FR3142689A1 - Process for thermoforming microreliefs on low Tg polymer sheet - Google Patents

Abstract

A method of thermoforming a sheet (2) made of a polymeric material having a glass transition temperature Tg less than or equal to 120 °C, the method comprising heating the sheet to a heating temperature greater than Tg and application on one side of the sheet of a gas pressure of between 2 MPa and 12 MPa to deform the sheet against a mold (7) comprising a mold relief (9) having a height of between 100 µm and 1000 µm. Figure for abstract: Fig. 8

Description

Process for thermoforming microreliefs on low Tg polymer sheet

The present invention relates to the manufacture of a sheet provided with micro-reliefs and made of a polymer material with a low glass transition temperature, preferably biosourced,

Multiple applications are known which use substrates on the surface of which microreliefs, for example microtips or microlenses, with a height generally between 500 and 1000 µm and having an aspect ratio greater than 1.

For example, devices are known which comprise such substrates, and which are intended to be brought into contact with the skin to introduce a substance into the body. Such microtips penetrate the epidermis without causing pain since they do not reach the innervated areas due to their low height. For example, it is known to increase the permeability of the skin by means of microtips, by generating pores in the superficial areas of the epidermis, which facilitates the delivery of the substance to these areas. The substance can either be applied to the microtips before perforation or be applied after perforation by the micropores by simple diffusion or by iontophoresis, ie . by means of an electric field.

The manufacturing techniques and materials known to make microreliefs are numerous as described in the article “ A Comprehensive Review of Microneedles : Types, Materials, Processes , Characterizations and Applications ”, Faisal Khaled Aldawood, Abhay Andar and Salil Desai, Polymers 2021, 13, 2815, doi:10.3390/polym13162815. For example, it is known to produce arrays of microreliefs of varied shapes by photolithography or by micromachining in a substrate made of a metal or a semiconductor. However, these techniques are expensive and restrictive to implement on an industrial scale.

Microtips made of polymeric materials such as poly-(lactic acid), poly-(glycolic acid), poly-(lactic-co-glycolic acid), known by the acronyms PLA, PGA and PLGA respectively, exhibit excellent biocompatibility and low toxicity which makes them particularly well suited to medical application. To mass manufacture such microtips on an industrial scale, the most suitable known techniques are injection molding of the molten polymeric material and stamping of a sheet made of the polymeric material, as described in “ A Review on Microfabrication of Thermoplastic Polymer-Based Microneedle Arrays ”, Herwig Juster, Bart van der Aar, Hans de Brouwer, Polym. Eng. Sci., 59:877–890, 2019, doi:10.1002/pen.25078.

To manufacture molds suitable for injection molding, the LIGA method, acronym in German for “ Lithographie, Galvanoformung and Abformung ” is known. It involves the manufacture of a blank comprising a relief network in the shape of a point by a lithography method by laser A metal mold is then produced by replicating the blank by applying a metal layer to the raised surface of the blank. The mold is separated by shrinkage from the blank during replication, then a. Polymeric sheet is stamped on the mold. However, only simple shapes can be obtained by the LIGA method.

Other known mold manufacturing methods are micro-milling, micro-grinding, electroerosion machining and laser percussion drilling which make it possible to produce molds of complex shape, in particular with form factors greater than 5.

Since known injection molding and stamping techniques use molds with hollow reliefs, the quality of the microtips obtained depends mainly on the ability of the polymeric material to flow to fill the reliefs. This ability is conditioned by many factors, including the temperature of the polymeric material, the temperature of the mold, the temperature of the stamping punch and the duration of injection or stamping where applicable. However, a small variation in one of these parameters can significantly impact the quality of the microtips obtained.

There is therefore a need for a new process making it possible to produce in industrial quantities a sheet equipped with microreliefs, in particular microtips, making it possible in particular to overcome the disadvantages of the prior art.

The invention proposes a process for thermoforming a sheet made of a polymeric material having a glass transition temperature T _g less than or equal to 120°C, the process comprising heating the sheet to a heating temperature greater than T _g and applying to one side of the sheet a gas pressure of between 2 MPa and 12 MPa to deform the sheet against a mold comprising a mold relief having a height of between 100 µm and 1000 µm.

