EP4288262A1

EP4288262A1 - Method for producing a mold element for producing microarrays, and mold element

Info

Publication number: EP4288262A1
Application number: EP22702399.1A
Authority: EP
Inventors: Olga GRÜNWALD; Michael Kulik
Original assignee: LTS Lohmann Therapie Systeme AG
Current assignee: LTS Lohmann Therapie Systeme AG
Priority date: 2021-02-04
Filing date: 2022-01-13
Publication date: 2023-12-13
Also published as: CA3206954A1; US20240083078A1; CN116802036A; DE102021102555A1; WO2022167191A1; JP2024506881A

Abstract

The invention relates to a method for producing a mold element (100) for producing microarrays, having the steps of: (i) providing a flat base element (10) which has a first surface (16) and a second surface (24) lying opposite the first surface (16), (ii) providing a flat auxiliary element (11) on the second surface (24), (iii) piercing the base element (10) starting from the first surface (40) in order to form mold openings (14), and (iv) reversibly or non-reversibly piercing the auxiliary element (11) upon piercing the base element (10). The invention additionally relates to a mold element (100) for producing microarrays, comprising a flat base element (10) which has a first surface (16) and a second surface (24) lying opposite the first surface (16), a flat auxiliary element (11) which is arranged on the second surface (16), and multiple mold openings (14) which extend from the first surface (16) of the base element (10) to the second surface the base element (10).

Description

Process for producing a shaped element for the production of microarravs and shaped element

The invention relates to a method for producing a shaped element for the production of microarrays. Furthermore, the invention relates to a shaped element for the production of microarrays, produced in particular with the method according to the invention.

Microarrays have a multiplicity of microneedles, which are usually arranged in or connected to a carrier element, such as in a patch, a plaster or the like. Microarrays have a large number of microneedles, the length of which is dimensioned such that when they are pressed into the skin of a patient, they penetrate the skin only far enough so that nerves and vessels are not touched by the needle tips as far as possible. The needles contain an active substance, for example a drug. The corresponding active substance can be applied to an upper side of the needle or can be arranged in the needles. When the agent is placed in the needles, the needles or parts of the needles are made of a material that dissolves in the patient's skin.

Microarrays are produced, for example, with the aid of silicone molds, which have a large number of mold openings designed as depressions, which serve as negative molds. In a variant for filling these depressions, a liquid provided with the active substance is usually applied to the upper side of the silicone matrix. After the liquid has dried, another liquid is applied if necessary.

The production of the silicone molds with their indentations is currently carried out, for example, by means of an injection molding process. The object of the invention is to create a method for producing a shaped element for the production of microarrays, which is inexpensive and preferably suitable for the production of large quantities. Furthermore, it is the object of the invention to create a corresponding shaped element.

The object is achieved according to the invention by a method according to claim 1 or a shaped element according to claim 8.

The method according to the invention for producing a shaped element for the production of microarrays is, in particular, a method for producing an open shaped element, in particular open on both sides, for the production of microarrays. In a first step of the method, a flat base element is provided. The base member has a first surface and a second surface opposite the first surface. The first surface is in particular the upper side of the base element, while the second surface is in particular the underside of the base element. A further, second step consists in providing a flat auxiliary element on the second surface. In particular, the step of providing the auxiliary element takes place before or after providing the base element, although it is particularly preferred that the auxiliary element is provided together with the base element. After the base element has been provided and after the auxiliary element has been provided, in a third step the base element is penetrated, starting from the first surface, in order to form mold openings in the base element. Penetration here means in particular a complete penetration of the base element, so that the base element is completely penetrated. The mold openings formed thereby preferably run from the first surface to the second surface, so that continuous openings are formed. When penetrating the base element, there is also penetration into the auxiliary element. For example, if the base element is penetrated by a punching tool, the punching tool completely penetrates the base element and also penetrates into the auxiliary element. It is particularly preferred that partial penetration into the auxiliary element takes place. It is hereby preferred that the auxiliary element is not completely penetrated. The penetration is reversible or non- reversible. In other words, non-reversible means invasive penetration into the auxiliary element, so that the penetration results in an, in particular permanent, open depression in the auxiliary element. The non-reversible penetration is therefore preferably a reshaping or separating penetration. If the penetration takes place, for example, by means of a punching tool, the base element is penetrated by the punching tool and the punching tool also partially penetrates into the auxiliary element, so that a partial opening occurs here as well. In contrast, reversible intrusion means, in other words, non-invasive intrusion. It is therefore particularly preferred that, in the event of reversible penetration, the auxiliary element is deformed back at the point of penetration, in particular after it has been pushed out of the auxiliary element. In particular, no opening remains at the point where the auxiliary element has penetrated. It is particularly preferred that the auxiliary element is designed to be deformable and/or elastic, so that a resilience can take place via the elasticity. Another preferred step after penetrating the base element and penetrating the auxiliary element consists in penetrating out of the base element and penetrating out of the auxiliary element. The penetration into the base element and the auxiliary element takes place in particular together, preferably with the same tool. It is particularly preferred that the ejection from the base element and the auxiliary element takes place together. If, for example, penetration and penetration take place by means of a punching tool, penetration occurs when the punching tool is withdrawn. In particular, the mold openings run through the base element and partially into the auxiliary element.

