A method for fabricating microneedles by adjusting the solubility of components in a casting formulation.

Abstract

A process for making microneedles or other objects by casting into a mold with deliberate and controlled precipitation of a drug or active agent, reduction in the solubility of the polymer or other film-forming components of the formulation, or a combination of both methods, and a method for improving the resulting parts produced by casting are provided. The selective reduction in solubility of the formulation components solves many of the problems associated with casting polymer formulations into a mold. The method is preferably adapted for making microneedles of biodegradable polymer and drug conjugates, 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

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 924,580, filed on 22 October 2019, and U.S. Provisional Patent Application No. 62 / 933,739, filed on 11 November 2019, which are incorporated herein by reference.

[0002] Description of research and development funded by the federal government. This invention was created with government support under the designation AID-0AA-A-15-00045, granted by the United States Agency for International Development. The U.S. Government reserves certain rights in this invention. [Background technology]

[0003] The present invention generally relates to casting formulations and related methods, and in particular to formulations for the production of microneedles in, for example, arrays of microneedles formed from polymer-chemical composites.

[0004] Microneedles are micron-scale structures that can deliver drugs in a minimally invasive manner. A microneedle patch having an array of microneedles that can be inserted into the skin, wherein when the microneedle patch is removed, the microneedles dissolve or detach from the rest of the microneedle patch, leaving behind the drug delivered into the skin, is disclosed by Georgia Tech Research Corporation in WO2019 / 075275 and incorporated herein by reference. This can be achieved when the microneedles are made from a water-soluble polymer formulation. In this case, when the microneedles are inserted into the skin, the tips of the needles begin to dissolve and their contents accumulate in the tissue. However, if the microneedle tips are made from a non-water-soluble polymer formulation, these non-dissolving tips need to detach from the rest of the microneedle patch so that they remain embedded in the tissue when the patch is removed. After the detached needle tips have accumulated in the skin, they can begin to release their contents, often accompanied by biodegradation of the microneedle tip material. In this way, microneedle patches can deliver drugs or other activators that are released within the skin over time.

[0005] A preferred method for producing such microneedles, or arrays of such microneedles, is to cast a liquid formulation onto / into a mold containing an array of microneedle cavities. However, there remains a need for novel and improved methods of casting microneedles, for example, to improve the filling of mold cavities, reduce the loss of chemicals to undesirable or unmanageable areas of the molded article, and assist in the detachment of microneedle tips. [Overview of the project]

[0006] In one embodiment, a method for producing polymer microneedles by casting is provided. According to some embodiments, the method comprises (a) preparing a casting solution containing at least one organic solvent, a polymer, and optionally a substance of interest, such that the polymer and the substance of interest are completely dissolved in the casting solution, if present; (b) (i) adding a solvent-free solution for the polymer to the casting solution and / or (ii) evaporating a portion of at least one organic solvent, such that adding and / or evaporating is effective in reducing the effective molecular volume of the polymer in the casting solution; and (c) casting the casting solution into a mold for microneedles. In some preferred embodiments, the at least one organic solvent comprises two different organic solvents.

[0007] In a preferred embodiment, the casting solution contains the substance of interest, and adding a solvent-free solution to the casting solution and / or evaporating at least a portion of at least one organic solvent is effective for precipitating the substance of interest as a colloid or suspension in the casting solution.

[0008] In some embodiments, the step of evaporating at least a portion of at least one organic solvent is performed before the casting solution is introduced into the mold. In some other embodiments, the step of evaporating at least a portion of at least one organic solvent is performed after the casting solution is introduced into the mold.

[0009] In some embodiments, the step of adding a solvent-free solution to the casting solution is performed before the casting solution is introduced into the mold.

[0010] Casting may include drying, centrifugation, and / or application of vacuum to the casting solution in the mold.

[0011] A mold, which can be formed from any suitable material, may contain one or more cavities, each having a microneedle tip portion and a funnel portion. In a preferred embodiment of this method, the casting solution forms the microneedle tip portion, and reducing the effective molecular volume is effective in avoiding the formation of a polymer film on the funnel portion.

[0012] In another embodiment, a method for producing 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 solvent-free substance to the casting solution and / or (ii) evaporating at least a portion of at least one organic solvent, wherein the addition and / or evaporation is effective in precipitating the substance of interest as a colloid or suspension in the casting solution; and (c) casting the casting solution into a mold for microneedles. In some preferred embodiments, the at least one organic solvent comprises two different organic solvents.

[0013] In some embodiments of this method, the step of evaporating at least a portion of at least one organic solvent is performed before the casting solution is introduced into the mold. In some other embodiments, the step of evaporating at least a portion of at least one organic solvent is performed after the casting solution is introduced into the mold.

[0014] In some embodiments, the step of adding a solvent-free solution to the casting solution is performed before the casting solution is introduced into the mold.

[0015] Casting may include drying, centrifugation, and / or application of vacuum to the casting solution in the mold.

[0016] A mold, which can be formed from any suitable material, may contain one or more cavities, each having a microneedle tip portion and a funnel portion. In a preferred embodiment of this method, the casting solution forms the microneedle tip portion, and reducing the effective molecular volume is effective in avoiding the formation of a polymer film on the funnel portion.

[0017] In some preferred embodiments of these methods, the mold is formed from silicone or another elastomer.

[0018] In another embodiment, a microneedle array configured to administer a substance of interest to a patient's biological tissue is provided. In some embodiments, the microneedle array is manufactured by a process comprising one of the methods described above. In one particular embodiment, the microneedle array comprises (a) a base and (b) two or more microneedles extending from the base, each of the two or more microneedles having (i) a tip portion mainly formed from a first material comprising a polymer and the substance of interest, and (ii) a funnel portion mainly formed from a second material, the funnel portion extending between the base and the tip portion, the first material being formed from a first casting and the second material being formed from a second casting, and the interface between the first and second materials being flat. In some preferred embodiments, the polymer comprises PLGA, PLA, or another biodegradable polymer.

[0019] The funnel portion may contain a water-soluble matrix material, and two or more solid microneedles may be configured to penetrate the patient's biological tissue under compression, with the tip portion configured to separate from the funnel portion upon at least partial dissolution of the water-soluble matrix material within the funnel portion. The funnel portion may further contain a foaming material.

[0020] The substances in question may contain active pharmaceutical components such as contraceptive hormones.

[0021] The target substance can be in the form of particles with a size of 1 nm to 1 μm dispersed in a polymer. For example, the particles can be 10 nm to 900 nm, 50 nm to 800 nm, 100 nm to 1 μm, or 500 nm to 1 μm. The particles can be formed in the microneedles by casting a polymer solution in which the target substance has precipitated as a colloid or suspension before casting.

[0022] In yet another aspect, a method for administering a target substance to a patient is provided. The method includes (a) inserting the microneedles of the microneedle array as described above into a biological tissue of the patient, such as the patient's skin; (b) separating the inserted microneedle tip portion from the funnel portion; and (c) releasing the target substance from the separated microneedle tip portion into the biological tissue. The separation can include dissolving a water-soluble polymer that forms part of the microneedle array, such as the funnel portion.