The thermoforming process according to the invention, by applying high pressure to a sheet whose deformability is optimal above the glass transition temperature, makes it possible to obtain at least one microrelief which has a substantially complementary shape. of the mold shape.

In particular, the method according to the invention has more particularly the advantage compared to the methods of the prior art, of making it possible to control the thickness of the deformed sheet at the bottom or at the top of the mold relief, that said mold relief either hollow or protruding respectively.

The glass transition temperature can be determined by differential scanning calorimetry, for example using the STA449 reference calorimeter sold by the company Netzsch® and the associated measurement data processing software.

Preferably, the polymeric material is biosourced. A “biosourced” material is obtained from an organic raw material, of animal or, preferably, plant origin, treated by a process other than a petrochemical process.

Preferably, the polymeric material is biocompatible. A “biocompatible” material is tolerated by a human or animal organism without its interaction with the biological tissues of the organism causing pathology. The polymeric material may also be bioresorbable.

Preferably, the polymeric material is chosen from poly-(lactic acid), poly-(glycolic acid), poly-(lactic-co-glycolic acid) and mixtures thereof.

Preferably, the polymeric material is poly-(lactic acid). Poly-(lactic acid) can be biosourced, for example obtained from corn and/or molasses, in particular from sugar cane.

The polymeric material may be amorphous.

According to a variant, the polymeric material may be semi-crystalline, the heating temperature being lower than the melting temperature of the polymeric material, preferably between 60°C and 120°C . The crystallization and melting temperature of the polymeric material can be determined by differential scanning calorimetry, for example by means of the device described above for determining the glass transition temperature.

A semi-crystalline polymer material facilitates the formation of at least one necking zone in the sheet during its shaping. The modulus of elasticity and/or the breaking stress of the polymeric material are thus increased locally within the necking zone(s), which improves the mechanical and/or optical properties of the microreliefs. A necking zone has, for example, an elongation greater than 30%.

The glass transition temperature may be above 60°C and/or below 100°C.

The sheet may have a length and/or width greater than 10 mm, preferably greater than 50 mm, preferably greater than 100 mm, or even greater than 200 mm, better still greater than 300 mm. For example, it has a length of 380 mm and a width of 320 mm. A sheet of such dimensions thus allows the production of several thousand microreliefs and is therefore perfectly suited to industrial mass production.

Preferably, the sheet has a thickness less than or equal to 250 µm, preferably less than or equal to 150 µm, preferably less than or equal to 100 µm, preferably less than or equal to 75 µm and/or greater than or equal to 20 µm , in particular 50 µm.

Heating is preferably carried out before the application of gas pressure.

In particular, the heating can be carried out in a heating unit and the gas pressure is applied in a forming unit remote from the heating unit, the method comprising a transfer step between the heating unit and the unit formatting.

The duration between the end of heating and the start of application of pressure is preferably less than 5 s in order to prevent the sheet from cooling.

The sheet is preferably heated by at least one radiative heating element, emitting for example in the infrared. The method may include measuring at least one temperature of the sheet, for example by means of a thermal camera, and controlling the temperature and/or the heat flow emitted by the heating element from the measurement. of the leaf temperature. Thus, the temperature of the sheet can be regulated to a set temperature.

Preferably, the sheet is heated by several radiative heating elements, in particular arranged on either side of the opposite faces of the sheet. The heating elements are preferably arranged in such a way as to completely heat the sheet, and preferably so that the temperature of the sheet is homogeneous, that is to say that it varies at most 4 ° C between two zones of leaf. They are for example arranged in a grid superimposed on the sheet. The heating elements can be controlled independently of each other to each emit a suitable heat flow towards a portion of the sheet. In particular, the method may include the measurement of at least one temperature per zone of the sheet covered by a heating element and the control of the temperature and/or the heat flow emitted by the corresponding heating element from the measurement of the temperature. Thus, the temperature of each zone of the sheet can be regulated independently at the same set temperature.

The temperature of the sheet reached during heating is chosen as a function of the temperature dependence of the mechanical properties, in particular the modulus of elasticity, of the polymeric material, so that the sheet can be deformed during the placing step. uniformly shaped.

