that can be obtained, where there is no precipitate on the funnel portion of the mold.

[0044] Improvements are achieved by selectively reducing the solubility of a drug or active agent and / or a polymer that constitutes a formulation to be cast into a mold. The selective reduction of the solubility of formulation components may seem counterintuitive, but it addresses many problems associated with casting a polymer formulation into a mold. That is, the improved methods described herein involve the unpredictable precipitation of a solution or the reduction of the solubility of one or more solutes within a castable liquid formulation to advantageously alter the casting characteristics and / or improve the quality of a solid object made by casting the formulation.

[0045] Thus, advantageously, the presently disclosed methods can be effectively used to (i) reduce or eliminate the formation of a film over a solvent-cast article in a silicone mold or a mold made of other materials, thereby improving the separation of microneedles made of water-insoluble materials; (ii) improve the loading of an active agent and a polymer into the cavities of a mold to produce high-quality parts; and (iii) increase the amount of an active agent that can be delivered to a mold by casting a polymer formulation.

[0046] Generally, the articles and methods described herein involve the intentional and controlled precipitation of a drug or active agent in a cast formulation, or the reduction of the solubility of a polymer or other film-forming component of the formulation, or a combination of the two methods, to produce a better-cast fluid formulation before the fluid formulation is transformed into a solid structure defined by a mold (e.g., before casting and drying are complete). That is, the formulation can improve the process of making microneedles or other devices by casting into a mold by increasing the amount of an active agent concentrated in a desired region of the mold (e.g., the tip portion), and thereby improve the quality of the final structure produced by casting / molding.

[0047] The methods described herein employ a new cast formulation that better fills the microneedle tip or other fine details of a silicone mold or other casting mold because the new cast formulation adheres less to the mold surface and is less likely to precipitate at the mold surface. Such a new formulation has been made and demonstrated in a microneedle mold to reduce the amount of film adhering to the mold above the needle tip, reduce the concavity of the cast microneedle tip, and increase the amount of drug or active agent in the microneedle tip. This advantageously improves the strength and quality of the cast microneedles and can ultimately increase the concentration of drug or active agent delivered from the microneedles to the skin.

[0048] In various embodiments of the method, the solute that precipitates (e.g., before casting) in the casting solution can be a drug or a polymer, and in both cases, the mechanism can be the addition of a non-solvent and / or the evaporation of a good solvent. And furthermore, it is not necessary to involve a drug and a polymer, but any pair of solutes can be involved, and even only one solute can be involved. In the following description and examples, the method can be associated with not precipitating a second solute, but rather does not require the presence of a second solute.

[0049] Precipitating solutes in the casting solution can be partially or completely precipitated, e.g., before casting (i.e., some may still be dissolved and, in general, this is the case).

[0050] Method

[0051] In some embodiments, the method includes reducing the solubility of the polymeric component of the formulation to improve casting characteristics and the final article cast from the formulation. In such a method, the solubility of the polymer is reduced to near the precipitation point by: (a) evaporating the good solvent of the polymer from a solution comprising a combination of at least one non-solvent of the polymer and the good solvent of the polymer, or (b) adding a non-solvent of the polymer to the solution of the polymer. In method (b), the effective solvent is evaporated after casting rather than before casting, causing polymer precipitation to occur directly within the mold cavity as the volatile solvent within the cast formulation evaporates. Reducing the polymer solubility to a point just before precipitation reduces the polymer conformation in the casting solution, which reduces the polymer's interaction with the surface of the silicone mold, resulting in less polymer adhering to the mold or localizing near the mold surface, so as to better fill the desired regions of the formulation in the mold and with little polymer film formation above where the polymer fills the mold cavity. Causing the polymer to precipitate directly within the mold cavity after casting also reduces the ability of the polymer to interact with the mold to form an unwanted film. Here, the term "effective solvent of the polymer" refers to a solvent in which the selected polymer is readily soluble / fully soluble. "Non-solvent of the polymer" includes solvents in which the polymer is insoluble or only poorly soluble.

[0052] Accordingly, in one aspect of the present invention, the method includes: (a) preparing a casting solution comprising at least one organic solvent and a polymer and optionally a substance of interest, wherein the polymer and the substance of interest (if present) are completely dissolved in the casting solution; (b) (i) adding a non-solvent of the polymer to the casting solution, and / or (ii) evaporating at least a portion of the at least one organic solvent, wherein the addition and / or evaporation effectively reduces the effective molecular volume of the polymer in the casting solution; and (c) casting the casting solution into a mold for a microneedle.

[0053] As used herein, the phrase "decrease the effective molecular volume of a polymer" means altering the polymer conformation such that it occupies less space; e.g., the polymer has a smaller effective molecular size, hydrodynamic radius, or radius of gyration. When the solvent composition is altered to decrease the effective molecular volume, the change in the solvent can render the solvent one that decreases the effective molecular volume of the polymer. When the concentration of the polymer approaches the solubility limit of the polymer in the solvent system; e.g., when the polymer concentration is within 10% of the polymer solubility limit, more preferably within 5% or even as close as within 1% to 2% of the polymer solubility limit, the effective molecular volume of the polymer becomes smaller.

[0054] Evidence of a decrease in the effective molecular volume can be obtained by visual observation of an increase in the opacity of a solution in which the polymer is dissolved or by measurement techniques including static light scattering, dynamic light scattering, or other experimental, theoretical, and computational methods known in the art. Measurement of the polymer concentration can be performed by spectroscopy, refractometry, chromatography, viscosity, density, and other methods known in the art. Determination of the solubility limit of the polymer in the solvent system can be made by measuring the concentration of the polymer in a saturated solution (e.g., where solid polymer is in equilibrium with the dissolved polymer) and other experimental, theoretical, and computational methods known in the art.

