CZ20003328A3 - A method of making a cold flow polysiloxane adhesive adhesive layer and its use - Google Patents

Abstract

In the method of making a layer of polysiloxane adhesive glue with reduced cold flow by applying and drying a single-component solution of polysiloxane adhesive glue on a suitable flat substrate, a complex of a metal ion from the group of calcium, magnesium, zinc, aluminum, titanium, zirconium or hafnium with a low-molecular complexing agent is added to the applied organic solution of the glue. The metal ion from the bond to the complexing agent is released only under the conditions of heating and/or drying of the glue solution. It is used for a medical plaster, which contains in its layered structure at least one layer of glue produced by the above-mentioned method.

Description

The present invention relates to silicone polymer-based crosslinking agents.

BACKGROUND OF THE INVENTION

These adhesive adhesive formulations, among other application possibilities, are of particular use in the manufacture of medical patches. Among medical patches, the newly crosslinked silicone adhesive adhesives are particularly suitable for the manufacture of medical patches containing the active ingredient, transdermal therapeutic systems (TTS).

The crosslinking agents described herein are applied in solvent application and drying of silicone adhesive adhesive formulations. Only under these conditions will the agents develop their cross-linking effect, which leads to the formation of a three-dimensional cross-linked polymer structure. Emerging layer of adhesive glue that ^- lose their ability to creep, so-called cold flow. Cold flow is an undesirable phenomenon, since the two surfaces bonded by an adhesive layer may, upon occurrence, already move under the influence of gravity, so that they no longer provide the connection of these surfaces in a precise position.

In the case of TTS, this is particularly true of sticking the system to the site of application in humans or animals. Furthermore, when a cold flow in the silicone adhesive layer is present, undesirable deformation or displacement within the system can already occur during the storage of the TTS due to weight, as well as the cohesive and adhesive forces.

SUMMARY OF THE INVENTION

Surprisingly, it has now been found that crosslinking agents, which are used to crosslink polyacrylate-based adhesive adhesives, despite the fundamentally different chemistry of silicone polymers, can be successfully used in them. Metallorganic complexes of certain metal cations have proven to be particularly effective. Among these, preferably used according to the invention, metal complexes such as aluminum, titanium, zirconium or ^- zinc. Acetylacetone is particularly suitable as an organic complexing agent for medical use. The crosslinking agents are added to the silicone adhesive adhesive solution only after the solvents or solvents have been removed. The stabilizing additives by drying exert their effect on cross-linking.

Adhesive adhesives based on silicone polymers are of particular importance for medical applications. This is based on their excellent skin tolerance in terms of inducing skin irritation (irritation) and inducing immunological reactions (sensitization, allergy). On the other hand, silicone adhesive adhesives on human skin have proven to be reliable and long-lasting, up to several days adhesive products. The water-repellent character also plays a role.

In the TTS field, silicone adhesive adhesives are characterized by their high chemical compatibility with pharmaceutical active and excipients, which promotes the chemical stability and shelf life of the products on this basis. Furthermore, the extremely high permeability (diffusibility) of the silicone polymers, which facilitates the dosing of the active and auxiliary substances contained, plays a special role.

In addition to these benefits, the marketed silicone adhesive for medical applications (eg the Bio-PSA Q7 product series from the Dow Corning Company) has a serious deficiency in theological properties. These are polysiloxane-based polymers that exhibit no, or only microscopic, limited cross-linking. They have essentially fibrous, little or no branching structure. It is desirable that the products can even be dissolved in organic solvents such as short-chain alkanes (heptane, gasoline) or ethyl acetate and subjected to solvent treatment.

Furthermore, these prior art polymers are single component polymer solutions. One-component means that the polymers contained in the solution are not intended for the reaction of the two components as understood for the resin and the hardener for further processing. On the other hand, a single component does not mean that there are no more types of polysiloxane polymers in solution, possibly even mixed with chemically different polymers (eg polyacrylates).

The processes described below for the treatment of one-component solutions of polysiloxane adhesive adhesives should not be confused with those processes and catalysts described in a multilateral manner for two-component silicone adhesives. Such systems contain at least two different types of polysiloxanes, such as those of the polysiloxanes. · Which, in the course of further processing, are intended to react to the three-dimensional network structure of the polymer in terms of resin and hardener.