Preferably, the heating temperature of the sheet is less than or equal to T _g + 30 °C, preferably between T _g + 15 °C and T _g + 20 °C. It can be measured on the sheet with a thermal camera.

The heating time of the sheet can be between 5 s and 30 s.

The application of gas pressure preferably includes a gas blowing phase to increase the gas pressure until the nominal gas pressure is reached.

The gas can be chosen from a neutral gas, air and their mixtures. Preferably, the gas is air.

Preferably, the nominal gas pressure is between 2 MPa and 10 MPa.

Preferably, the duration of the blowing phase is preferably less than or equal to 5.0 s, preferably less than or equal to 1.0 s, for example 0.5 s, in order to limit the cooling of the sheet and to limit, where applicable, the friction of the sheet against the mold which may occur during the blowing phase and which may influence the quality of the micro-relief(s) formed on the sheet.

The method preferably further comprises a phase of maintaining the nominal gas pressure, following the gas blowing phase, in order to press the sheet against the mold and form at least one micro-relief against the mold relief. Preferably, the nominal gas pressure is applied for a holding time of less than 20 s, preferably between 1 s and 6 s.

The gas temperature is between T _g - 10 °C and T _g + 140 °C, during the blowing phase and/or during the phase of maintaining the nominal gas pressure. Preferably, it is between T _g + 10 ° C and T _g + 40 ° C, so as to ensure that the temperature of the sheet is higher than the glass transition temperature of the polymeric material during blowing and/or placing. in the shape of the leaf respectively.

The temperature of the mold is preferably between T _g - 35 °C and T _g + 70 °C, preferably between T _g - 10 °C and T _g + 10 °C. Preferably, it is less than T _g , in order to avoid creep of the polymeric material against the mold during the phase of maintaining the nominal gas pressure.

The mold relief can be recessed or protruding.

The mold relief may have the shape of a portion of a sphere, in particular a hemispherical shape, so as to form a micro-relief in the sheet in the form of a lens.

As a variant, in particular in order to form a microrelief in the form of a microtip, the mold relief preferably has an aspect ratio greater than 1, preferably greater than 2, or even greater than 5, better still greater than 10.

The “aspect ratio” of a mold relief is the ratio of the height of the mold relief to the width of the mold relief.

The “height” of the mold relief is equal to the depth of said mold relief when this mold relief is hollow. The height of the relief can be less than or equal to 900 µm, or even less than or equal to 800 µm.

The “width” of a mold relief corresponds, in the transverse section located halfway up said relief, to the diameter of the smallest circle circumscribed by said relief in said transverse section. The width of the mold relief may be less than or equal to 1 mm, preferably less than or equal to 500 µm, or even less than or equal to 300 µm, or even less than 200 µm.

The mold relief may have a shape chosen from a cone, a truncated cone, in particular beveled, a cylinder of revolution, in particular beveled, a pointed pencil shape comprising a cylinder of revolution surmounted by a point, in particular conical.

The mold relief may have a point, when it is protruding, or a bottom, when it is recessed, having a point radius of between 1 and 10 µm.

Preferably, the mold relief is projecting and has at its base a hole passing right through the bottom of the mold towards a gas evacuation vent, the hole preferably having a diameter less than 50 µm.

Alternatively, the mold relief can be hollow and have a bottom opening into a cavity extending the mold relief through a hole. In this way, a gas pocket trapped between the sheet and the mold can fill the cavity, which prevents the pressure induced by this pocket from preventing the polymeric material from creeping against the bottom of the mold relief. Preferably, the hole has a diameter less than 100 µm to prevent creep of the polymeric material into the hole.

The mold preferably comprises a plurality of mold reliefs. It may include recessed mold reliefs and projecting mold reliefs. It may include mold reliefs of a first shape and reliefs of a second shape.

The mold reliefs can be arranged periodically in at least one, preferably two orthogonal directions on the surface of the mold, so as to form a network of microreliefs on the face of the shaped sheet.

The mold may include at least one recessed relief, or even only recessed mold reliefs.

The mold may include vents, for example crossing it from side to side, in order to purge air pockets forming during the application of the nominal gas pressure, between the sheet and the mold.