Brief Description of the Drawings

[0023] [Figure 1] It is a cross-sectional view illustrating an embodiment of a microneedle extending from the base or backsheet of a microneedle patch. [Figure 2] It is a cross-sectional view comparing the microneedle tip portions formed in a mold. The left figure illustrates defective tip formation due to film formation in the upper region of the mold (obtained using a conventional process), and the right figure illustrates good tip formation where the casting formulation has migrated to the tip portion of the mold (obtained using the process described herein). [Figure 3] It illustrates two embodiments of adjusting a casting liquid for forming the microneedle tip portions described herein. [Figure 4] It illustrates an embodiment of adjusting a casting liquid for forming the microneedle tip portions described herein. [Figure 5] It is a schematic view of a manufacturing process for manufacturing an embodiment of a microneedle patch. [Figure 6A]This is a micrograph showing the film within the funnel region remaining after a standard process using a soluble polymer / chemical compound in an organic solvent. [Figure 6B] This is a micrograph showing an example of a cast microneedle tip formed in a mold, demonstrating the cast tip produced by the improved method of the present invention using reduced-solubility polymers and chemicals. [Figure 7] This is a schematic diagram comparing a conventional process with one embodiment of the process of the present disclosure for forming microneedle tips in a mold by casting. [Modes for carrying out the invention]

[0024] An improved method has been developed that involves casting a solvent-based formulation into a mold, particularly a silicone or other elastomer mold, which reduces or eliminates the problems associated with conventional casting methods.

[0025] These improved methods can be applied to the fabrication of microneedles, other precision medical devices, or other three-dimensional articles. In a preferred embodiment, the method is used to fabricate a microneedle array for a microneedle patch configured to deliver a therapeutic or prophylactic agent to the skin.

[0026] Identifying the issues that need to be resolved One common method for fabricating microneedle patches is by casting a liquid formulation onto a silicone mold containing an array of microneedle cavities. Once placed on the mold, the formulation is processed into microneedle cavities using a variety of methods, including vacuum suction, centrifugation, and pressure. These processes remove or replace any trapped air beneath the liquid formulation, allowing the liquid to fill the fine microneedle tips of the mold. Once the formulation fills the microneedle cavities, the solvent in the formulation evaporates, leaving behind a solid formulation that forms the needle tips. One problem associated with this microneedle casting method is that, due to the expansion of the silicone by the solvent and the diffusion of the solvent into the silicone mold, the solid of the formulation tends to accumulate at the interface with the silicone mold (or molds made of other materials). This can create a film of material where the formulation contacts the mold, rather than transferring all the solid material towards the microneedle tips where it is needed. The result is a film of formulation in the concave center of the microneedle tips and in the undesirable upper regions of the mold. Please refer to the left side of Figure 2. This problem is most pronounced when using formulation solvents that have the greatest expansion effect on silicone, and when using aqueous formulations that are at least somewhat undesirable by the hydrophobic silicone surface.

[0027] After casting, the film formed by a silicone microneedle mold above the tip of the solid formulation becomes problematic when a non-water-soluble polymer is used, as this film can prevent the needle tip from detaching from the subcutaneous tissue after insertion. Microneedles made of biodegradable polymers can, for example, be covered with a water-soluble backing that forms the primary structure of the microneedle patch. When the patch is inserted into the skin, tissue fluid comes into contact with the water-soluble backing, causing the backing to dissolve, exposing the biodegradable polymer tips and allowing them to deposit within the skin. If a film of biodegradable polymer is present in the area above the needle tip where the water-soluble polymer should be, this water-insoluble film can block the migration of interstitial fluid to the water-soluble backing, potentially preventing tip detachment. This can result in some of the microneedle tips remaining with the patch when it is removed, reducing the amount of drugs or activators that were intended to be delivered to the skin by the microneedle tips. When a drug / polymer film forms in the mold cavity above the tip of the microneedle, it reduces the amount of activator within the tip, thereby reducing the amount of drug or activator delivered to the skin by the tip.

[0028] Another problem encountered in the fabrication of microneedles is the difficulty in casting formulations containing suspended particles of activators. When insoluble particles must be suspended in a microneedle casting formulation, it is difficult to produce a stable suspension of particles small enough that they do not aggregate and clump together within 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 if not agitated, the particles also settle in the storage container. Settlement of pharmaceutical particles can cause fluctuations in the concentration of the pharmaceutical within a given lot of cast microneedles. These are limitations commonly observed in the use of formulations in which activators are suspended from powder, and therefore, an improved method is needed for suspending insoluble particles of activators in a castable polymer / pharmaceutical formulation. By the method of the present invention, the activator can be precipitated directly and in situ within a castable formulation, creating a stable colloidal suspension of the activator with a particle size much smaller than that typically can be achieved by a suspension of dry particles of the same activator. The resulting colloidal suspension is far less likely to settle from the solution, adhere to the silicone mold surface, and aggregate into particle clusters. The smaller particle size of the in-situ formed colloidal particles also allows them to fill deeper areas of the sharp tip cavity, generating much higher drug concentrations at the tip than is often achieved with a dry powder suspension of the same activator.

[0029] The expansion of silicone mold materials is another issue associated with casting solvent-based formulations containing soluble surfactants into silicone or other polymer molds. The solvent used to dissolve the polymer and chemicals diffuses into the silicone mold, which can and generally cause the mold to expand. During expansion, the chemicals dissolved in the formulation are carried into the silicone by the flow of the diffusing solvent, potentially reducing the amount of surfactant remaining at the tips of the formed microneedles. The flow of the solvent into the mold also allows the ends of soluble polymer chains to migrate short distances into the mold surface, leaving a polymer film where the polymer solution contacts the mold, reducing polymer migration to the tips where it is needed. The polymer thus deposited also captures and deposits surfactants, reducing their concentration at the tips.

[0030] Therefore, there is a critical need for novel methods of casting microneedles that reduce or eliminate the film formed on the surface of the microneedle mold, thereby improving filling and delamination of the microneedle tips and reducing the amount of chemical that does not accumulate in the mold cavity where the chemical is required. There is also a need for improved casting formulations containing stable suspensions of insoluble activators to reduce soluble chemical loss during mold expansion. The same need exists in the casting of many other types of devices into molds of any material that is directed toward microneedle casting but expands in the solvent of the casting formulation.

[0031] Improvements and solutions for identified problems The methods disclosed herein address one or more of the aforementioned needs for a wide range of castable devices and materials.