The term polysiloxane also encompasses blended polymers of polysiloxanes in which chemically different regions, such as polyethylene oxide, polypropylene oxide, polyvinylpyrrolidone or polyacrylate and polymethacrylate, are embedded or set in the polymer chain.

In the field of manufacturing TTS, the processing of polysiloxane adhesive adhesive solutions involves smoothing and drying to thin, adhesive adhesive polymer films. In the processed state, the lack of three-dimensional crosslinking appears to be a drawback, since the fibrous polymer chains retain, albeit an extremely slow flowability. This is referred to in the technical language as a cold flow, since it already occurs at room temperature. The forces that drive such creep are:

1. weight,

2. any mechanical forces which may have exerted a bearing on the product during manufacture or storage,

3. adhesion forces between adhesive polymer and coated surfaces (contraction and stratification result),

4. cohesive forces in the polymer itself (contraction).

Cold flow practically always has disadvantageous effects during TTS storage, which can typically be two years or more. In this way, for example, the products may stick together with their packaging. The phenomenon also becomes undesirable after application to human or animal skin, supported mainly by heat of body temperature. If worn for several hours or more, TTS may slip off the skin due to proper creep. Silicone adhesive adhesives with slow creep can spread across the skin over the originally applied surface. This, after removal of the system, often leads to residues along the peripheral zone of the system. These residues are considered very disturbing by the user.

The cold-flow problem of silicone adhesive adhesives is known. US 5,232,706 discloses a large number of means against it. Very different fillers and additives are mentioned, but none of them is described as crosslinking agent. Transverse cross-linking reactions are even explicitly described as problematic resp. impossible due to the high temperatures required or the lack of biocompatibility of reagents (paragraph 5, lines 3-10). Instead, a large number of other cohesive enhancers are described.

Since these means do not always solve the problem in practice, it was an object of the invention to provide novel and effective methods for cold flow suppression for silicone adhesive adhesives. Surprisingly, this object was achieved by the addition of agents which are used to suppress the cold flux of a completely different class of substances between adhesive polymers, the polyacrylates. Such transferability was not expected because polysiloxanes, as the backbone of silicone polymers, are of a completely different chemical nature to polyacrylates built on pure hydrocarbon chemistry.

For polyacrylate adhesives containing polymer-bound free carboxyl or hydroxyl groups, it is known in the art to achieve three-dimensional crosslinking of polymer chains by the addition of polyvalent ions such as calcium, magnesium or zinc, in particular aluminum and Group 4 elements, titanium , zirconium and hafnium. Aluminum comes only as a trivalent ion, for the elements of the fourth group, a stable oxidation degree of +4 is used.

In this way, it becomes possible to convert the accumulation of fibrous polymer chains only after drying out of solution into an ineffective, three-dimensional structure. In order to use metal ions mostly in organic solvents, on the one hand, and on the other hand to premature crosslinking reaction, organic, low molecular complexing agents are first bound to the metal ions. Among these complexing agents, acetylacetone occupies a special position in the medical field because it is relatively toxicologically problem-free and, in addition, can be easily removed from the product during drying processes. Acetylacetone is a vinylog of acid in its chemical enol form and forms complexes with the metal ions, corresponding to the acetylacetonates. These complexes have their own chemical nature with particular stability and cannot be compared to conventional salts of organic acids and the metals concerned. Aluminum and titanyl acetylacetonate are used to crosslink polyacrylate adhesive adhesives during drying from organic solutions. Crosslinking results in the transition of metal ions from the complexing agent to the functional groups of the acrylate polymers, whereby multiple functional groups on different polymer chains are linked together.

Surprisingly, aluminum- and titanyl-acetylacetonates, a very frequently used crosslinking agent in polyacrylates, have been found to have phenomenologically practically the same effect on polysiloxanes, in spite of their completely different chemistry for polysiloxanes: creep ability silicone adhesive adhesives are clearly reduced. The characteristic of this change in polysiloxanes is that which is so similar in polyacrylates that one can start from a three-dimensional cross-linking by an unknown mechanism.