With the invention, filling of the mold openings on both sides can advantageously be implemented. The filling can preferably take place from above and from below. This results in advantages such as shorter process times or the concentration of an active ingredient in the tip of the needle. The method according to the invention is advantageous compared to an alternative method for producing open structures, in which openings are produced in a laser process downstream of an injection molding process. Such a disadvantageous injection molding and laser process is very complicated and expensive. In contrast, the method according to the invention is inexpensive and preferably suitable for the production of large quantities the simplified process management and the combination of both processes, the production and opening of the mold openings, realized in one step.

In a preferred embodiment, the auxiliary element is connected to the base element. The connection between the auxiliary element and the base element is preferably designed to be detachable. It is particularly preferred that the connection is adhesive, in particular releasably adhesive. The planar auxiliary element is connected in particular with a planar side to the second surface of the base element. The detachable connection advantageously means that after the mold openings have been formed, the auxiliary element can be removed from the base element and the base element can thus be used as a mold device.

It is preferred that the base element and the auxiliary element are provided by jointly providing a composite element. In this case, the composite element has the base element and the auxiliary element. It is particularly preferred that the composite element has a film composite, in particular consists of it.

It is preferred that the penetration is by embossing. The embossing takes place here in particular with at least one, preferably a large number of embossing tools having complementary elevations to the mold openings. It is particularly preferred that the penetration takes place by hot embossing. The embossing temperature is preferably 80° - 260° C.

The penetration, in particular the embossing, takes place in particular continuously or discontinuously.

It is preferred that when penetrating with the embossing tool, the same embossing tool is used for the penetration as well. The auxiliary element makes it particularly advantageous for the embossing tool to be protected from damage and/or wear during embossing, since it is shielded when it penetrates the auxiliary element and is therefore not connected to other objects or the like. come into contact, which could lead to damage. As an alternative or in addition to the embossing penetration, it is possible for the penetration to take place by means of drilling and/or milling and/or punching.

If the penetration is done by embossing, it is preferred that this is done by means of an embossing roller. If, on the other hand, there is punching, it is preferred that this is done by means of a punching roller. It is also possible, for example, for embossing to take place using an embossing stamp or punching using a punch.

After the penetration, in particular after a subsequent escape, a further step takes place in particular: cooling. At least one cooling of the base element preferably takes place. Cooling of the auxiliary element also preferably takes place. Cooling to room temperature preferably takes place.

A further step of the method consists in removing the auxiliary element from the base element. Pulling off the auxiliary element from the base element is particularly preferred. In particular, the step of removing the auxiliary member from the base member occurs after the penetrating step, but it is particularly preferred that the removing step occurs after cooling.