[0055] As used herein, the term "precipitation" means the process by which a solvent exits a solution and forms a new phase (usually a solid phase, whether crystalline or non-crystalline, whether particulate or thin film geometry).

[0056] In some embodiments, the method includes precipitating a non-polymer solute (such as a drug or active agent) within a formulation by evaporating a good solvent for the solute from a solution comprising at least one non-solvent (also a poor solvent for the solute) and a good solvent for the solute. In a preferred embodiment, the drug is dissolved in a polymer solution containing a good solvent for the drug and a non-solvent for the drug, where the good solvent has a faster evaporation rate, and the drug precipitates as a fine colloidal suspension in the polymer solution upon evaporation of the good solvent for the drug. The formulation with the precipitated drug is then cast into a mold (e.g., a silicone microneedle mold). See Figure 3 Here, a good solvent is one in which the solubility of a compound (e.g., a drug or active agent) is higher than the solubility of the compound in the non-solvent. The non-solvent does not necessarily have zero solubility for the compound but must have a very low and much lower solubility than the effective solvent such that precipitation of the compound occurs upon evaporation of the good solvent. As a non-limiting example, the solubility of the compound in the good solvent is at least one order of magnitude higher than its solubility in the non-solvent.

[0057] The present method effectively improves the amount of drug or active agent delivered to the fine details of a complex mold. In a preferred embodiment, the drug is delivered to the tip of the microneedle mold during fabrication. This is also accomplished by reducing the amount of formulation adhering to the silicone mold. By creating a formulation that reduces the solvent swelling of the mold, improves the migration of the polymer / drug to the tip of the mold, and reduces the film deposited above the tip, the amount of drug lost due to migration into the mold and the film above the tip is minimized, and the amount of formulation with the active agent deposited in the microneedle tip is maximized.

[0058] In some embodiments, methods are provided for creating a fine colloidal suspension of a drug or active agent within a castable formulation by in-situ precipitation of the active agent within the formulation via evaporation of an effective solvent for the drug / agent or via titration of a non-solvent having the drug / agent. These methods are superior to conventional methods of suspending particles in a formulation because they produce smaller particles of higher concentration (i.e., higher number of particles per volume) in the suspension, and these smaller particles are less likely to settle and / or aggregate within the formulation compared to larger suspended particles. The suspended or colloidal particles also adhere less to the silicone mold and are thus more easily concentrated in the microneedle tip portion of the mold.

[0059] Using the casting methods described herein, microneedles can be produced that are capable of increasing the amount of drug or active agent delivered to the skin. This is accomplished by minimizing the film deposited on the mold above the tip, thereby maximizing the amount of drug / active agent in the microneedle tip and facilitating complete separation and delivery of the microneedle tip to the skin, and also creating a higher concentration suspension of the drug / active agent in the formulation used to cast the microneedles.

[0060] The present method can be used to produce polymer articles by casting, where a non-solvent is added prior to casting the solution into an elastomeric mold to reduce the solubility of the polymer component of the formulation and thereby reduce its interaction with the mold, resulting in better loading of the formulation into the mold. The mold can be made of a silicone elastomer. In a preferred embodiment, the polymer article is a microneedle or at least a portion thereof, such as the microneedle tip.

[0061] In some embodiments, the method is used to prepare a polymer-drug composite device manufactured by casting a polymer solution, where the drug has been precipitated, e.g., as a colloid, by evaporation of an effective solvent for the drug from the formulation prior to casting, which is Figure 3 Route A in the process shown. In such embodiments, the polymer and the drug can be any pair of molecules with different solubility characteristics. The polymer-drug composite device can be a microneedle array, e.g., as part of a microneedle patch.

[0062] In some other embodiments, the method is used to prepare a polymer-drug composite device made by casting a polymer solution, in which the drug has been precipitated by adding a non-solvent of the drug before casting, for example, precipitated as a colloid, which is Figure 3 Route B in the process shown in. The polymer-drug composite device can be a microneedle array, for example, as part of a microneedle patch.

[0063] In some other further embodiments, the drug is precipitated before casting using a combination of (i) evaporating the effective solvent of the drug from the formulation and (ii) adding a non-solvent of the drug to the formulation.

[0064] For any of these methods, the resulting microneedle patch can be composed of a biodegradable polymer and at least one drug or active agent (such as a contraceptive hormone).

[0065] In some embodiments, a process for making microneedles or other objects in a mold is provided, wherein the process includes casting a liquid onto / in a mold (such as a mold including one or more cavities in the shape of microneedles), wherein the liquid includes at least two solvents in which at least one solute is dissolved and at least one solute precipitated in the solvents. Thus, the liquid can be both a solution and a suspension. In a preferred embodiment, the precipitate is a fine colloidal suspension that does not settle significantly during the process of making microneedles or other objects. One solute can be a drug or other active agent, and the other solute can be a polymer, such as a biodegradable polymer. Other solutes and polymers can be included. The solute precipitated in the casting liquid can be a drug or a polymer.

[0066] In some embodiments, a process for making microneedles or other objects in a mold is provided, wherein the process includes the following steps: (i) forming a solution including one or more solutes and at least two solvents, (ii) preferentially removing a portion (e.g., by evaporation) of one or more of the solvents but not all of the solvents in an amount that can effectively preferentially precipitate at least one (but not all) of the solutes or reduce the solubility of the solute in the case of a polymer, wherein the precipitated solute is more soluble in the preferentially removed solvent than in the non-preferentially removed solvent, (iii) casting or otherwise applying the suspension onto / in the mold, and (iv) removing the remaining solvent to form microneedles, a microneedle array, or another object composed of the solute.