In a particular embodiment of the invention, the sheet is made of poly-(lactic acid) and has a thickness of between 40 µm and 200 µm, preferably 50 µm. It is heated to a temperature above 60°C, preferably between 70°C and 110°C. Preferably, the mold temperature is between 25°C and 130°C, preferably between 50°C and 70°C, and preferably less than 60°C. Preferably, the temperature of the gas, preferably the air, during blowing and maintaining pressure is between 50°C and 200°C, preferably between 70°C and 100°C.

The invention finally relates to a device comprising a thermoformed sheet obtained by the method according to the invention, the device being chosen from a transdermal patch or a matrix of microlenses.

Other characteristics and advantages of the invention will appear further on reading the detailed description, presented for illustrative and non-limiting purposes, which follows and the appended drawing in which:

schematically illustrates an example of implementation of the invention,

is a cutaway of an enlargement of a schematic transverse section of a mold according to an example of implementation of the method according to the invention,

represents a perspective view of a mold comprising mold reliefs of different shapes,

illustrates different shapes of mold reliefs

is a photograph of a mold for an example of implementation of the method according to the invention,

a) to c) are photographs of different microrelief patterns formed by the method according to the invention,

, , And are photographs of microreliefs obtained from the process according to the invention as a function of different process parameters, and

And are graphs representing different kinetics of rise and maintenance at the nominal pressure followed by depressurization.

The proportions of the different elements represented in the figures have not necessarily been respected, for the sake of clarity of the drawing.

We have illustrated schematically on the an example of implementation of the method according to the invention.

In a heating unit 1 shown in the a), a sheet 2 of a polymeric material having a glass transition temperature Tg less than or equal to 120 ° C is heated by means of radiative heating elements 3, each radiative element emitting a heat flow towards a zone 4 of the sheet. The temperature of each zone of the sheet is measured by means of a thermal probe 5 and the temperature of each radiative element can be modified so that the temperature in the sheet is homogeneous, that is to say that the temperatures of the different zones are substantially equal.

For example, for a sheet with a width of 320 mm and a length of 380 mm, heating can be carried out using an array of 6x7 heating elements.

The sheet, once heated, is transferred to a shaping unit 6, as illustrated in the b).

In the example shown, the sheets are heated one after the other in the heating unit then transferred to the shaping unit. According to a variant, a film can be unrolled then heated while moving in the heating unit before being transferred to the shaping unit.

In the shaping unit 6, the sheet 2 is placed between a mold 7 and a bell 8 by means of positioning pins 18, visible on the .

The mold 7 includes a plurality of mold reliefs 9 which project from the bottom 10 of the mold.

The bell 8 is then hermetically closed on the mold, as illustrated in the c), such that the mold 8 and the bell 9 pinch the periphery 11 of the sheet in order to ensure airtightness.

Air at a temperature of at least 50°C is then blown by means of an air compressor 12 into the bell on the sheet, as indicated by the arrow F in order to impose on the face 13 of the sheet, opposite the mold, a nominal air pressure greater than 2 MPa. The sheet heated by the heating unit and maintained above its glass transition temperature by the flow of hot air is thus deformed against the mold 7 and in particular against the mold reliefs 9. The mold may include vents which pass through the mold from side to side in its thickness, in order to avoid the formation of air pockets preventing the sheet from being pressed against the mold.

After returning to atmospheric pressure and unmolding, as illustrated in the d), the thermoformed sheet has micro-reliefs 15 projecting from the face opposite to the face 16 which was in contact with the mold.

As illustrated in the , the projecting mold reliefs 9 may have at their base a hole 16 passing right through the bottom 10 of the mold to a gas evacuation vent 17. Preferably, the diameter of the hole is less than 50 µm to prevent the polymeric material from flowing into the hole.

There represents a mold 7 comprising a plurality of projecting mold reliefs of different shapes. Zones A to D spaced from each other can thus each include reliefs of the same shape, for example arranged periodically in a network, with for example different spacings between the mold reliefs.

For example, zones A, B and C, and D may include mold reliefs in the shape of a pointed pencil 20, that is to say comprising a cylindrical portion of revolution 21 surmounted by a conical point 22, in the shape of truncated cylinder of revolution 23, or of conical shape 24 as illustrated respectively on the .