The shaped element according to the invention for the production of microarrays has a flat base element. The base member has a first surface and a second surface opposite the first surface. The first surface is preferably the top, while the second surface is preferably the bottom of the base member. A flat auxiliary element is arranged on the side of the second surface of the base element. The auxiliary element is preferably arranged on the second surface of the base element. The auxiliary element is particularly preferably connected to the second surface of the base element. Further, the mold member has a plurality of mold openings extending from the first surface of the base member through the second surface of the base member. The mold openings thus run completely through the base element. In other words, the base element is thus continuously open on both sides. It is preferred that the mold openings are embossed mold openings. Both Mold openings are in particular negative molds for microarrays to be produced.

It is preferred that the mold openings partially extend into the auxiliary element. It is thus preferred that the mold openings run from the first surface of the base element into a part of the auxiliary element. In particular, the mold openings do not extend completely through the auxiliary element.

In a preferred embodiment, the auxiliary element is connected to the base element. In particular, the connection between the auxiliary element and the base element is detachable. It is particularly preferred that the connection between the auxiliary element and the base element is adhesive, preferably detachable-adhesive.

In a preferred embodiment, the base element and/or the auxiliary element has, in particular, consists of thermoplastic and/or thermoplastic elastomer. The base element and/or the auxiliary element particularly preferably has TPU, PC, APET, PPC and/or PETG, and in particular consists of them.

It is preferred that the base element and/or the auxiliary element has a film, in particular consists of it. The film preferably has a thickness of 0.2-2.0 mm, particularly preferably 0.5-1.5 mm. It is particularly preferred that the base element has a film with a thickness of 0.5-1.5 mm and/or the auxiliary element has a film with a thickness of 0.1-2 mm.

It is preferred that the mold openings are cylindrical or conical. If, for example, the mold openings are formed by embossing, it is preferable for the embossing tool to have one or more cylindrical or conical elevations that are complementary to the cylindrical or conical mold openings. The mold openings preferably correspond to negative molds of the microarrays to be produced. It is preferred that the base of the cylindrical or conical mold opening is on the first surface of the base member. In particular, the base of the cylindrical or conical mold opening is a circle, an oval, a rectangle or a square. If the mold openings are conical, they can also be truncated cones. The cross section of the mold openings preferably tapers from the top of the base element towards the bottom. The mold openings are preferably symmetrical in the longitudinal direction, in particular rotationally symmetrical, so that the opening provided on the underside is arranged centrally in relation to a base area of the mold opening

It is preferred that the auxiliary element, in particular the material from which the auxiliary element is made, has a higher hot forming temperature than the base element, in particular than the material from which the base element is made. The auxiliary element preferably has a higher melting temperature than the base element. It is preferred that the auxiliary element has a substantially higher hot forming temperature than the base element. The auxiliary element preferably has a higher elasticity than the base element. In particular, the auxiliary element has a smaller modulus of elasticity than the base element. The auxiliary element can have a porous structure, for example. It is possible that the auxiliary element has one or more of the features described in this paragraph.

Each individual mold opening on the first surface preferably has a cross-sectional area of 0.04 mm ² - 0.16 mm ² , in particular 0.04 - 0.08 mm ² . The mold openings themselves preferably have a depth of 600 μm to 2200 μm, in particular 600 μm to 1000 μm. It is preferred that the mold openings extend through the entire thickness of the base element. In particular, the mold openings extend into the auxiliary element with a depth of 10 μm to 500 μm, preferably with a depth of 50 μm to 300 μm, particularly preferably with a maximum depth of 80 μm.

The base element, which is designed in particular as a film, preferably has a thickness of 500 μm-1.5 mm.

The auxiliary element, which is designed in particular as a film, preferably has a thickness of 100 μm ± 2 mm.

The mold openings on the second surface of the base member and / or the Openings on the auxiliary element preferably have a cross-sectional area of <1200 μm ² , in particular <100 μm ² . Alternatively or additionally, the shaped openings on the second surface of the base element and/or the openings on the auxiliary element preferably have a diameter of <40 μm, in particular <10 μm.

The preferred composite element, which has at least the base element and the auxiliary element and which is designed in particular as a film composite, preferably has a thickness of 600 μm to 3.5 mm.

It is preferred that the auxiliary element can be at least partially detached from the base element, in particular can be pulled off. It is possible for the auxiliary element to be present at least partially detached from the base element, in particular pulled off.