[0067] In some embodiments, a process for making microneedles or other objects in a mold is provided, where the process includes the following steps: (i) forming a solution containing at least two solutes and at least two solvents, (ii) casting or otherwise applying the solution onto / in the mold, (iii) preferentially removing a portion (e.g., by evaporation) but not all of one or more solvents in an amount effective to preferentially precipitate at least one (but not all) of the solutes, where the precipitated solute is more soluble in the preferentially removed solvent than in the non-preferentially removed solvent, and (iv) removing the remaining solvent to form microneedles, a microneedle array, or another object composed of the solutes. This is illustrated by route A in the process shown in Figure 4 as shown in

[0068] In the foregoing method, the at least two solutes are different substances from each other. For example, one solute can be a drug that can ultimately become the dispersed phase in the solid microneedle, and the second solute can be a polymer that can ultimately become the continuous phase (matrix material), where the drug is dispersed in the solid microneedle.

[0069] In Figures 3 to 4 a variation of these methods shown in

[0070] the casting solution includes only a single solute. The single solute can be, for example, a polymer.

[0071] In some embodiments, a formulation comprising a polymer with good solubility tolerance to water and a drug is dissolved in a solvent system containing a strongly volatile solvent and a low volatile solvent to form a true solution of all components, i.e., the solute is completely dissolved in the solvent. Then water (i.e., a strong non-solvent for the polymer) is gradually added to the formulation until the solution becomes turbid, indicating that the polymer, which is less water-tolerant than the drug, is approaching precipitation from the solution and exists in the formulation in a more compact polymer conformation. The solution becomes turbid when the polymer conformation in the solution becomes compact enough to reflect light, but the polymer has not yet precipitated from the solution. In this embodiment, the volatile solvent is designed to rapidly evaporate from the mold after casting, which causes the polymer, which is already close to its solubility limit in the solution, to rapidly precipitate within the mold. It is hypothesized that due to the compact polymer conformation, the polymer has little ability to interact with the mold surface, especially a porous mold surface (such as a silicone surface), to form a thin film. After casting, the mold is placed in a centrifuge, which is then used, for example, to pack the polymer / drug complex into the tip of the microneedle cavity as it dries the formulation, leaving little or no polymer film adhering to the mold above the filled tip. The resulting microneedle tip is substantially free of a film adhering to the silicone above the tip, and the tip exhibits little concavity, which is typically seen when casting a true polymer solution that would leave a polymer / drug film in the upper region of the mold.

[0072] Microneedles and other casting structures

[0073] In another aspect, a microneedle is provided having a tip portion and a funnel portion, wherein the interface between the primary material in the tip portion and the primary material in the funnel portion is flat. As used herein, the term "flat" means, for example, that the interface is substantially flat or planar when observed on the Figure 6B scale shown. That is, the primary material in the tip portion does not also exist as a thin film extending along the edge of the device into the funnel portion. The tip portion can be made of a material that is water-insoluble (which can degrade in water), wherein the tip portion is configured to separate from the funnel portion after contact with water and / or after insertion into tissue (such as skin). As used herein, the "funnel" portion may or may not be tapered. That is, the term "funnel" as used herein refers to a portion of the microneedle structure that is disposed between the microneedle tip portion and the base portion (e.g., the backing portion of the microneedle patch) and connects the microneedle tip portion and the base portion.

[0074] In addition to manufacturing microneedles, the methods described herein can be applied to a wide range of polymer and drug combinations to manufacture a wide range of other cast structures, components, and products, including but not limited to other medical devices. Examples of such medical devices include controlled drug delivery devices, such as implantable drug delivery devices, which include biodegradable or bioerodible polymer-drug complexes. A non-limiting example is a device that includes a biodegradable polymer and a contraceptive hormone. Those skilled in the art will appreciate that the methods are applicable to many other polymer-drug combinations or other combinations of molecules with different solubility characteristics to manufacture many other castable devices or other three-dimensional objects.

[0075] Additional details

[0076] Substance of interest / Active pharmaceutical ingredient

[0077] The methods described above can be used with substantially any substance of interest. As used herein, the term "substance of interest" includes active pharmaceutical ingredients, allergens, vitamins, cosmetic agents, cosmeceuticals, diagnostic agents, markers (e.g., colored dyes or radioactive dyes or markers), and other materials that are desired to be introduced into biological tissue. "Substance of interest" is sometimes referred to herein as a drug or active agent.

[0078] In some embodiments, the substance of interest is a prophylactic, therapeutic, or diagnostic agent useful in medical or veterinary applications. In some embodiments, the substance of interest is a prophylactic or therapeutic substance that can be referred to herein as an API. In some embodiments, the API is selected from suitable proteins, peptides, and fragments thereof that can occur naturally, be synthesized, or be recombinantly produced. Representative examples of the types of APIs for delivery include antibiotics, antiviral agents, analgesics, anesthetics, antihistamines, anti-inflammatory agents, anticoagulants, allergens, vitamins, anti-tumor agents.

[0079] In some embodiments, the substance of interest is a hormone. Hormones can include contraceptive hormones, such as progesterone. Examples of contraceptive hormones include levonorgestrel, etonogestrel, and norelgestromin. Hormones can include glucagon-like peptide-1 (GLP-1). Hormones can include testosterone. Hormones can include estrogens, such as ethinyl estradiol.

[0080] In some embodiments, the substance of interest includes vaccines. Examples of vaccines include infectious disease vaccines, therapeutic vaccines for cancer, neurological disorders, allergies, and smoking cessation or other addictions.

[0081] Therapeutic agents can be selected from small molecules as well as larger biotechnology-produced or purified molecules (e.g., peptides, proteins, DNA, RNA).