Examples

Thermoforming tests of a 50 µm thick sheet made of poly-(L-lactic acid), known by the acronym PLLA, having a glass transition temperature of 63 °C and a crystallization temperature of 92 °C were carried out using a mold as illustrated in Figures 3 and 5. The glass transition temperature and the crystallization temperature were measured by differential scanning calorimetry.

PLLA is a biosourced, biocompatible and biodegradable poly-(lactic acid). It is also semi-crystalline.

The mold used included areas presenting different mold reliefs, the shapes and dimensions of which are summarized in the following table 1:

Ref Shape Base diameter (µm) Total height (µm) Height of the cylindrical base portion Height of the beveled or conical portion Aspect ratio (H/d) Pattern density A1 Sharp pencil 300 700 400 300 2.33 4x4 A2 5x5 A3 7x7 A4 500 200 7x7 B1 Beveled cylinder 300 700 600 100 7x7 B2 500 200 7x7 B3 400 300 4x4 B4 5x5 C1 7x7 C2 Cone 300 600 - - 2 7x7 C3 300 800 - - 2.67 7x7 C4 200 700 - - 3.5 7x7 D1 500 700 - - 1.4 7x7 D2 300 700 - - 2.33 4x4 D3 - - 5x5 D4 - - 7x7

As observed on the a) to c), microreliefs having substantially shapes close to a pointed pencil 20, a beveled cylinder 23 and a cone 24 respectively could thus be obtained by applying the essential parameters of the method according to the invention.

Specific examples were then produced and measurements carried out on a mold relief in the shape of a pointed pencil 20 with a height of 700 mm, the height of the cylindrical portion 21 being 400 µm and the height of the cone 22 being 300 µm, the diameter of the mold relief being 300 µm. The aspect ratio of the mold relief was therefore 2.33.

A mold relief having such a shape thus aims to form a micro-relief in the form of a micropoint or microneedle.

Different configurations for implementing the process were thus tested.

The following process parameters were tested:
- the heating duration Dc and the resulting temperature of the sheet at the end of heating Tc,
- the nominal duration of air blowing Ds,
- the temperature of the blown air Ts,
- the holding time Dm of the sheet under the nominal air pressure during shaping, and
- the nominal air pressure applied to the sheet during shaping P.

The influence of these different parameters was determined by measuring the height and width of the microrelief formed on the sheet and comparing it to the height and aspect ratio of the mold relief.

For all the tests carried out, microreliefs were obtained which have a microdot shape, substantially similar to the shape of the mold relief on which they were formed.

Table 2 summarizes the different test parameters as well as the measurement results.

Essay Fig DC
(s) Tc
(°C) Ds(s) Ts
(°C) Dm
(s) P
(MPa) H
(mm) L
(mm) H/L T38 7a) 20 75±3 0.5 70 3.5 2 595 394 1.51 T39 7b) 25 78.5±1.5 0.5 70 3.5 2 552 392 1.41 T36 7c) 20 75±3 0.5 70 3.5 4 570 407 1.40 T41 7d) 25 78.5±1.5 0.5 70 3.5 4 587 392 1.50 T42 8 25 78.5±1.5 0.5 100 3.5 4 584 392 1.49 T45 10a) 25 78.5±1.5 0.5 100 1.5 4 566 398 1.42 T44 10b) 25 78.5±1.5 0.5 100 5.5 4 587 383 1.54 T46 12a) 25 78.5±1.5 2 100 2 4 570 391 1.46 T47 12b) 25 78.5±1.5 4 100 0 4 540 365 1.48

As observed by comparing examples T38, T39, T36 and T42, it appears that a nominal pressure of 2 MPa (i.e. 20 bar) associated with a sheet temperature at the end of heating of 75°C makes it possible to manufacture a microneedle with a flared base. An increase in the nominal pressure to 40 bar associated with an increase in the sheet temperature to 78.5 °C makes it possible to obtain a microneedle which has a shape closer to the mold relief in the shape of a pointed pencil, with a cylindrical wall thin and substantially vertical surmounted by a substantially conical tip, as is illustrated on the d).