[0032] Experiments have shown that when polymers are cast onto, for example, a silicone mold using an organic solvent, the air interface above the deposited film is typically convex and conical, and not flat as desired. This is thought to be due to a combination of solvent flow into the silicone material of the mold during expansion and evaporation of the solvent from the formulation after casting, both of which leave the polymer deposited across the entire silicone contact surface. The phenomenon of polymer deposition due to mold expansion can be likened to filtration, where the solvent is drawn away from the solution, leaving behind solid matter that cannot follow it. The main part of this method is the discovery that the amount of film formed on the silicone mold surface can be reduced by reducing the solubility of the polymer in the casting formulation. This can be attributed to two things: reduction of mold expansion by increasing the proportion of solvent-free polymers with low expansion in the formulation when their solubility decreases due to evaporation of a good solvent or addition of a poor solvent or no solvent, and reduction of the polymer conformation in the solution. The polymer conformation in solution can be defined as the average distance from one end of a polymer chain to the other, as the polymer is irregularly coiled in the solution. Intermolecular interactions between polymer chain segments and coordinating solvent molecules have associated energies, which can be positive or negative. For good solvents, the interaction between polymer segments and solvent molecules is energetically favorable, expanding the polymer coil. For poor solvents, polymer-polymer self-interactions are preferable, causing the polymer coil to contract. The quality of the solvent depends on both the chemical composition of the polymer and solvent molecules, as well as the solution temperature. Reducing the polymer conformation in solution by either evaporating a good solvent or adding a poor solvent, thereby bringing the polymer closer to its precipitation point, reduces the interaction between the polymer molecules and the mold surface, allowing the polymer molecules to be easily pushed down by the fine cavities of the mold, for example, by centrifugation or suction. This significant discovery has enabled the creation of improved methods for fabricating microneedles, improving the quality of the microneedles through better packing of the mold cavities.These methods allow for the creation of a substantially flatter (better) interface between the microneedle tip and the funnel portion. See the right side of Figure 2.

[0033] Figure 7 also illustrates an example of an improved result obtainable by the method described herein, showing a better microneedle tip structure obtainable without sediment on the funnel portion of the mold.

[0034] The improvement is achieved by selectively reducing the solubility of the chemicals or activators, and / or polymers, that comprise the formulation cast into the mold. While selective reduction in the solubility of formulation components may seem counterintuitive, it solves many problems associated with casting polymer formulations into molds. In other words, the improved method described herein, involving unpredictable solution precipitation or a reduction in the solubility of one or more solutes in a castable liquid formulation, preferably alters the casting properties and / or improves the quality of the solid object produced from the casting of the formulation.

[0035] Accordingly, the methods of the present disclosure may be effective for (i) reducing or eliminating the formation of a film on the article being cast from the solvent in a mold made of silicone or other materials, and improving the peeling of microneedles made of water-insoluble materials, (ii) improving the loading of activators and polymers into the mold cavity to produce high-quality parts, and (iii) increasing the amount of activators that can be delivered to the mold by casting of polymer formulations.

[0036] In general, the articles and methods described herein, involving the intentional and controlled precipitation of chemicals or activators in the cast formulation, reduction of the solubility of polymers or other film-forming components in the formulation, or a combination of both methods, produce a better cast fluid formulation before the fluid formulation is converted into a solid structure defined by the mold, for example, before the completion of casting and drying. That is, the formulation can improve the process for fabricating microneedles or other devices by increasing the amount of activator concentrated within a desired area of ​​the mold (e.g., the tip portion) when cast into the mold, thereby improving the quality of the resulting structure produced by casting / molding.

[0037] The methods described herein utilize novel casting formulations that pack better with the microneedle tips or other fine details of the silicone or other casting molds because they are less likely to adhere to the mold surface and less likely to precipitate on the mold surface. Such novel formulations have been fabricated and demonstrated in microneedle molds to reduce the amount of film adhering to the mold above the needle tips, reduce the recesses at the tips of the casting microneedles, and increase the amount of drug or activator within the microneedle tips. This can beneficially improve the strength and quality of the casting microneedles and ultimately increase the concentration of drug or activator delivered from the microneedles to the skin.

[0038] In various embodiments of this method, for example, the solute that precipitates in the casting solution before casting may be a chemical or a polymer, and the reaction mechanism may be the addition of a solvent-free substance and / or the evaporation of a good solvent in both cases. Furthermore, it is not necessary to include a chemical and a polymer, but it may include any pair of solutes, or even just one solute. In the following description and examples, this method may be associated with not precipitating a second solute, but the presence of a second solute is not essential.

[0039] The precipitated solute in the casting solution may be partially or completely precipitated before casting, for example (i.e., some may remain dissolved, which is generally the case).

[0040] method In some embodiments, the method involves reducing the solubility of the polymer components of a formulation to improve the casting properties of the formulation and the resulting articles. In this method, the polymer's solubility is reduced to near the precipitation point by (a) evaporation of the good solvent for the polymer from a solution containing a combination of at least one solvent-free solvent for the polymer and a good solvent for the polymer, or (b) addition of a solvent-free solvent for the polymer to a solution of the polymer. In method (b), the effective solvent evaporates after casting rather than before casting, and as the volatile solvent in the casting formulation evaporates, polymer precipitation occurs directly in the mold cavity after casting. By reducing the polymer solubility to a point just before precipitation, the polymer conformation in the casting solution is reduced, which reduces the interaction between the polymer and the silicone mold surface, resulting in reduced polymer adhesion to the mold or localization near the mold surface, better packing of the formulation into desired areas of the mold, and little to no polymer film formation above where the polymer fills the mold cavity. Directly precipitation of the polymer into the mold cavity after casting also reduces the polymer's ability to interact with the mold and form unwanted films. Here, the term "effective solvent for polymer" refers to a selected solvent for the polymer in which the polymer is readily / completely soluble. "Solvent-free for polymer" includes solvents in which the polymer is insoluble or only partially soluble.

[0041] Accordingly, in one aspect of the present invention, the method comprises (a) preparing a casting solution containing at least one organic solvent, a polymer, and optionally a substance of interest, wherein the polymer and the substance of interest are completely dissolved in the casting solution, if present; (b) (i) adding a solvent-free solution for the polymer to the casting solution and / or (ii) evaporating a portion of at least one organic solvent, wherein the addition and / or evaporation is effective in reducing the effective molecular volume of the polymer in the casting solution; and (c) casting the casting solution into a mold for microneedles.

[0042] As used herein, the phrase "reduce the effective molecular volume of a polymer" means altering the conformation of a polymer so that it occupies less space, for example, so that it has a smaller effective molecular size, hydrodynamic radius, or radius of gyration. When the effective molecular volume is reduced by changing the solvent composition, the change in the solvent is that the solvent can be made a theta solvent, which reduces the effective molecular volume of the polymer. The effective molecular volume of a polymer becomes smaller when the polymer concentration is close to the solubility limit of the polymer in the solvent system, for example, when the polymer concentration is close to 10%, more preferably 5%, or 1% to 2% of the polymer's solubility limit.

[0043] Evidence of a reduction in effective molecular volume can be obtained by visual observation of an increase in the opacity of the 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. Polymer concentration can be measured by optical spectroscopy, refraction, chromatography, viscosity, density, and other methods known in the art. The solubility limit of the polymer in a solvent system can be determined by measuring the concentration of the polymer in a saturated solution (for example, using a solid polymer in equilibrium with the dissolved polymer), among other experimental, theoretical, and computational methods known in the art.

[0044] As used herein, the term “precipitation” means the process by which a solvent separates from a solution and forms a new phase, typically a solid phase, whether crystalline or amorphous, particulate or thin film in form.

[0045] In some embodiments, the method involves precipitating a nonpolymer solute, such as a chemical or activator, in a formulation by evaporation of the good solvent for the solute from a solution containing a combination of at least one solvent-free (and also a poor solvent for the solute) and a good solvent for the solute. In a preferred embodiment, the chemical is dissolved in a polymer solution containing a good solvent for the chemical and a solvent-free for the chemical, the good solvent having a faster evaporation rate, and the chemical precipitates as a fine colloidal suspension in the polymer solution by evaporation of the good solvent for the chemical. The formulation having the precipitated chemical is then cast into a mold, for example, a silicone microneedle mold. See Figure 3. Here, the good solvent is one in which the compound (e.g., chemical or activator) has a higher solubility than its solubility in the solvent-free. The solvent-free does not necessarily have to contain a compound with zero solubility, but it must have a solubility that is very low and much lower than that of the effective solvent so 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 an order of magnitude higher than its solubility in the solvent-free.