[0082] Microneedles, arrays, and patches

[0083] Microneedles can be in an array and configured as a microneedle patch, which can be a combination of multiple microneedles extending from a base substrate or backing, as known in the art. The microneedles can be made of a biodegradable, bioerodible, or bioabsorbable polymer (e.g., polylactic acid and poly(lactic-co-glycolic acid)), and the polymer can encapsulate a drug such as a contraceptive hormone (e.g., progesterone such as levonorgestrel, etonogestrel, or norethisterone acetate) for sustained release for at least two weeks and in some embodiments for four weeks or longer.

[0084] The microneedle array includes a base substrate and two or more microneedles extending from the surface of the base substrate. Each microneedle can have a proximal end directly or indirectly attached to the base substrate via one or more funnel portions, and a distal tip end that is sharp and can effectively pierce biological tissue. The microneedles can have a tapered sidewall between the proximal end and the distal end.

[0085] Figure 1 An example of a microneedle in such a microneedle patch is shown. The tip portion here includes the substance of interest (drug).

[0086] The funnel portion can be integrally formed with the microneedle. In some embodiments, the outer surface of the funnel portion can be distinguished from the microneedle portion of the protruding structure by a distinct change / expansion in the angles of the surfaces defining different portions of the structure, which distinct change / expansion can be regarded as a rapid expansion in at least one dimension (e.g., radially) when advancing from the distal end of the microneedle towards the proximal end. The funnel portion is wider at its base than at its microneedle end. In some embodiments, the microneedle array includes an effervescent material dispersed in the funnel portion, and the expansion can be designed to permit at least a portion of the funnel portion to be inserted into the target tissue layer such that biological fluid (e.g., interstitial fluid) can contact the funnel portion. In some embodiments, the funnel portion does not include the substance of interest.

[0087] The length (L MN ) of the microneedles can be between about 50 μm and 2 mm. In most cases, they are between about 200 μm and 1200 μm, such as between about 500 μm and 1000 μm. The length (height) (L FUN ) of the funnel can 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. The ratio L FUN / L MN can be between about 0.1 and 10, more typically between about 0.3 and 4, and more preferably between 0.5 and 2 or between about 0.5 and 1, but ratios between about 1 and 2 are also usable. The ratio L FUN / L MN can be less than about 1 or can be greater than about 1. The sum L MN +L FUN can be between about 60 μm and 1.2 cm, more typically between about 300 μm and 1.5 mm, and more preferably between about 700 μm and 1.2 mm. L MN +L FUN can be greater than about 1 mm, or greater than about 1.2 mm, or greater than about 1.5 mm.

[0088] The volume (V MN ) of the microneedles can be between about 1 nl and 100 nl. In most cases, the volume is between about 5 nl and 20 nl. The volume (V FUN ) of the funnel can be from about 1 nl to 20,000 nl, more typically between about 5 nl and 1000 nl, and more preferably between about 10 nl and 200 nl. The ratio V FUN N MN can be between about 0.1 and 100, more typically between about 0.5 and 20, and more preferably between 1 and 10 or between about 2 and 5.

[0089] The microneedle patch can include any one or more of the features and / or configurations described in U.S. Patent Application Publication No. 2017 / 0050010, which is incorporated herein by reference.

[0090] Matrix material / Excipient

[0091] The matrix material forms the body of the microneedles, the funnel portion (including the main funnel portion and the auxiliary funnel portion), and optionally the base substrate. The microneedles, the main funnel portion, and the auxiliary funnel portion can be formed of the same or different matrix materials. The matrix material typically includes a biocompatible polymeric material alone or in combination with other materials. The effervescent material can be dispersed in the matrix material used to form the funnel portion, a part of the microneedles, or a combination thereof. The agent can be dispersed in the matrix material used to form the microneedles and / or the funnel portion.

[0092] The matrix material can be biodegradable, bioerodible, and / or bioabsorbable. One or more matrix materials can be selected based on the rate at which one or more matrix materials biodegrade, bioerode, or are bioabsorbed. In some embodiments, the matrix material is water-soluble. The water-soluble matrix material can dissolve within minutes to tens of minutes upon contact with a fluid such as a biological fluid.

[0093] In some embodiments, the microneedles are formed from a biodegradable, bioerodible, and / or bioabsorbable matrix material, and the matrix material encapsulates the agent of interest. The agent of interest is released as the matrix material degrades, erodes, is absorbed, or a combination thereof.

[0094] In some embodiments, the body of the microneedle is formed from a matrix material including polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, or a combination thereof. In some embodiments, the funnel portion (including the primary funnel portion and / or the secondary funnel portion) is formed from a matrix material including polyvinyl alcohol, a carbohydrate, or a combination thereof. In some embodiments, the carbohydrate is sucrose. In some embodiments, the funnel portion (including the primary funnel portion and / or the secondary funnel portion) is formed from a matrix material including polyvinylpyrrolidone. However, other matrix materials are contemplated.

[0095] As used herein, the terms “matrix material” and “excipient” are used interchangeably when referring to any excipient that cannot be evaporated or otherwise removed during the drying and formation of the microneedle and the funnel.

[0096] The fluid solution used in the mold filling process described herein can include any of a variety of excipients. One or more excipients of the following types of excipients may be not used, used singly, or used in combination: stabilizers, buffers, fillers or bulking agents, adjuvants, surfactants, disintegrants, antioxidants, solubilizers, cryoprotectants, antibacterial agents, anti-adhesives, pigments, lubricants, viscosity enhancers, slip aids, and preservatives.

[0097] In some preferred embodiments, the microneedles are made of a biodegradable matrix material encapsulating an API, and after insertion into a patient, the entire microneedle detaches and degrades slowly in the skin.

[0098] Method of making microneedles

[0099] Microneedles or other objects can be fabricated during a molding process that involves providing a suitable mold; filling the mold with a suitable fluid material; drying the fluid material to form a microneedle tip; filling the mold with a suitable matrix material to cover the tip and form a base substrate; drying the matrix material; and then removing the formed part from the mold. An example of this is shown in Figure 5 which is depicted. The filling and drying steps may be referred to herein as “casting”. The improved casting method described above focuses on the first step of forming a microneedle tip that includes a drug. The method typically includes two or more castings.

