DE102019128888A1 - Process for the production of microstructures - Google Patents

Abstract

In a method for producing microstructures, in particular for producing a microneedle array, a solution is dosed onto an upper side of a die in a first step. The die has a multiplicity of depressions which form the microstructures or the microneedle array. The dosed volume of solution is greater than a target volume. In a second step, part of the dosed solution is sucked off, preferably a volume being sucked off such that the target volume is reached.

Description

The invention relates to a method for producing microstructures, in particular microneedle arrays having such microstructures.

The microstructures to be produced are preferably microneedles which are in particular arranged in a microneedle array. Microneedles are used to deliver active ingredients directly into the skin, also known as transdermal administration. For this purpose, the microneedles are of such a length that they only penetrate into the outer layers of the skin, but preferably not to reach nerves and blood vessels and thus leave them unharmed. Nevertheless, microneedles create small holes in the upper layers of the skin, which significantly increases the absorption of active ingredients compared to a purely external application of active ingredients to the skin.

Microneedle arrays, which have a multiplicity of microneedles, for example attached to a carrier surface, can be used for short-term administration or for long-term application. A preferred option for the release of active ingredient from the microneedles into the skin consists in that areas of the microneedles or the entire microneedle that contain active ingredient dissolve or detach and are thus absorbed by the body through the skin. For this purpose, the microneedles are in particular made, at least in part, from water-soluble substances or materials. In addition to the direct release of active ingredient through the microneedles per se, it is also possible for the microneedles to have pores or cavities or to be designed as hollow needles in order to enable active ingredient to be released to the skin in this way. In addition, microneedles can also be free of active ingredients per se. Here, for example, the active ingredient can be applied externally to the outside of the microneedles or an active ingredient-containing substance can only be applied to the corresponding skin area after the microneedles have been removed from the skin in order to administer such active ingredients using microneedles.

Microneedles can be made of ceramic, metal, or polymer, among others. It is preferred that one or more active ingredient components are added to these materials and such a formulation of the microneedles results.

Methods known up to now for the production of therapeutic or diagnostic microneedles or microneedle arrays are not suitable, or are only suitable to a limited extent, for production in sufficient quality and / or quantity.

A common method for producing microneedles consists in casting the microneedles or entire microneedle arrays, for example using a silicone mold. In particular, because of the hydrophobic properties between the casting mold and the mostly liquid formulation applied to it, numerous problems arise with such manufacturing processes.

In particular, when applying aqueous liquids over the entire surface of the casting mold with a die usually made of silicone, the problem arises that due to the hydrophobic properties of the casting mold, the liquid is not evenly distributed and may not get into all the microneedle depressions in the casting mold.

Even if the liquid is applied in a spiral to the surface of the casting mold, this problem can be reduced, but the reject rate is relatively high. Even with such methods, it is therefore not possible to reliably manufacture a high-quality product with a low percentage of rejects in the microneedle arrays produced.

In particular, the quality of the manufactured product is strongly influenced by the positioning of the dosing needle that supplies the liquid to the casting mold. If the distance between the dispensing needle and the casting mold is too small, the liquid is not distributed evenly, so that individual recesses provided in the casting mold are not or not completely filled. If necessary, the tips of the dispensing needles can rub against individual cavities, especially when moving with respect to the casting mold. The dosing process is therefore unstable. If, on the other hand, the distance between the dosing tip and the surface of the casting mold is too great, it can lead to tear-offs. This in turn means that the dosing liquid is not distributed evenly over the depressions or cavities of the casting mold. This also leads to problems when shaping individual needles of the microneedle array.

Furthermore, a certain volume of liquid, the so-called target volume, has to be supplied. The challenge is to distribute the small target volume over the entire structured area. This turns out to be difficult due to the hydrophobic properties of the structured silicone matrix. The dosed liquid tends to withdraw into a drop. In the event of a tear-off of the droplets, two or more individual droplets can also arise from this, which also want to contract into one droplet. This effect is prevented by distributing the mass over the structured surface. If the mass is moved over a structure, it sticks to the edges the structure and is thereby prevented from retreating into a drop. The dosed volume is thus forced by the structure to flatten the drop due to the adhesion processes on structure edges. This process is all the more unstable the smaller the volume or the larger the surface to be wetted.

The object of the invention is to create a method for producing microstructures, in particular for producing microneedle arrays, with which high-quality products can be produced.

The object is achieved according to the invention by a method according to claim 1.