A comparison of examples T41 and T42 indicates that for the parameters of these tests, a variation of 30°C in the air blowing temperature has a limited effect on the height and more generally on the shape of the microrelief. This is also visible by comparing the d) with the .

A comparison of examples T42, T44 and T45 highlights the influence of the duration of maintenance at the nominal gas pressure during shaping. For this, the kinetics of rise and maintenance at the nominal pressure illustrated on the were implemented.

As observed by comparing Figures 10 a), 8 and 10 b), a holding time of 5.5 s according to test T44 at the nominal pressure appears most favorable to the formation of a microrelief having a shape the most porch of the mold relief.

A comparison of examples T42, T46 and T47 highlights the influence of the speed of rise to the nominal gas pressure during shaping. For this, the kinetics of rise and maintenance at the nominal pressure illustrated on the were implemented.

Comparison of these tests as well as observation of the shapes of the micro-reliefs in Figures 8, 12 a) and 12 b) shows that a rapid rise to the nominal pressure according to test T42 followed by a long holding time is more favorable to the formation of a high and slender micro-relief than a slow rise followed by a short holding time, as according to test T47. A slow rise to the nominal pressure seems to lead to significant friction of the sheet against the mold.

Claims (16)

A method of thermoforming a sheet (2) made of a polymeric material having a glass transition temperature T _g less than or equal to 120 °C, the process comprising heating the sheet to a heating temperature greater than T _g and applying to one side of the sheet a gas pressure of between 2 MPa and 12 MPa to deform the sheet against a mold (7) comprising a mold relief (9) having a height of between 100 µm and 1000 µm . Method according to claim 1, the polymeric material being biosourced. Method according to any one of claims 1 and 2, the polymeric material being bioresorbable. Process according to any one of the preceding claims, the polymeric material being chosen from poly-(lactic acid), poly-(glycolic acid), poly-(lactic-co-glycolic acid) and mixtures thereof. Process according to any one of the preceding claims, the polymeric material being semi-crystalline, the heating temperature being furthermore lower than the melting temperature of the polymeric material, preferably between 60°C and 120°C. Method according to any one of the preceding claims, the heating temperature being between T _g + 15 °C and T _g + 20 °C. Method according to any one of the preceding claims, comprising a gas blowing phase to increase the gas pressure until the nominal gas pressure is reached, the duration of the blowing phase being preferably less than or equal to 5, 0 s, preferably less than or equal to 1.0 s, for example 0.5 s. Method according to any one of the preceding claims, comprising a phase of maintaining the nominal gas pressure, following the phase of blowing the gas, preferably the nominal gas pressure being applied for a holding period of less than 20 s, preferably between 1 s and 6 s. Method according to any one of the preceding claims, the nominal gas pressure preferably being between 2 MPa and 10 MPa. Method according to any one of the preceding claims, the temperature of the mold being preferably between Tg - 35 °C and Tg + 70 °C, preferably between Tg - 10 °C and Tg + 10 °C, and preferably lower at Tg. Process according to any one of the preceding claims, the temperature of the gas being between T _g - 10°C and T _g + 140°C, preferably between T _g + 10°C and T _g + 40°C. Method according to any one of the preceding claims, the sheet having a thickness less than or equal to 250 µm, preferably less than or equal to 150 µm, preferably less than or equal to 100 µm, preferably less than or equal to 75 µm and/ or greater than or equal to 20 µm, in particular 50 µm. Method according to any one of the preceding claims, the mold relief having the shape of a portion of a sphere, in particular hemispherical. Method according to any one of the preceding claims, the mold relief having an aspect ratio greater than 1, preferably greater than 2, or even greater than 5, better still greater than 10 and/or having a shape chosen from a cone, a truncated cone, in particular beveled, a cylinder of revolution, in particular beveled, a pointed pencil shape. Method according to the preceding claim, the mold relief being projecting and having at its base a hole (16) passing right through the bottom (10) of the mold towards a gas evacuation vent (17), the hole having preferably a diameter less than 50 µm. Device comprising a thermoformed sheet obtained by the method according to any one of the preceding claims, the device being chosen from a transdermal patch or a microlens matrix