[0100] The methods described herein may include one or more features, parts, and / or techniques described in or adapted from U.S. Patent Application Publication No. 2017 / 0050010 and WO2019 / 075275, which are incorporated herein by reference.

[0101] The composition of the filling solution generally reflects the desired materials in the final microneedle array, except for the solvent that can be completely or substantially removed during the process.

[0102] In some embodiments, the substance of interest is preferentially loaded into the microneedles and their tips, rather than into the funnel portion. The substance of interest is part of the delivery of the filling material to the mold. The filling material includes a liquid carrier. The filling material can be in the form of a solution, slurry, or suspension of particles, or a combination of any of these forms. As described above, the filling material preferably includes a colloidal suspension of fine particles, a polymer whose solubility has been reduced to near the point of precipitation from solution, or both. One or more of these forms can be used in a multi-step filling process. This "filling material" may be referred to herein as "solution" or "fluid material".

[0103] In various filling steps, the filling material can include a liquid carrier. The term "liquid carrier" may be referred to herein as "solvent" or "carrier fluid". In various embodiments, the filling material can include (1) only solvent, (2) no solvent, (3) only matrix material, (4) a combination of solvent and matrix material without the substance of interest, (5) a combination of only solvent and the substance of interest, or (6) a combination of solvent, the substance of interest, and matrix material. The solvent can 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, tert-butyl methyl ether, methyl isobutyl ketone, dimethyl sulfoxide, 2-methyl-1-propanol, ethanol, pentane, ethyl acetate, 1-pentanol, ethyl ether, 1-propanol, ethyl formate, 2-propanol, formic acid, and propyl acetate. Other solvent examples include bis(2-methoxyethyl) ether (diethylene glycol dimethyl ether), tetrahydrofuran, dimethylacetamide, dimethylformamide, xylene, dichloromethane, chloroform, hexane, limonene, methylcyclohexane, and combinations thereof. When the microneedle array includes an effervescent material, the liquid carrier including the effervescent material should be an anhydrous liquid carrier. As used herein, the term "anhydrous" refers to a liquid that includes less than 1 volume % water.

[0104] The microneedles and the funnel cavity can be completely filled, partially filled, or overfilled. After the filling step occurs, a drying or curing step typically follows. The drying or curing step can be achieved, for example, by heating and / or reducing pressure.

[0105] In a preferred embodiment, a two-step filling process is used, where the first filling step contains the substance of interest, which migrates substantially into the microneedles and their tips during the drying / curing process. This process is typically repeated for another casting of the same material. After the first casting with the substance of interest has been cast and dried, a second filling step and subsequent drying / curing process follow. This second filling step contains the matrix material, which provides the microneedles and gives their mechanical structure a funnel shape and can be overfilled to form the base substrate or a part of the base substrate. The second filling step can result in the entrapment of air bubbles between the material applied during the first filling step and the material applied during the second filling step.

[0106] The mold can be filled with a first solution containing the active agent (and possibly excipients), which is then dried. In some cases, the mold is filled again with the same solution and dried. This can be repeated until the desired amount of active agent is loaded into the microneedles. This can be followed by one or more final filling steps, where the mold is filled with excipients (which can be the same and / or different excipients as in the previous filling) without the active agent, and the excipients provide the microneedles with their mechanical structure after drying.

[0107] In some embodiments, a centrifuge or similar device is used to rotate the mold, creating a gravitational force to drive the solution down into the microneedles as the solution dries / cures. This process can also be used to drive larger molecules (e.g., the active agent) down into the microneedles and their tips while the filling fluid is still in solution state. The term "larger molecules" is used to mean molecules that are larger than those of the liquid carrier or solvent and can also include nanoparticles, microparticles, and other particles composed of any molecules.

[0108] In various embodiments, the microneedle molding process includes one or more of the following steps before, during, and / or after any or all of the mold filling steps: applying vibration, ultrasound, pressure, vacuum, electromagnetic fields, and centrifugation.

[0109] The volume of the solution deposited into the microneedle mold can be controlled by the volume of the cavity within the mold (i.e., filling the cavity completely with the solution and then cleaning the surface) or the volume of the filler (i.e., dispensing or loading a controlled volume, mass, etc.). For a microneedle array produced by multiple filling steps, both volume control methods can be used. For example, a solution containing the active agent is blanket-coated over the entire surface, filling the microneedles and funnel cavities, cleaning the solution from the surface of the mold, drying the solution, depositing a second solution in a controlled amount by the filler, drying the second solution, etc.

[0110] In some embodiments, fluid handling / distribution techniques / systems known in the art that are capable of depositing a solution onto a mold are used. Some are suitable for "blanket" coating (regionally or across the entire patch), targeted deposition, or both. The filling head can be automated and movable, the mold can be movable, or both can be movable to deposit the solution in the desired location. This can be in the form of a single cavity mold, a multi-cavity template, or in a continuous roll-to-roll process.

[0111] Many drying and / or curing methods can be used throughout the manufacturing process. Heat can be applied in the form of a batch process, but heat can preferably be integrated into a semi-batch or continuous process. Some of the drying methods that harden the solution by removing the solvent via evaporation 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, sterile air or nitrogen blower, 3) vacuum: exposure to reduced pressure, 4) ambient drying, 5) centrifugal force, 6) desiccation, 7) lyophilization or freeze drying, 8) dielectric drying (e.g., RF or microwave), 9) supercritical drying, and 10) a combination of one or more of these drying methods.