[0046] This method is effective for improving the amount of chemicals or activators delivered to the minute details of complex molds. In a preferred embodiment, the chemical is delivered to the tip of the microneedle mold during fabrication. This is also achieved by reducing the amount of formulation adhering to the silicone mold. By creating a formulation that reduces solvent expansion of the mold, improves the transfer of polymer / chemicals to the mold tip, and reduces the film deposited above the tip, the amount of chemical lost due to transfer into the mold and the film above the tip is minimized, while the amount of formulation with activators deposited within the microneedle tip is maximized.

[0047] In some embodiments, methods are provided for producing fine colloidal suspensions of a drug or activator in a castable formulation by evaporation of an effective solvent for the drug / pharmaceutical, or by in-situ precipitation of the activator in the formulation by titration of a solvent-free formulation for the drug / pharmaceutical. These methods are advantageous over conventional methods for suspending particles in a formulation because they produce smaller-sized particles at higher concentrations (i.e., higher particle count per unit volume) in the suspension, which are less likely to settle and / or aggregate in the formulation compared to larger suspended particles. The suspended or colloidal particles are also less likely to adhere to silicone molds and are therefore easily concentrated by the microneedle tip portion of the mold.

[0048] Using the casting method described herein, microneedles can be produced that can increase the amount of drug or activator delivered to the skin. This is achieved by minimizing the film deposited on the mold above the tip, thereby maximizing the amount of drug / activator within the microneedle tip and assisting complete detachment and delivery of the microneedle tip to the skin, as well as by creating a higher concentration drug / activator suspension in the formulation used to cast the microneedles.

[0049] This method can be used to produce polymer articles by casting, and the addition of a solvent-free solution before the solution is cast into the elastomer mold is used to reduce the solubility of the polymer components of the formulation, thereby reducing the interaction of the formulation with the mold, and as a result the formulation is better packed by the mold. The mold can be made from a silicone elastomer. In a preferred embodiment, the polymer article is a microneedle, or at least a portion thereof, such as the tip of a microneedle.

[0050] In some embodiments, this method is used to prepare polymer-chemical composite devices fabricated by casting a polymer solution, where the chemical is precipitated, for example, as a colloid, by evaporation of an effective solvent for the chemical from the formulation before casting, which is route A in the process shown in Figure 3. In such embodiments, the polymer and chemical can be any pair of molecules having different solubility properties. The polymer-chemical composite device may be, for example, a microneedle array as part of a microneedle patch.

[0051] In some other embodiments, the method is used to prepare polymer-chemical composites fabricated by casting a polymer solution, where the chemical is precipitated, for example, as a colloid by adding a solvent-free solution for the chemical to the formulation before casting, which is route B in the process shown in Figure 3. The polymer-chemical composite device may be, for example, a microneedle array as part of a microneedle patch.

[0052] In some other embodiments, the chemical is precipitated before casting by a combination of (i) evaporation of an effective solvent for the chemical from the formulation and (ii) addition of a solvent-free substance for the chemical to the formulation.

[0053] The microneedle patches produced by any of these methods may consist of a biodegradable polymer and at least one drug or activator, such as a contraceptive hormone.

[0054] In some embodiments, a process is provided for fabricating microneedles or other objects in a mold, the process comprising casting a liquid onto / into a mold (such as a mold having one or more cavities in the shape of a microneedle), the liquid comprising at least two solvents having at least one solute dissolved inside and at least one solute precipitated in the solvent. Thus, the liquid can be both a solution and a suspension. In a preferred embodiment, the precipitate is, for example, a fine colloidal suspension that does not settle sufficiently during the process of fabricating the microneedles or other objects. One solute may be a chemical or other activator, and another solute may be a polymer, such as a biodegradable polymer. Other solutes and polymers may be included. The precipitated solute in the casting liquid may be a chemical or a polymer.

[0055] In some embodiments, a process is provided for fabricating microneedles or other objects within a mold, the process comprising: (i) forming a solution comprising one or more solutes and at least two solvents; (ii) preferentially removing, but not all, portions of one or more solvents (e.g., by evaporation) in an amount effective for preferential precipitation, or, in the case of a polymer that reduces the solubility of at least one, but not all, of the solutes, the solute to precipitate being more soluble in the solvents preferentially removed than in the solvents not preferentially removed; (iii) casting or otherwise applying the suspension onto / to a mold; and (iv) removing the remaining solvent to form microneedles, an array of microneedles, or another object comprising solutes.

[0056] In some embodiments, a process is provided for fabricating microneedles or other objects within a mold, the process comprising: (i) forming a solution containing at least two solutes and at least two solvents; (ii) casting or otherwise applying the solution onto / to a mold; (iii) preferentially removing, not all, but a portion of one or more solvents (e.g., by evaporation) in an amount effective for preferentially precipitating at least one of the solutes, not all of them, such that the precipitating solute is more soluble in the solvents preferentially removed than in the solvents not preferentially removed; and (iv) removing the remaining solvent to form microneedles, an array of microneedles, or another object consisting of solutes. This is represented by path A in the process shown in Figure 4.

[0057] In the method described above, at least two solutes are different substances. For example, one solute could be a chemical that can ultimately become the dispersed phase within the solid microneedle, and the second solute could be a polymer that can ultimately become the continuous phase (matrix material) in which the chemical is dispersed within the solid microneedle.

[0058] In the variations of these methods illustrated in Figures 3 and 4, the casting solution contains only a single solute. This single solute may be, for example, a polymer.

[0059] In the method described above, at least two solvents are also different substances from each other. For example, they may be different organic liquids, or an aqueous liquid and an organic liquid. The solvents are selected with respect to their relative solubility with respect to the solute and their solubility with respect to each other, as described herein.

[0060] In some embodiments, a formulation containing a polymer and a chemical having a good solubility tolerance in water is dissolved in a solvent system containing a strong 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. Water, a strong solvent-free solvent for the polymer, is then gradually added to the formulation until the solution becomes cloudy, indicating that the polymer, which was less resistant to water than the chemical, is on the verge of precipitation from the solution and exists in a tighter polymer conformation within the formulation. The solution becomes cloudy at the point where the polymer conformation in the solution is tight enough to reflect light, but the polymer has not yet precipitated from the solution. In this embodiment, the volatile solvent is designed to evaporate rapidly from the mold after casting, thereby causing the polymer, already close to its solubility limit in the solution, to rapidly precipitate within the mold. Due to its tight polymer conformation, it is assumed that the polymer has little ability to interact with the mold surface, particularly porous mold surfaces such as silicone surfaces, to form a film. After casting, the mold is placed, for example, in a centrifuge and then used to pack the polymer / chemical complex into the tips of the microneedle cavities as the compound dries, with little to no polymer film adhering to the mold above the filled tips. The resulting microneedle tips produced by this method have virtually no film adhering to the silicone above the tips, and the tips exhibit little of the recesses typically seen when casting true polymer solutions, leaving the polymer / chemical film within the upper region of the mold.