In the method according to the invention for producing microstructures, in particular for producing microneedle arrays, a solution is metered which has the material of the microstructure or microneedle arrays to be produced. Since the corresponding solution partially evaporates during drying, for example an active ingredient concentration in the solution to be dosed differs from the active ingredient concentration in the microstructure produced. Such solutions, referred to as ball solutions, can be, for example, solutions with, in particular, water-soluble active ingredients. For example, it is a sugar solution or a PVP (polyvinyl pyrrolidone) solution. Furthermore, it is possible to dose different solutions in several dosing steps, this representing a preferred development of the invention and initially only the dosing of one solution will be described.

The solution is applied to a die with a large number of wells. These depressions or cavities form the microstructures and in particular the microneedle array. In the metering step, according to the invention, a volume is metered which is greater than the target volume. The target volume defines the amount of solution that should ideally be applied in order to ensure that all cavities or depressions are filled and, in addition, to achieve a continuous cover layer or connecting layer above the depressions or cavities.

In the next step, according to the invention, part of the dosed solution or solution applied to the die is sucked off. It is particularly preferred that the solution is distributed on the die immediately after or when it is applied. According to the invention, too much solution or an excess of solution is thus initially supplied. This ensures that the solution wets the entire structured surface. This process step forms the basis for penetration and the complete filling of all depressions or cavities. A sufficient cover layer, which connects the needles formed in the depressions to one another, is also ensured. Subsequent suctioning off part of the dosed solution ensures, on the one hand, that the preferably distributed solution does not retreat into a drop, but rather sticks to the edges of the structures and thus ensures that the array is completely covered. The target volume is also maintained. It is also avoided that too high a dosage would result in a waste of material.

A volume is preferably sucked out of the dosed solution such that the volume remaining on the die corresponds to the target volume. This ensures that high-quality products are manufactured with, in particular, consistent quality.

The solution is preferably metered using at least one metering nozzle. It is preferred here that when the solution is metered onto the die, there is a relative movement between the die and the at least one metering nozzle in order to ensure uniform distribution of the solution. A spiral movement is preferred here, this preferably beginning inside or in the middle of the die and a spiral movement of the at least one metering nozzle taking place outwards.

The metered amount added in the first step is preferably at least 120%, particularly preferably 140% of the target volume. The upper limit of the metered quantity supplied is preferably a maximum of 180% of the target volume.

In a preferred embodiment, the target volume to be achieved is calculated from the sum of the volumes of the individual depressions plus an approx. 1 mm thick layer with a diameter of approx. 10 mm. Of course, the layer covering the depressions does not have to be circular-cylindrical, but can also have other shapes, such as, for example, rectangular, polygonal or the like.

The suction according to the invention of excess solution or part of the dosed solution is preferably carried out with at least one suction needle. It is preferred that the suction needle is not the metering nozzle, but a separate device. When sucking off the liquid, it is also preferred that a relative movement only takes place between the at least one suction needle and the die, which in turn can take place in a spiral.

After some of the excessively dosed solution has been sucked off, hardening preferably takes place, in particular by drying the solution. After the solution has hardened, the microstructure or the microneedle array can be removed from the die.

In a preferred development of the invention, different solutions are dosed. Thus, an active ingredient solution is first dosed onto the upper side of the die or into the depressions and then at least one further solution, which in particular does not contain any active ingredient. This has the particular advantage that no solution with active ingredient is sucked off and parts of the microstructure that are not given to the patient are not provided with active ingredient. This reduces the cost. It is particularly preferred that the active ingredient solution is also supplied via at least one metering nozzle. This can be the same or a separate dosing nozzle or several dosing nozzles. Furthermore, when the active substance solution is being metered, there is preferably a relative movement between the at least one metering nozzle and the die in order to ensure that the active substance solution reaches all of the depressions.

Furthermore, it is preferred to allow the active ingredient solution to dry at least partially or in particular completely before the further solution is dosed onto the die. It should be noted here that the active ingredient solution may only have 10-30% of the original volume after drying. The active ingredient solution is therefore only arranged in the lower areas or tips of the depressions. Then, in a preferred development of the method, as described above, the solution is then metered with a volume that is greater than the target volume. When calculating the target volume, it must be taken into account that the lower areas or tips of the depressions are already filled with active ingredient solution.

If necessary, a third solution can also be dosed, this third solution then preferably being used to form an approximately 1 mm thick layer over the depressions.