[0112] As used herein, the terms "dried", "being dried", or "drying" when referring to the material in the mold (e.g., the substrate material and / or the agent of interest) mean that the material becomes at least partially solidified. In an embodiment, the microneedles can be removed from the mold before complete drying. 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 strong enough to be pulled or peeled out of the mold. It has been found that this can improve demolding without damaging the microneedles. As used herein, the term "operational state" means that the microneedles are rigid enough for their intended purpose, e.g., 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 too flexible to pierce the intended tissue, e.g., the skin. For example, microneedles (such as microneedles composed of a body / substrate material including polyvinyl alcohol and sugar) will enter a rubbery state when undergoing a drying process as their moisture content decreases, and then enter an operational state.

[0113] Methods of using microneedles and arrays

[0114] The microneedles, arrays, and patches described herein can be self-administered or administered by another individual. The microneedle patches provided herein can be directly handled and administered by the person applying the patch without the use of an applicator to apply the required force / pressure.

[0115] In some embodiments, the method of using a microneedle array includes a simple and effective method of administering a substance of interest with a microneedle patch. The method may include identifying the application site and preferably disinfecting the area (e.g., using an alcohol wipe) before applying the microneedle patch. If desired, the application site may be allowed to dry before applying the microneedle patch. The patch is then applied to the patient's skin / tissue and manually pressed into the patient's skin / tissue by applying sufficient pressure (e.g., using the thumb or finger) to insert one or more microneedles into the patient's skin / tissue.

[0116] In some embodiments, the microneedles then separate from the microneedle patch after dissolution in the funnel portion, e.g., if the funnel portion includes an effervescent material. When the funnel portion includes an effervescent material, the microneedles may separate from the microneedle patch within about 10 seconds to about 120 seconds after the microneedle patch is pressed into the patient's skin / tissue. In some embodiments, the microneedles separate from the microneedle within about 40 seconds to about 60 seconds after the microneedle patch is pressed into the patient's skin / tissue.

[0117] After the microneedles separate from the patch, the patch can be removed from the patient's skin / tissue. The patch can be removed by manually grasping and pulling on the tab portion (e.g., between the thumb and finger) and discarding the patch. Since the microneedles separate from the patch, the patch can be discarded as non-sharp item waste.

[0118] In some embodiments, after the microneedles separate, the microneedles can dissolve readily (within minutes to tens of minutes). In some embodiments, the microneedles can dissolve, bioerode, biodegrade, and / or be bioabsorbed over days, weeks, or months.

[0119] In some embodiments, the microneedle patches described herein are used to deliver one or more substances of interest (e.g., vaccines, therapeutics, vitamins) into the body, tissue, cells, and / or organs. In some embodiments, microneedles are used to deliver an active agent into the skin by inserting the microneedles through the stratum corneum (the outer 10 to 20 microns of skin that serves as a barrier to transdermal transport) into the viable epidermis and dermis. The microneedles are preferably dissolvable and once in the intradermal space, they dissolve in the biological fluid and release the active agent into the skin. The microneedles can be formulated to release the active agent over an extended period. The extended period can be at least two weeks, at least four weeks, at least six weeks, at least eight weeks, at least three months, at least six months, at least nine months, or at least one year.

[0120] Unless defined otherwise herein or in the remainder of the specification below, all technical and scientific terms used herein have the meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. It will also be understood that the terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting. When describing and claiming the current embodiments, the following terms will be used in accordance with the definitions set forth below.

[0121] As used herein, the term "about" indicates that a given value of a quantity can include amounts within 10% of the stated amount, or alternatively within 5% of the value, or in some embodiments within 1% of the value.

[0122] Examples

[0123] The present invention can be further understood with reference to the following non-limiting examples.

[0124] Example 1 - Formulation for Reducing Polymer Solubility

[0125] Prepare a solution of 50:50 acid-terminated diethylene glycol dimethyl ether (DGM) containing 10% poly(D,L-lactide-co-glycolide) (PLGA). Weigh out a sample of the DGM solution of 10% PLGA and add 5% levonorgestrel (LNG) dissolved in DGM, which is equivalent to 50:50 of PLGA and LNG. Then add dioxane in an amount equivalent to 20% of the solvent composition of the PLGA / LNG solution. Then add a calculated amount of DGM to adjust the PLGA concentration to 3%. Then stir the clear solution and add water dropwise until the solution becomes turbid, assuming this indicates that the polymer conformation has tightened and the PLGA is close to precipitation or has just started to precipitate. Then cast the formulation onto a silicone microneedle mold, which is centrifuged at 4200 rpm for 40 minutes at 40 °C to fill the needle tips of the mold with the formulation and evaporate the solvent. The result of such casting is that the needle tips of the microneedle mold are filled with 50% LNG / 50% PLGA, with little or no additional polymer film above the filled tips. This result is achieved without the solvent washing that is typically required after casting PLGA / drug formulations. Figures 6A to 6B Shows a comparison of the microneedle cavities cast with a true solution of LNG / PLGA ( Figure 6A ) and the formulation of Example 1 ( Figure 6B ). In the image above, the film in the funnel region of the mold has been removed from the mold surface glass for better visualization. In the image below, there is little or no visible film in the funnel region, and most or all of the LNG and PLGA are in the tip region of the mold.

[0126] Subsequently, it was found that performing the initial centrifugation at a colder temperature further reduced the formation of a film in the funnel region of the mold, and the formulation of Example 1 was centrifuged at 10 °C for 15 minutes and then centrifuged again at 40 °C for 30 minutes to further dry the formulation.