The mold openings preferably have a small spacing or a high density. In particular, 9-350 mold openings are provided per square centimeter in a particularly regular arrangement. An arrangement of mold openings, for example in rows, is also possible, with the adjacent rows being arranged in a staggered manner.

The preferred size ratios described above are produced in a particularly preferred embodiment by the method described above, so that the corresponding features in a particularly preferred embodiment can also define the preferred embodiment of the method individually or in combination.

The method according to the invention described above can preferably be supplemented by one or more features of the shaped element according to the invention described above. The shaped element according to the invention described above can preferably be supplemented by one or more features of the method according to the invention described above.

The invention is explained in more detail below using a preferred embodiment with reference to the accompanying drawings. Show it:

1 shows a schematic side view of a composite element with a base element and an auxiliary element,

2 shows a schematic side view of a composite element together with an embossing roller,

Fig. 3 shows a schematic side view of an embossed composite element, and

4 shows a schematic detailed view of the section from FIG. 3 with a mold opening produced by the method according to the invention,

5 shows a schematic side view of another composite element together with an embossing roller, and

6 shows a schematic side view of another composite element together with an embossing roller.

Similar or identical parts or elements are identified in the figures with the same reference numerals or variations thereof (e.g. 10 and 10'). In order to improve clarity in particular, elements that have already been identified are preferably not provided with reference numbers in all figures.

1 shows an example of a composite element 13 as the starting point for the production of a shaped element using the method according to the invention. The composite element 13 has a base element 10 and an auxiliary element 11 . In particular, the base element 10 and the auxiliary element 11 are films, so that the composite element 13 corresponds to a film composite. To form the composite element 13, the base element 10 and the auxiliary element 11 are shown provided, with the provision being shown here by feeding from the left. A second surface side 24 of the base element 10 is adhesively bonded to a first surface 40 to form the composite element 13 . The adhesive connection takes place in particular by means of adhesive, which is arranged, for example, on the first surface 40 of the auxiliary element 11 and/or on the second surface of the base element 10. For example, the adhesive can be an adhesive layer that is connected to the first surface 40 of the auxiliary element and/or to the second surface 24 of the base element 10 . On the other hand, it is possible to create the adhesive connection through the molecular forces of the foil surfaces.

Shown on the right, the auxiliary element 11 and the base element 10 are adhesively connected to the composite element 13 and are continued, shown by arrow 44.

The first surface 16 of the base element 10 is located opposite the second surface 24 of the base element 10. The second surface 42 of the auxiliary element 11 is located opposite the first surface 40 of the auxiliary element 11. The first surface is preferably an upper side and/or or, in the case of the second surface, an underside.

To produce a shaped element using the method according to the invention, a composite element 13, in particular in the form of a film composite, is moved from the left (arrow 44) in the direction of arrow 12 in the exemplary embodiment shown in FIG. The composite element 13 shown in FIG. 2 is preferably the composite element 13 from FIG. 1.

In order to produce mold openings 14 in a first surface 16 of the base element 10, an embossing roller is preferably provided, which rotates in the direction of an arrow 20, counterclockwise in the exemplary embodiment. A large number of elevations 22 are provided on an outside of the embossing roller 18 . Regularly recurring areas of the outside of the embossing roller are provided with elevations 22 . Alternatively, it is possible for elevations 22 to be distributed regularly over the entire outside of the embossing roller 18 . The cross section of the elevations 22 shown corresponds to the cross section of the mold openings 14 . The mold openings 14 shown here extend completely through the base element 10 and continue further into a part of the auxiliary element 11 . The part of the mold opening 14 that extends through the base element 10 corresponds to a base mold opening 15, which is preferably used later as a matrix used to produce the microarrays. The part of the mold opening 14 in the auxiliary element 11 represents an auxiliary opening 17 in this case. The elevations 22 are, in particular, configured in the shape of a pyramid and have a cross-section that is preferably square or round.

The height of the elevations 22 and thus the depth of the mold openings 14 is less than the thickness of the composite element 13. The elevations 22 thus do not come into contact with a substrate 48 during the embossing process by hitting the ground 48. It is also implemented in a particularly advantageous manner that the mold openings 14 for the underside shown are protected by the auxiliary element 11 from the environment and are therefore protected from contamination.