The method according to the invention has the particular advantage that the distribution of the liquid on a hydrophobic surface is promoted. This leads to a reliable process with regard to the positioning of the dosing nozzle opposite the top of the die and thus results in greater process robustness.

The invention is explained in more detail below with the aid of sketches of a preferred embodiment.

• 1 und 2: jeweils eine schematische Draufsicht einer Matrize mit fehlerhaft verteilter Lösung,
• 3: eine schematische Draufsicht einer Matrize nach Dosierung eines Volumens an Flüssigkeit, das über dem Zielvolumen liegt gemäß dem ersten Schritt des erfindungsgemäßen Verfahrens,
• 4: eine schematische Schnittansicht der in 3 dargestellten Matrize,
• 5: eine schematische Draufsicht einer Matrize nach Absaugen eines Teils der dosierten Lösung gemäß dem zweiten Schritt des erfindungsgemäßen Verfahrens und
• 6: eine schematische Seitenansicht der in 5 dargestellten Matrize.

Show it:

• 1 and 2 : each a schematic top view of a die with an incorrectly distributed solution,
• 3 : a schematic top view of a die after dosing a volume of liquid which is above the target volume according to the first step of the method according to the invention,
• 4th : a schematic sectional view of the in 3 shown die,
• 5 : a schematic plan view of a die after sucking off part of the dosed solution according to the second step of the method according to the invention and
• 6th : a schematic side view of the in 5 shown die.

In the 1 and 2 a schematic plan view of a die according to the prior art is shown, in which the depressions shown as squares are not completely filled with solution. In the 1 and 2 The wells shown in black are not filled with solution.

From the 3 and 4th the inventive step of the method can then be seen, in which an amount of solution is supplied which is greater than the target volume. How out 3 can be seen, but this ensures that the wells are filled with solution. Out 4th it can be seen that due to the relatively large dosage there is a kind of drop 10 on the top 12th the die 14th trains. After the suction has been carried out according to the second step according to the invention, the depressions are in the die 14th , as in 5 shown still completely filled.

The excess material was vacuumed away, leaving the on top 12th drops located is reduced and only a relatively thin connecting layer 18th remains.

After the solution has dried, the microneedle array with the multiplicity of needles that have formed in the depressions can pass through the connecting layer 18th together from the die 14th can be easily demolded.

According to the preferred development of the invention, before the metering of the solution, as based on 3 and 4th described, the drug solution dosed. The solution subsequently dosed with an excess volume, as described above, then preferably no longer has any active substance.

The dosing is preferably carried out in each case via at least one dosing nozzle, with a relative movement taking place with respect to the at least one dosing nozzle and the upper side of the die. This is preferably spiral-shaped in order to ensure reliable distribution of the solution, possibly the active ingredient solution and the solution without active ingredient.

Claims (14)

Method for the production of microstructures, in particular for the production of a microneedle array, with the steps: Dosing a solution having the material of the microstructure or the microneedle array onto a plurality of wells having matrix, wherein the metered volume is greater than a target volume and Aspiration of part of the dosed solution. Procedure according to Claim 1 , whereby a volume is sucked off from the dosed solution, so that the supplied volume is reduced to the target volume. Procedure according to Claim 1 or 2 , in which the solution is supplied with at least one dosing nozzle. Procedure according to Claim 3 , in which the at least one metering nozzle and the die are moved relative to one another, in particular in a spiral. Method according to one of the Claims 1 to 4th , in which the dosage amount is at least 110%, particularly preferably 120% of the target volume. Method according to one of the Claims 1 to 5 , in which the target volume is the sum of the volumes of the wells plus the volume of a cover layer approx. 10 mm in diameter and approx. 1 mm in height. Method according to one of the Claims 1 to 6th , in which suction takes place by means of at least one suction needle. Procedure according to Claim 7 , in which the at least one suction needle and the die are moved relative to one another, in particular in a spiral, for suction. Method according to a Claims 1 to 8th , in which after suction the solution hardens, in particular by drying. Procedure according to Claim 9 , in which, after curing, the microstructure or the microneedle array is removed or demolded from the die. Procedure according to Claim 1 to 10 , in which an active ingredient solution is dosed onto the multitude of wells before the solution is dosed. Procedure according to Claim 11 , in which the active ingredient solution is supplied with at least one dosing nozzle. Procedure according to Claim 12 , in which the at least one metering nozzle and the die are moved relative to one another, in particular in a spiral. Method according to one of the Claims 11 to 13th , in which the active ingredient solution dries, the recesses of the die being only partially filled with active ingredient solution after drying.

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