[0127] Example 2 - Formulation for Reducing Polymer Solubility

[0128] A strongly volatile solvent was used to dissolve the drug into a polymer solution containing water, a non-solvent for the drug and the polymer, and a low-volatility solvent that is a weak solvent for the drug. The volatile solvent was allowed to evaporate, and this caused the drug to precipitate as a fine colloidal suspension within the polymer solution. When the formulation was cast into silica microneedles and dried by centrifugation, it was found that the colloidal drug particles more easily filled and loaded into the microneedle cavities, resulting in less concave tip filling, where the amount of film adhering to the silica mold above the tip cavity was significantly reduced. This led to a greater amount of drug being loaded into the tips of the microneedle patch and reduced the drug lost during casting.

[0129] Example 3 - Precipitated Drug Formulation (PDS)

[0130] Prepare a solution of 50:50 ester-terminated diethylene glycol dimethyl ether (DGM) containing 5% poly(D,L-lactide-co-glycolide) (PLGA). Weigh out a sample of the 5% PLGA in DGM solution and add 5% levonorgestrel (LNG) dissolved in tetrahydrofuran (THF), which is equivalent to 60:40 PLGA to LNG. Then slowly add water dropwise until an amount of water equivalent to 8% of the pre-calculated amount is added based on the total solvent composition. The solution of PLGA and LNG remains clear. Then weigh the capped vial and open the lid of the vial and allow it to stir open on a hooded stir plate for two days to allow the THF to evaporate. After two days of evaporation, the initially clear solution has become a white suspension of colloidal LNG particles in the DGM / aqueous solution of PLGA. Cap the vial and weigh it to determine the total amount of solvent lost due to evaporation, and add additional DGM and water to achieve a PLGA concentration of approximately 4% for casting the microneedles. Then cast the formulation onto a silicone microneedle mold, which is centrifuged at 4200 rpm for 40 minutes at 40 °C to fill the needle tips of the mold with the formulation and evaporate the solvent. Then wash the microneedle mold with 20 μl of 5% H2O in DGM by centrifuging at 4200 rpm for 30 minutes at 40 °C. Then cast the formulation onto the mold a second time and dry it by centrifugation. Then wash the mold a third time with 5% H2O in DGM, where drying is done by centrifugation. The final microneedle tips are uniformly filled with 40% LNG / PLGA and there is no additional polymer film above the filled tips. Then dry the microneedle mold with the tips and back it with a standard water-soluble backing material by a standard microneedle finishing method.

[0131] Example 4 - Precipitated Drug Formulation (PDS)

[0132] Repeat the formulation of Example 3 three different times, varying the drug loading of the microneedles to 50% LNG, 60% LNG, and 70% LNG (the remainder being PLGA). Each of these formulations produced high-quality microneedles, but it should be noted that the microneedle tips of the 70% formulation were fragile and more of these formulation tips were broken during removal from the mold.

[0133] Example 5 - Precipitated Drug Formulation (PDS)

[0134] Repeat the formulation and casting of Example 3, except perform centrifugation at 10 °C for 15 minutes to improve tip filling, followed by a second centrifugation at 40 °C for 15 minutes to dry the mold. The colder initial centrifugation reduces the need to wash the final tips from three times to only once, thus significantly shortening the time to fabricate the microneedle tips and producing uniformly filled tips with no additional film of the formulation above the tips.

[0135] Example 6 - ENG - based PDS Formulation

[0136] It has been found that etonogestrel (ENG) is more soluble and water - resistant than LNG, and it will not precipitate in the formulation of Example 3. Therefore, new formulations must be created to precipitate the colloids of ENG in a biodegradable polymer solution. This requires the identification of non - solvents for ENG that are effective solvents for the polymer. Solubility studies of ENG, PLA, and poly(L - lactide) (PLA) were used to determine that xylene is a non - solvent for ENG and a solvent for PLA but not PLGA. Then a solution containing 5% PLA and 0.55 to 0.75 dL / g of ester - terminated xylene (XYL) was prepared. The strongly volatile solvent chosen to dissolve ENG in PLA / XYL was dichloromethane (DCM). A sample of the XYL solution of 5% PLA was weighed out, and 5% ENG dissolved in DCM was added, which corresponded to a 60:40 ratio of PLA to ENG. A clear solution was formed. Then the capped vial was weighed, and the lid of the vial was opened and allowed to stir open on a covered stirring plate for 24 hours to allow DCM to evaporate. After 24 hours of evaporation, the initially clear solution became a white suspension of colloidal ENG particles in a xylene solution of PLA. The vial was capped and weighed to determine the total amount of solvent lost due to evaporation. The mass balance indicated that DCM had evaporated from the solution. Then additional XYL was added to adjust the concentration of PLA to approximately 4% to cast the microneedles. The formulation was used to cast the microneedle tips by centrifugation, as described in Example 3, except that the wash solvent was 50:50 XYL:DGM, which is a non - solvent for ENG. Then a water - soluble backing of polyvinyl alcohol and sucrose was cast on top of the dried PLA / ENG tips using a standard microneedle manufacturing method with a silicone mold to fabricate a complete microneedle patch.

[0137] Example 7 - Water - Soluble PDS Formulation

[0138] Prepare an ethanol (EOH) solution containing 20% polyvinylpyrrolidone (PVP, K90). Weigh out a sample of the EOH solution of 20% PVP and add 4% levonorgestrel (LNG) dissolved in tetrahydrofuran (THF), which is equivalent to a 60:40 ratio of PVP to LNG. Then slowly add water dropwise until an amount of water equivalent to 27% of the pre-calculated amount is added based on the total solvent composition. A clear solution is formed. Then weigh the capped vial and open the lid of the vial and allow it to stir open on a covered stirring plate for two days to allow the THF to evaporate. After two days of evaporation, the initially clear solution has turned into a white suspension of colloidal LNG particles in an ethanol / aqueous solution of PVP. Cap the vial and weigh it to determine the total amount of solvent lost due to evaporation, and add additional EOH / H2O to achieve a PVP concentration of approximately 5% for casting the microneedles. Then fabricate the microneedle patch using a mold by standard methods.