It is preferable for the auxiliary element 11 to be removed, in particular pulled off, from the base element 10 before or after the base mold openings 15 are filled.

The composite element 13 running in the direction of the arrow 12 and having embossed mold openings 14 corresponds to a molded element 100 to be produced. On the one hand, it is possible for the mold element 100 to be formed by connecting the auxiliary element 11 to the base element 10 or for the auxiliary element 11 to be partially removed from the base element 10 or that auxiliary element 11 is completely removed from the base element 10.

3 shows an exemplary embodiment of a shaped element 100 according to the invention, which was preferably produced using an embodiment of the method according to the invention. It is preferred that the shaped element 100 from FIG. 3 is the shaped element 100 from FIG. 2 . The shaped element 100 is fed in from the left in the direction of the arrow 12 .

As shown, the shaped element 100 has areas 102 , 102 ′ with embossed shaped openings 14 and region 104 without embossed shaped openings 14 . Shown on the right-hand side, the auxiliary element 11' is removed, in particular pulled off, from the base element 10' in the direction of the arrow 108. The base element 10', which is continued in the direction of the arrow 106, thus has the base mold openings 15 on, while the removed auxiliary element 11 'has the auxiliary depressions 17. Thus shown, the base element 10' with base mold openings 15 and the auxiliary element 11' removed therefrom with auxiliary depressions 17 form the mold element 10'. The shaped element 100 shown thus corresponds to a first exemplary embodiment of a shaped element according to the invention, for example a shaped element with a partially removed auxiliary element 11'. The molded element 100' also shown corresponds to a second exemplary embodiment of a molded element to be produced, for example a molded element with a connected auxiliary element 11. The molded element 100" also shown corresponds to a third exemplary embodiment of a molded element to be produced, for example a molded element with the auxiliary element 11' completely removed these different versions of the shaped element in particular to different states and/or areas of a shaped element to be produced according to the invention.

FIG. 4 shows a detail of area IV from FIG. 3. A side length a of the square or round base of the pyramid-shaped opening preferably has a dimension of a=200-400 μm. The side length a of the mold opening 14 preferably also corresponds to the side length of the base area of the base mold opening 15. The side length b of the base area of the auxiliary depression 17 preferably has a dimension of b=3-20 μm. The depth of the mold opening 14 is preferably t = 600 pm - 2,200 pm. The depth of the auxiliary depression 17 is in particular 1H=50-500 μm. The depth of the base mold opening 15 is preferably tβ=550-2150 μm or 550-1700 μm. The thickness of the composite element 13 is in particular d=800 μm−4 mm. The thickness dß of the base element is preferably 600 pm - 2 mm. The thickness of the auxiliary element dH is preferably 200 μm-2 mm.

The embodiment from Fig. 5 essentially corresponds to that from Fig. 2. In contrast to the embodiment from Fig. 2, the auxiliary element 11 in Fig. 6 has a high elasticity and/or a high embossing temperature, so that after the penetration of the elevations 22 into the auxiliary element 11, no auxiliary depressions 17 (see FIG. 2) remain in the auxiliary element 11, but the auxiliary element 11 preferably returns to its original shape. Accordingly, the mold openings 14 according to the exemplary embodiment from FIG Base mold openings 15.

The exemplary embodiment from FIG. 6 essentially also corresponds to the exemplary embodiment from FIG. 2. In contrast to the exemplary embodiment from FIG. 1, the auxiliary element 11 from FIG. The depressions 46 are designed, for example, in the shape of pyramids, cylinders or part circles. The indentations 46 are preferably distributed regularly on the first surface of the auxiliary element 11 . The indentations 46 are aligned in such a way that the tips of the elevations 22 penetrate into the indentations 46 during the embossing process and thus do not deform the auxiliary element 11 . Once again, a mold opening 14 corresponds to a base mold opening 15 in the exemplary embodiment from FIG.