[0061] Microneedles and other casting structures In another embodiment, a microneedle is provided having a tip portion and a funnel portion, wherein the interface between the material primarily in the tip portion and the material primarily in the funnel portion is flat. As used herein, the term “flat” means that the interface is substantially flat or planar when viewed on a scale illustrated, for example, in Figure 6B. That is, the material primarily in the tip portion does not exist in the funnel portion as a thin film extending along the end of the device. The tip portion may be made of a non-water-soluble material (which may be degradable in water), and the tip portion is configured to separate from the funnel portion upon contact with water and / or insertion into tissue such as skin. As used herein, the “funnel” portion may or may not be tapered. That is, as used herein, the term “funnel” refers to a portion of the microneedle structure that is positioned between the microneedle tip portion and the base portion, for example, the backing portion of a microneedle patch, and connects them.

[0062] In addition to the fabrication of microneedles, the methods described herein can be applied with a wide range of polymer and chemical combinations to fabricate a diverse array of other castable structures, components, and products, including other medical devices. Examples of such medical devices include controlled drug delivery devices, such as implantable drug delivery devices, which may involve biodegradable or bioerodible polymer-chemical composites. One non-limiting example is a device containing a biodegradable polymer and a contraceptive hormone. Those skilled in the art will understand that the methods are applicable to many different polymer-chemical combinations, or to other combinations of molecules with different solubility properties, to fabricate many other castable devices or other three-dimensional objects.

[0063] Additional details Target substance / active pharmaceutical component The methods described above can be used with virtually any target substance. As used herein, the term “target substance” includes active pharmaceutical ingredients, allergens, vitamins, cosmetics, medicated cosmetics, diagnostic agents, markers (e.g., colored dyes, radioactive dyes, or markers), and other materials desirable for introduction into biological tissues. “Target substance” may be referred to herein as a drug or activator.

[0064] In some embodiments, the substance of interest is a preventive, therapeutic, or diagnostic agent useful for medical or veterinary applications. In some embodiments, the substance of interest is a preventive or therapeutic agent that may be referred to herein as an API. In some embodiments, the API is selected from suitable proteins, peptides, and their fragments that may occur naturally, be synthesized, or be recombinantly produced. Typical examples of types of APIs for delivery include antibiotics, antivirals, analgesics, anesthetics, antihistamines, anti-inflammatory agents, anticoagulants, allergens, vitamins, and antineoplastic agents.

[0065] In some embodiments, the substance in question is a hormone. The hormone may include contraceptive hormones such as progestins. Examples of contraceptive hormones include levonorgestrel, etonogestrel, and nestron. The hormone may include glucagon-like peptide-1 (GLP-1). The hormone may include testosterone. The hormone may include estrogens, such as ethinylestradiol.

[0066] In some embodiments, the substance in question includes vaccines. Examples of vaccines include vaccines for infectious diseases, and therapeutic vaccines for cancer, neurological disorders, allergies, and smoking cessation or other addictions.

[0067] Therapeutic agents can be selected from small molecules and larger molecules produced or purified by biotechnology (e.g., peptides, proteins, DNA, RNA).

[0068] Microneedles, arrays, and patches Microneedles may be located in an array and may be configured as a microneedle patch, which may be a combination of multiple microneedles extending from a base material or a backing material, as is known in the art. Microneedles may be made of biodegradable, bioerosive, or bioabsorbable polymers (e.g., polylactic acid and poly(lactic acid-coglycolic acid)) that can encapsulate drugs such as contraceptive hormones (e.g., progestins such as levonorgestrel, etonogestrel, or nestron) for continuous opening for at least two weeks, and in some embodiments for four weeks or more.

[0069] A microneedle array comprises a base substrate and two or more microneedles extending from the surface of the base substrate. Each microneedle may have a proximal end attached directly to the base substrate or indirectly via one or more funnel portions, and a distal tip end that is sharp and effective for penetrating biological tissue. The microneedles may have tapered sidewalls between the proximal and distal ends.

[0070] Figure 1 shows an example of microneedles in such a microneedle patch. The tip of the microneedle contains the target substance (medicine).

[0071] The funnel portion can be integrally formed with the micro needle. In some embodiments, the outer surface of the funnel portion can be distinguished from the micro needle portion of the protruding structure by a distinct change / expansion at the angle of the surface defining different parts of the structure, which can be seen as a rapid expansion in at least one dimension (e.g., radial direction) as it progresses from the distal end towards the proximal end of the micro needle. The funnel portion is wider at its base end than at its micro needle end. In some embodiments, the micro needle array includes a foaming material dispersed within the funnel portion, and the expansion can be designed to allow at least a portion of the funnel portion to be inserted into the target tissue layer so that a biological fluid, e.g., interstitial fluid, can contact the funnel portion. In some embodiments, the funnel portion does not contain any of the target substances.

[0072] The length (L MN ) of the micro needle can be from about 50 μm to 2 mm. In most cases, they are from about 200 μm to 1200 μm, such as from about 500 μm to 1000 μm. The length (height) (L FUN ) of the funnel can be from about 10 μm to 1 cm. In most cases, the funnel is from about 200 μm to 2000 μm, more preferably from about 500 μm to 1500 μm. The L FUN / L MN ratio can be from about 0.1 to 10, more typically from about 0.3 to 4, more preferably from about 0.5 to 2, or from about 0.5 to 1, although a ratio of about 1 to 2 can also be useful. The L FUN / L MN ratio can be less than about 1 or greater than about 1. The sum of L MN +L FUN can be from about 60 μm to 1.2 cm, more typically from about 300 μm to 1.5 mm, more preferably from about 700 μm to 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.

[0073] The volume (V of the micro needle MNThe volume of the funnel (V) can be approximately 1 nl to 100 nl. In most cases, it is approximately 5 nl to 20 nl. FUN ) can be approximately 1 nl to 20,000 nl, more typically approximately 5 nl to 1,000 nl, and more preferably approximately 10 nl to 200 nl. FUN N MN The ratio can be approximately 0.1 to 100, more typically approximately 0.5 to 20, more preferably approximately 1 to 10, or approximately 2 to 5.

[0074] A microneedle patch may include 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.

[0075] Matrix material / excipient The matrix material forms the microneedles, the funnel portion including the primary and secondary funnel portions, and optionally the majority of the base substrate. The microneedles, primary and secondary funnel portions may be formed from the same or different matrix materials. The matrix material typically includes biocompatible polymer materials, either alone or in combination with other materials. Foaming materials may be dispersed within the matrix material used to form the funnel portions, portions of the microneedles, or combinations thereof. The substance of interest may be dispersed within the matrix material used to form the microneedles and / or funnel portions.

[0076] The matrix material may be biodegradable, bioerosive, and / or bioabsorbable. One or more matrix materials may be selected based on the rate at which they are biodegraded, bioerosive, or bioabsorbed. In some embodiments, the matrix material is water-soluble. Water-soluble matrix materials may dissolve within minutes to tens of minutes upon contact with a fluid such as a biofluid.