[0139] Based on the foregoing detailed description, modifications and variations of the methods and apparatuses described herein will be apparent to those skilled in the art. Such modifications and variations are intended to fall within the scope of the appended claims.

Claims

1. A method for fabricating microneedles, the method comprising: Preparing a casting solution, the casting solution comprising at least one organic solvent and a polymer, wherein the polymer is completely dissolved in the casting solution; (i) Adding a non-solvent of the polymer to the casting solution, and / or (ii) evaporating at least a portion of the at least one organic solvent, wherein the adding and / or the evaporating effectively reduces the effective molecular volume of the polymer in the casting solution; And then Casting the casting solution into a mold for the microneedles.

2. The method according to claim 1, wherein the casting solution further comprises a target substance, and wherein adding the non-solvent of the polymer to the casting solution and / or evaporating at least a portion of the at least one organic solvent effectively precipitates the target substance as a colloid or suspension in the casting solution.

3. The method according to claim 1, wherein the non-solvent of the polymer is added to the casting solution before introducing the casting solution into the mold.

4. The method according to claim 1, wherein at least a portion of the at least one organic solvent is evaporated before introducing the casting solution into the mold.

5. The method according to any one of claims 1 to 4, wherein the casting comprises drying, centrifuging, and / or applying a vacuum to the casting solution in the mold.

6. The method according to any one of claims 1 to 4, wherein the at least one organic solvent comprises two different organic solvents.

7. The method according to any one of claims 1 to 4, wherein the mold is formed of silicone or another elastomer.

8. The method according to claim 7, wherein the mold comprises a cavity having a microneedle tip portion and a funnel portion.

9. The method according to claim 8, wherein the casting solution forms the microneedle tip portion, and the reduction of the effective molecular volume of the polymer effectively avoids the formation of a polymer film on the funnel portion.

10. A method for fabricating microneedles, the method comprising: Preparing a casting solution, the casting solution comprising at least one organic solvent, a polymer, and a target substance, wherein the polymer and the target substance are completely dissolved in the casting solution; (i) Adding a non-solvent of the polymer to the casting solution, and / or (ii) evaporating at least a portion of the at least one organic solvent, wherein the adding and / or the evaporating effectively precipitates the target substance as a colloid or suspension in the casting solution; And then Casting the casting solution into a mold for the microneedles.

11. The method according to claim 10, wherein the non-solvent of the polymer is added to the casting solution before introducing the casting solution into the mold.

12. The method according to claim 10, wherein at least a portion of the at least one organic solvent is evaporated before introducing the casting solution into the mold.

13. The method according to any one of claims 10 to 12, wherein the casting comprises drying, centrifuging and / or applying a vacuum to the casting solution in the mold.

14. The method according to any one of claims 10 to 12, wherein the at least one organic solvent comprises two different organic solvents.

15. The method according to any one of claims 10 to 12, wherein the mold is formed of silicone or another elastomer.

16. The method according to claim 15, wherein the mold comprises a cavity having a microneedle tip portion and a funnel portion.

17. The method according to claim 16, wherein the casting solution forms the microneedle tip portion, and the reduction of the polymer conformation effectively avoids the formation of a polymer film on the funnel portion.

18. A microneedle produced by the method according to any one of claims 1 to 17.

19. A microneedle array comprising a plurality of microneedles produced by the method according to any one of claims 1 to 17.

20. A microneedle array for administering a substance of interest to a biological tissue of a patient, the microneedle array comprising: a base; and two or more microneedles extending from the base, wherein each of the two or more microneedles has (i) a tip portion formed of at least a first material comprising a polymer and a substance of interest, and (ii) a funnel portion formed of at least a second material, the funnel portion extending between the base and the tip portion, wherein the first material is formed by a first casting of a first casting solution comprising at least one organic solvent, the polymer and the substance of interest, wherein the polymer and the substance of interest are completely dissolved in the first casting solution, wherein the second material is formed by a second casting of a second casting solution comprising the second material and a solvent for the second material, and wherein, before the first casting, (i) a non-solvent of the polymer is added to the first casting solution, and / or (ii) at least a portion of the organic solvent is evaporated from the first casting solution, wherein the addition and / or the evaporation effectively reduces the effective molecular volume of the polymer in the first casting solution, thereby producing a flat interface between the first material and the second material.

21. The microneedle array according to claim 20, wherein the polymer comprises poly(D,L-lactide-co-glycolide), poly(L-lactide) or another biodegradable polymer.

22. The microneedle array according to claim 20 or 21, wherein the funnel portion comprises a water-soluble matrix material, and the two or more solid microneedles are configured to pierce into the biological tissue of the patient under pressure and then separate the tip portion from the funnel portion when at least a portion of the water-soluble matrix material in the funnel portion dissolves.

23. The microneedle array according to claim 20 or 21, wherein the funnel portion further comprises an effervescent material.

24. The microneedle array according to claim 20 or 21, wherein the target substance comprises an active pharmaceutical ingredient.

25. The microneedle array according to claim 20 or 21, wherein the target substance comprises a contraceptive hormone.

26. The microneedle array according to claim 20 or 21, wherein the target substance is in the form of particles of 1 nm to 1 μm dispersed in the polymer.

27. The microneedle array according to claim 20 or 21, wherein the microneedles have been formed by casting a polymer solution in which the target substance has been precipitated as a colloid or suspension prior to casting.

28. The microneedle array according to claim 27, wherein the precipitation has been carried out by evaporating the solvent of the target substance from a solution of at least one non-solvent containing the target substance.

29. The microneedle array according to claim 20, wherein the tip portion is formed only of a first material comprising a polymer and a target substance.

30. The microneedle array according to claim 29, wherein the funnel portion is formed only of the second material.

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