Claims

patent claims

1. A method for producing a shaped element (100) for the production of microarrays, with the steps:

Providing a flat base element (10) having a first surface (16) and a second surface (24) opposite the first surface (16),

Providing a flat auxiliary element (11) on the second surface (24),

penetrating the base element (10) starting from the first surface (40) to form mold openings (14), and reversibly or non-reversibly penetrating the auxiliary element (11) when penetrating the base element (10).

2. The method according to claim 1, characterized in that the auxiliary element (11) is connected to the base element, in particular detachably, it being preferred that the auxiliary element is adhesively connected to the base element (10).

3. The method according to claim 1 or 2, characterized in that the provision of the base element and the provision of the auxiliary element (11) by providing a, the base element (10) and the auxiliary element (11) having, composite element (13), preferably one Film composite, takes place.

4. The method according to any one of claims 1 to 3, characterized in that the penetration is carried out by embossing, in particular hot embossing, the embossing with an embossing tool having at least one, preferably a large number of, complementary to at least some of the mold openings (14). /en Survey(s) (22). Method according to Claim 4, characterized in that the embossing takes place by means of an embossing roller (18) or an embossing die. Method according to one of Claims 1 to 5, characterized by cooling the base element (10) and preferably the auxiliary element (11) after penetration. Method according to one of Claims 1 to 6, characterized by removing, in particular pulling off, the auxiliary element (11) from the base element (10). Shaped element (100) for the production of microarrays, which was produced in particular by the method according to one of Claims 1 to 7, having a first surface (16) and a second surface (24) opposite the first surface (16) having a flat base element (10), a flat auxiliary element (11) arranged on the second surface (16), in particular connected to the second surface (24), and a plurality of, in particular embossed, mold openings (14) extending from the first surface (16) of the base member (10) to extend through the second surface of the base member (10). A mold element (100) according to claim 8 or a method according to any one of claims 1 to 7, characterized in that the mold openings (14) partially extend into the auxiliary element (11). Shaped element (100) according to Claim 8 or 9, characterized in that the auxiliary element (11) is connected to the base element (10), in particular detachably, it being preferred that the auxiliary element (11) is adhesive to the base element (10). connected is. Molded element (100) according to one of Claims 8 to 10 or method according to one of Claims 1 to 7, characterized in that the base element (10) and/or the auxiliary element (11) has TPU, PC, APET, PPC and/or PETG , in particular consists of it. Form element (100) according to any one of claims 8 to 11 or method according to any one of claims 1 to 7, characterized in that the base element

(10) and/or the auxiliary element (11) has a film, in particular consists of it, it being preferred that the base element has a thickness of 0.5 - 1.5 mm and/or the auxiliary element has a thickness of 0.1 - 2mm. Shaped element (100) according to one of Claims 8 to 12 or method according to one of Claims 1 to 7, characterized in that the shape openings (14) are cylindrical or conical, preferably with a round, triangular or quadrangular, particularly preferably square, cross section. Shaped element (100) according to any one of claims 8 to 13 or method according to any one of claims 1 to 7, characterized in that the auxiliary element

(11): has a higher hot forming temperature than the base element (10), and/or has a higher elasticity than the base element (10). Form element (100) according to any one of claims 8 to 14 or method according to any one of claims 1 to 7, characterized in that the mold openings (14) on the first surface have a cross-sectional area of 0.04 mm ² - 0.16 mm ² , in particular of 0.04 mm ² - 0.08 mm ² . Shaped element (100) according to one of Claims 8 to 15 or method according to one of Claims 1 to 7, characterized in that the shape openings have a depth of 600 μm to 2200 μm, in particular from 600 μm to 1000 μm.

16 Shaped element (100) according to one of Claims 8 to 16 or method according to one of Claims 1 to 7, characterized in that the base element (10) has a thickness of 500 μm to 1.5 mm and/or the auxiliary element (11) has a thickness from 100 pm to 2 mm. Shaped element (100) according to one of Claims 8 to 17 or method according to one of Claims 1 to 7, characterized in that the shaped openings (14) on the second surface and/or on one surface of the auxiliary element (11) have a cross-sectional area of <1200 pm ² , in particular <100 pm ² .

17