[0077] In some embodiments, the microneedles are formed from a matrix material that is biodegradable, bioerosive, and / or bioabsorbable, the matrix material encapsulating the target substance. The target substance is released when the matrix material is decomposed, eroded, absorbed, or a combination thereof.

[0078] In some embodiments, the majority of the microneedle is formed from a matrix material containing polylactic acid, polyglycolic acid polylactic acid, polycaprolactone, or a combination thereof. In some embodiments, the funnel portion, including a primary funnel portion and / or a secondary funnel portion, is formed from a matrix material containing polyvinyl alcohol, a carbohydrate, or a combination thereof. In some embodiments, the carbohydrate is sucrose. In some embodiments, the funnel portion, including a primary funnel portion and / or a secondary funnel portion, is formed from a matrix material containing polyvinylpyrrolidone. However, other matrix materials are also conceivable.

[0079] As used herein, the terms “matrix material” and “excipient” are used interchangeably to refer to any excipient that does not volatilize or otherwise remove during the drying and formation of the microneedles and funnels.

[0080] The fluid solution used in the mold filling process described herein may contain any of the following excipients: one or more of the following categories of excipients may be used, or none may be used: stabilizers, buffers, fillers or additives, auxiliaries, surfactants, disintegrants, antioxidants, solubilizers, anti-dissolution agents, antimicrobial agents, anti-adhesion agents, colorants, lubricants, thickeners, gliding agents, and preservatives.

[0081] In some preferred embodiments, the microneedles are made of a biodegradable matrix material that encapsulates the API, and upon insertion into the patient, the entire microneedle separates and slowly decomposes within the skin.

[0082] How to make microneedles Microneedles or other objects may be manufactured by a molding process comprising: 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 material; drying the matrix material; and then removing the formed portion from the mold. An example of this is illustrated in Figure 5. The filling and drying steps may be referred to herein as “casting”. The improved casting method described above focuses on a first step in which a microneedle tip containing a chemical is formed. The method typically comprises two or more castings.

[0083] The methods described herein may include one or more features, components, 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.

[0084] The composition of the packing solution generally reflects the desired material in the final microneedle array, with the exception of any solvents that may be completely or substantially removed during the process.

[0085] In some embodiments, the substance of interest is preferentially loaded onto the microneedle and its tip, rather than into the funnel portion. The substance of interest is part of the filler material transferred to the mold. The filler material comprises a liquid vehicle. The filler material may be in the form of a solution, slurry, or suspension of particles, or a combination of any of these forms. As described above, the filler material preferably comprises a colloidal suspension of fine particles, a polymer whose solubility has been reduced to near its precipitation point from the solution, or both. One or more of these forms may be used in a multi-step filling process. This “filler material” may be referred to herein as “solution” or “fluid material”.

[0086] In various filling processes, the filling material may include a liquid vehicle. The term “liquid vehicle” may be referred to herein as “solvent” or “carrier fluid.” In various embodiments, the filling material may include (1) solvent only, (2) no solvent, (3) matrix material only, (4) a combination of solvent and matrix material without the substance of interest, (5) a combination of solvent and substance of interest only, or (6) a combination of solvent, substance of interest, and matrix material. The solvent may be an organic solvent such as water, 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 examples of solvents include bis(2-methoxyethyl) ether (diglym), tetrahydrofuran, dimethylacetamide, dimethylformamide, xylene, dichloromethane, chloroform, hexane, limonene, methylcyclohexane, and combinations thereof. When the microneedle array contains a foaming material, the liquid vehicle containing the foaming material should be a non-aqueous liquid vehicle. As used herein, the term "non-aqueous" refers to a liquid containing less than 1% by volume of water.

[0087] The microneedles and funnel cavities may be fully filled, partially filled, or overfilled. Generally, a drying or curing process follows the filling process. This drying or curing process can be achieved, for example, by heating and / or reducing pressure.

[0088] In a preferred embodiment, a two-step filling process is used, the first filling step containing the target substance which substantially migrates to the microneedles and their tips during the drying / curing process. This process is often repeated for another cast of the same material. After the first cast containing the target substance has been cast and dried, a second filling step and subsequent drying / curing process follow. This second filling step contains a matrix material which gives the microneedles and funnels their mechanical structure and may be overfilled to create a base substrate or a portion of a base substrate. The second filling step may result in the trapping of air bubbles between the material applied during the first filling step and the material applied during the second filling step.

[0089] The mold may be filled with a first solution containing an active substance (and possible excipients) and then dried. In some cases, the mold may be filled again with the same solution and dried. This may be repeated until the desired amount of active substance is loaded onto the microneedles. One or more final filling steps may follow, in which the mold may be filled with an excipient (which may be the same as or different from the previous excipient) and dried, without the active substance that provides the microneedles with their mechanical structure.

[0090] In some embodiments, a centrifuge or similar device is used to rotate the mold, creating gravity that drives the solution downwards through the microneedles as the solution dries / hardens. This process may also be useful for driving larger molecules (e.g., active molecules) downwards through the microneedles and their tips while the filling fluid is still in solution. The term "larger molecules" is used to mean molecules larger than the molecules of the liquid vehicle or solvent, and may also include nanoparticles, fine particles, and other particles consisting of many molecules.

[0091] 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: the application of vibration, ultrasound, pressure, vacuum, electromagnetic field, and centrifugation.

[0092] The volume of solution deposited in a microneedle mold can be controlled by the volume of the cavities within the mold (i.e., completely filling the cavities with the solution and then washing the surface) or by the filler (i.e., a distributed or loaded volume, mass, etc.). For microneedle arrays produced by multiple filling steps, both of these volume control methods can be used. For example, a solution containing an active substance may be blanket-coated over the entire surface, filling the microneedles and funnel cavities, washing the solution from the mold surface, drying the solution, depositing a second solution in a volume controlled by the filler, and drying the second solution.

[0093] In some embodiments, known fluid handling / distribution techniques / systems in the art are used to deposit a solution onto a mold. Some are suitable for "blanket" coating (local or full patch), targeted deposition, or both. To deposit the solution in the desired location, the filling head may be automated and move, the mold may move, or both may move. This can be in the form of a single cavity mold, a multi-cavity mold plate, or a continuous reel-to-reel process.

[0094] Several drying and / or curing methods can be used throughout the manufacturing process. Heat may be applied in the form of a batch process, but it may be preferable to integrate it into a semi-batch or continuous process. Some drying methods that cure a solution by removing the solvent through evaporation include 1) heat through convection, conduction (i.e., hot plate or heated surface), and / or radiation (heat lamp, IR or NIR light), 2) convection drying, drying, sterile air or nitrogen blower, 3) vacuum exposure under reduced pressure, 4) ambient drying, 5) centrifugal force, 6) drying, 7) freeze-drying or freeze-drying, 8) dielectric drying (e.g., RF or microwave), 9) supercritical drying, and 10) application of a combination of one or more of these drying methods.

[0095] As used herein, the terms “dry,” “dried,” or “cooked” when referring to materials in a mold (e.g., matrix material and / or target material) refer to materials that have begun to solidify at least partially. In embodiments, microneedles may be removed from the mold before they are completely dry. In one embodiment, microneedles are removed from the mold after they have dried to a working state. However, in preferred embodiments, microneedles are removed from the mold when they are rubbery but strong enough to resist being pulled out or peeled from the mold. This has been found to improve the removal of microneedles from the mold without damage. As used herein, the term “working state” means that the microneedles are rigid enough to be used for their intended purpose, e.g., to penetrate skin. As used herein, the term “rubbery state” means that the microneedles are not working because they are too soft and flexible to penetrate their intended target tissue, e.g., skin. For example, microneedles made of bulk / matrix materials containing polyvinyl alcohol and sugars will enter a rubbery state before becoming operational as their moisture content decreases during the drying process.

[0096] Methods using microneedles and arrays The microneedles, arrays, and patches described herein may be self-administered or administered by another person. The microneedle patches provided herein do not require the use of an applicator to apply the required force / pressure and may be handled and administered directly by the person applying the patch.

[0097] In some embodiments, the method using a microneedle array includes a single and effective method for administering a substance of interest using a microneedle patch. This method may include identifying the application site and, preferably, disinfecting the area (e.g., using an alcohol wipe) before applying the microneedle patch. If necessary, the application site may be dried before applying the microneedle patch. The patch is then applied to the patient's skin / tissue and pressed into the patient's skin / tissue manually (e.g., using a thumb or finger) by applying sufficient pressure to insert one or more microneedles into the patient's skin / tissue.

[0098] In some embodiments, the microneedles then separate from the microneedle patch when the funnel portion dissolves, for example, if the funnel portion contains an effervescent material. When the effervescent material is contained within the funnel portion, the microneedles may separate from the microneedle patch within about 10 to 120 seconds after the microneedle patch is pressed against the patient's skin / tissue. In some embodiments, the microneedles separate from the microneedle patch within about 40 to 60 seconds after the microneedle patch is pressed against the patient's skin / tissue.

[0099] After the microneedles have separated from the patch, the patch can be removed from the patient's skin / tissue. The patch can be removed by manually grasping the tab portion (e.g., between the thumb and fingers), pulling, and discarding the patch. With the separation of the microneedles from the patch, the patch can be disposed of as non-sharp waste.

[0100] In some embodiments, after separation of the microneedles, they may dissolve readily (within a few minutes to a few tens of minutes). In some embodiments, the microneedles may dissolve, be bioeroded, biodegraded, and / or bioabsorbed over several days, weeks, or months.

[0101] In some embodiments, the microneedle patches described herein are used to deliver one or more target substances (e.g., vaccines, therapeutic drugs, vitamins) to the body, tissues, cells, and / or organs. In some embodiments, microneedles are used to deliver active substances to the skin by inserting them across the stratum corneum (the outer 10-20 micrometer layer of skin that is a barrier to transdermal transport) and into the living epidermis and dermis. The microneedles are preferably soluble, and once they enter the intradermal space, they dissolve in the biofluid, releasing the active substance into the skin. The microneedles can be formulated to release the active substance over a long period of time. The extended period may 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.

[0102] Unless otherwise specifically defined herein or in the remainder thereof, all technical and scientific terms used herein have meanings that are generally understood by those skilled in the art to which this disclosure belongs. It should also be understood that the terms used herein are solely for the purpose of describing a particular embodiment and are not intended to be limited thereto. In the description and claims of these embodiments, the following terms will be used according to the definitions set forth below.

[0103] As used herein, the term “about” indicating a value of a given quantity may include quantities within 10% of the indicated value, or optionally within 5% of that value, or in some embodiments within 1% of that value. [Examples]

[0104] The present invention may be further understood by referring to the following non-limiting embodiments.

[0105] Example 1 - Formulation with reduced polymer solubility A solution containing 10% poly(D,L-lactide-co-glycolide) (PLGA), 50:50, acid-terminated, in diglyme (DGM) was prepared. Aliquots of 10% PLGA in the DGM solution were weighed, and the amount of 5% levonorgestrel (LNG) dissolved in the DGM was added in an amount corresponding to the 50:50 PLGA to LNG ratio. Then, an amount of dioxane corresponding to 20% of the solvent composition of the PLGA / LNG solution was added. Next, the calculated amount of DGM was added to adjust the PLGA concentration to 3%. The clear solution was then stirred, and water was added dropwise until the solution became cloudy, which is assumed to indicate that the polymer conformation was becoming tight and the PLGA was on the verge of precipitation or had just begun to precipitation. The formulation was then cast onto a silicone microneedle mold centrifuged at 4200 rpm for 40 minutes at 40°C, packing the formulation with the needle tip of the mold, and the solvent was evaporated. The casting result was a microneedle mold with a needle tip packed in 50% LNG / 50% PLGA, with little to no additional polymer film above the packed tip. This result was achieved without the use of solvent washing, which is often required after casting PLGA / chemical formulations. Figures 6A and 6B show a comparison of microneedle cavities cast from a true solution of LNG / PLGA (Figure 6A) with the formulation of Example 1 (Figure 6B). In the upper image, the film within the funnel region of the mold has been peeled from the mold surface for better visualization. In the lower image, there is little to no visible film within the funnel region, and LNG and PLGA are almost entirely within the tip region of the mold.

[0106] Initial centrifugation at lower temperatures further reduced film formation in the funnel region of the mold, and it was later found that the formulation of Example 1 was further dried by centrifugation at 10°C for 15 minutes followed by a further 30 minutes at 40°C.

[0107] Example 2 - Formulation with reduced polymer solubility Strong volatile solvents were used to solubilize the chemicals in polymer solutions containing water, solvent-free solutions for the chemicals and polymers, and low-volatility solvents, which are weaker solvents for the chemicals. The volatile solvents were evaporated, which precipitated the chemicals as a fine colloidal suspension in the polymer solution. When the formulations were cast onto a silicone microneedle mold and dried by centrifugation, it was found that the colloidal chemical particles filled more easily, packed into the microneedle cavities, and produced much less concave tip filling, with a significantly reduced amount of film adhering to the silicone mold above the tip cavities. This allowed for a greater amount of chemical to be loaded into the tips of the microneedle patches and reduced chemical loss during casting.

[0108] Example 3 - Formulation of precipitated chemicals (PDS) A solution containing 5% poly(D,L-lactide-co-glycolide) (PLGA), 50:50, ester-terminated, in diglyme (DGM) was prepared. Aliquots of 5% PLGA in the DGM solution were weighed, and an amount of 5% levonorgestrel (LNG) dissolved in tetrahydrofuran (THF) was added in an amount corresponding to a 60:40 PLGA to LNG ratio. Water was then slowly added dropwise to the stirred solution until a pre-calculated amount equivalent to 8% water, based on the total solvent composition, was added. The PLGA and LNG solution remained clear. The capped vial was then weighed, the cap removed, and the THF was evaporated by open stirring on a stirring plate in a hood for two days. After two days of evaporation, the initially clear solution became a white suspension of colloidal LNG particles in the PLGA solution in DGM / water. The vial was capped, weighed, and the total amount of solvent lost by evaporation was determined. Additional DGM and water were added to achieve a PLGA concentration of approximately 4% for casting the microneedles. The formulation was then cast onto a silicone microneedle mold, centrifuged at 4200 rpm for 40 minutes at 40°C, packing the needle tips of the mold with the formulation, and the solvent was evaporated. The microneedle mold was then washed with 5% H2O in 20 μl of DGM by centrifuging at 40°C for 30 minutes at 4200 rpm. The formulation was then cast a second time on the mold and dried by centrifugation. The mold was then washed three more times with 5% H2O in DGM while drying by centrifugation. The resulting microneedle tips were evenly packed with 40% LNG / PLGA, with no additional polymer film above the packed tips. Next, the microneedle mold with the tip was oven-dried and backed with a standard water-soluble backing material using a standard microneedle finishing method.

[0109] Example 4 - Formulation of precipitated chemicals (PDS) The formulation of Example 3 was repeated three times at different rates, varying the chemical load on the microneedles to 50% LNG, 60% LNG, and 70% LNG (the remainder being PLGA). Each of these formulations produced high-quality microneedles, but it was noted that the tips of the microneedles in the 70% formulation were brittle, and many of the tips of this formulation broke during removal from the mold.

[0110] Example 5 - Precipitated chemical formulation (PDS) The compounding and casting process of Example 3 was repeated, except that a second centrifugation was performed at 10°C for 15 minutes, followed by a second centrifugation at 40°C for 15 minutes to dry the mold, in order to improve the packing of the tip. The initial cold centrifugation reduced the need for final tip washing from three times to just one, significantly shortening the time required to produce the microneedle tip and resulting in a uniformly packed tip without an additional film of compound on top of the tip.

[0111] Example 6 - PDS formulation for etonogestrel Etonogestrel (ENG) was found to be more soluble and water-resistant than LNG and did not precipitate in the formulation of Example 3. Therefore, a new formulation had to be prepared to precipitate the colloid of ENG in the biodegradable polymer solution. This required identifying a solvent-free solvent for ENG that was effective for the polymer. Solubility studies using ENG, PLGA, and poly(L-lactide) (PLA) were used to determine that xylene was a solvent-free solvent for ENG and a solvent for PLA, not for PLGA. Next, a solution containing 5% PLA, 0.55–0.75 dL / g, and ester-terminated in xylene (XYL) was prepared. The strong volatile solvent selected to solubilize ENG in PLA / XYL was dichloromethane (DCM). Aliquots of 5% PLA in the XYL solution were weighed, and the amount of 5% ENG dissolved in DCM was added in an amount corresponding to a PLA to ENG ratio of 60:40. A clear solution was formed. Next, the capped vial was weighed, the cap was removed, and the solution was stirred open on a stirring plate in a hood for 24 hours to evaporate the DCM. After 24 hours of evaporation, the initially clear solution became a white suspension of colloidal ENG particles in a PLA solution in xylene. The vial was capped and weighed to determine the total amount of solvent lost by evaporation. The mass balance indicated that the DCM had evaporated from the solution. Next, additional XYL was added to adjust the PLA concentration to approximately 4% for casting microneedles. Using the formulation, the microneedle tips were cast by centrifugation as described in Example 3, except that the washing solvent was 50:50 XYL:DGM, which is solvent-free for ENG. The finished microneedle patches were then fabricated from a silicone mold by casting a water-soluble backing of polyvinyl alcohol and sucrose onto the top of the dried PLA / ENG tips using a standard microneedle fabrication method.

[0112] Example 7 - Water-soluble PDS formulation A solution containing 20% ​​polyvinylpyrrolidone (PVP, K90) in ethanol (EOH) was prepared. Aliquots of 20% PVP in the EOH solution were weighed, and an amount of 4% levonorgestrel (LNG) dissolved in tetrahydrofuran (THF) was added, corresponding to a PVP to LNG ratio of 60:40. Then, water was slowly added dropwise to the stirred solution until a pre-calculated amount equivalent to 27% water, based on the total solvent composition, was added. A clear solution was formed. The capped vial was then weighed, the cap was removed, and the THF was evaporated by open stirring on a stirring plate in a hood for two days. After two days of evaporation, the initially clear solution became a white suspension of colloidal LNG particles in the PVP solution in ethanol / water. The vial was capped, weighed to determine the total amount of solvent lost by evaporation, and additional EOH / H2O was added to achieve a PVP concentration of approximately 5% for casting microneedles. Next, microneedle patches were fabricated from molds using standard methods.

[0113] Modifications and variations of the methods and devices described herein will be apparent to those skilled in the art from the above detailed description. Such modifications and variations are intended to fall within the scope of the accompanying claims.

Claims

1. A method for fabricating microneedles, The present invention relates to preparing a casting solution comprising at least one organic solvent, a polymer, and a target substance, wherein the polymer and the target substance, if present, are completely dissolved in the casting solution. (i) adding a non-solvent for 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 is effective in reducing the effective molecular volume of the polymer in the casting solution, and thereafter, A method comprising casting the casting solution into a mold for microneedles.

2. The method according to claim 1, wherein adding a non-solvent to the casting solution and / or evaporating at least a portion of the at least one organic solvent is effective for precipitating the target substance as a colloid or suspension in the casting solution.

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

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

6. The method according to any one of claims 1 to 5, wherein the at least one organic solvent comprises two different organic solvents.

7. The method according to any one of claims 1 to 6, 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 tip portion of the microneedle, and the reduction of the effective molecular volume of the polymer is effective in avoiding the formation of a polymer film on the funnel portion.

10. A method for fabricating microneedles, The present invention relates to preparing a 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 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 is effective in precipitating the target substance as a colloid or suspension in the casting solution, and thereafter, A method comprising casting the casting solution into a mold for microneedles.

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

13. The method according to any one of claims 10 to 12, wherein the casting includes drying, centrifugation, and / or application of vacuum to the casting solution in the mold.

14. The method according to any one of claims 10 to 13, wherein the at least one organic solvent comprises two different organic solvents.

15. The method according to any one of claims 10 to 14, 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 tip portion of the microneedle, and the reduction of the polymer conformation is effective in avoiding the formation of a polymer film on the funnel portion.

18. A microneedle array for administering a target substance to a patient's biological tissue, Bass and, A microneedle comprising two or more microneedles extending from the base, each of the two or more microneedles having (i) a tip portion mainly formed from a first material comprising a polymer and a target substance, and (ii) a funnel portion mainly formed from a second material, wherein the funnel portion extends between the base and the tip portion, A microneedle array in which the first material is formed from a first casting, the second material is formed from a second casting, and the interface between the first material and the second material is flat.

19. The microneedle array according to claim 18, wherein the polymer comprises PLGA, PLA, or another biodegradable polymer.

20. The microneedle array according to claim 18 or 19, wherein the funnel portion comprises a water-soluble matrix material, and two or more solid microneedles are configured to penetrate the patient's biological tissue under compression, and then, when at least a portion of the water-soluble matrix material dissolves in the funnel portion, the tip portions separate from the funnel portion.

21. The microneedle array according to any one of claims 18 to 20, wherein the funnel portion further comprises a foaming material.

22. The microneedle array according to any one of claims 18 to 21, wherein the target substance includes an active pharmaceutical component.

23. The microneedle array according to any one of claims 18 to 22, wherein the target substance includes a contraceptive hormone.

24. The microneedle array according to any one of claims 18 to 23, wherein the target substance is in the form of particles measuring 1 nm to 1 μm dispersed in the polymer.

25. The microneedle array according to any one of claims 18 to 24, wherein the tip portion and the funnel portion are tapered at different angles to each other.

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