DETAILED DESCRIPTION OF THE INVENTION

The new cross-linking method has been tested on two very important groups of silicone adhesive adhesives for medical use. It is a polydimethylsiloxane based adhesive on the one hand in an amine-incompatible form and on the other in an amine-compatible form. The amine-incompatible form is characterized in that the remainder of the silanol groups (hydroxyl groups bonded to silicon) remain in the polymer during polymerization. This is a standard type capable of unwanted reaction with primary, secondary or tertiary amino groups via silanol groups. Since many pharmaceutically active substances contain amino groups, amine-compatible types are available specifically for use with TTS. They are so-called ehd-ending: the silanol groups are inactivated by suitable agents, for example by attachment of a trimethylsilyl group. A polyacrylate-based adhesive adhesive having a small proportion of carboxyl groups was used as a comparison. The three-dimensional crosslinkability of such acrylate crosslinkers discussed herein is generally known in the art.

The following formulations were examined:

Crosslinker: aluminum acetylacetonate [wt% Al ³⁺ ] - - 0.01 0,025 0.05 Durotak 387-2051 Polyacrylate Adhesive A11 A12 A13 A14 Silicone adhesive Bio-PSA Q7-4602 S31 - - S32

Crosslinker: titanylacetylacetonate [wt% Ti ⁴⁺ ] - 0.05 0.1 0.2 Silicone adhesive Bio-PSA Q7-4602 S11 S12 S13 S14 Silicone adhesive Bio-PSA Q7-4301 S21 S22 S23 S24

Crosslinker concentration data refer to the dried adhesive mass.

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Bio-PSA Q7-4602, manufactured by Dow Corning, is an amine-incompatible silicone adhesive adhesive solution in ethyl acetate. Produt 4301 differs from this by amine compatibility. The solvent here is heptane. Durotak 387-2051, manufactured by National Starch, is a solution of polyacrylate adhesive in a mixture of ethyl acetate and heptane without the addition of a crosslinker.

The preparation of the adhesive compositions was carried out by adding an appropriate amount of a 2% solution of titanyl acetylacetonate in ethanol and ethanol, respectively. Of a 4% solution of aluminum acetylacetonate in ethyl acetate to the adhesive solution, followed by mixing.

The viscous adhesive solutions were applied in a thin layer on a film of polyethylene terephthalate (PET) (Hostaphan RN 100; Hoechst) using a film coating frame and dried at 80 ° C for 10 minutes in a ventilated oven. For all formulations, the thickness was adjusted so that the basis weight of the dried film was 60 g / m ² ± 5%. This corresponds to 6 mg / cm ² and a layer thickness of about 60 µm.

The application to PET results in a hardly releasable bond in all adhesive adhesives tested herein. Alternatively, adhesive film films were otherwise prepared under otherwise identical conditions with a carrier film repellent treated by the application of a fluorinated polymer (ScotchPak 1022, 3M). Under these conditions, the adhesive adhesive film may be slightly mechanically separated from the carrier film and further processed.

The effects of cross-linking agent addition were investigated in two layers of the adhesive adhesive made by two apparatuses:

The adhesion or adhesion of an adhesive adhesive describes its ability to anchor itself spontaneously on the surface. This spontaneous bonding occurring even after the shortest contact time without a noticeable contact force depends to a large extent on the flowability of the adhesive. The high creep capability allows rapid contact formation involving the microstructure of the substrate surface over the entire surface area, i.e. high adhesion. It is not the only one, but it is the most important adhesion determining property.

The Rolling Bales method is suitable as a measurement procedure for determining adhesion. In this case, a ball of suitable material is imparted to the initial velocity and then allowed to roll over the adhesive bonded in a thin layer on a planar support. The section after which the ball is stopped by the adhesive-dependent braking effect of the adhesive glue can be evaluated, or the time that the ball takes to cross a certain section without stopping within that section is measured.

-7 ·· .. ···· · f ················

The results of the last variant are often not misrepresented by the misalignment of the ball.

The ball run time was measured on an inclined plane (1 cm glass plate) with an adjustable tilt angle, over a 59 cm section. In this case, the ball was allowed to roll first over a defined 17.5 cm section on a film of adhesive which, on its side, was fixed to the PET film. Measurement of run time was performed between two infrared light sensors using a connected electronic timer with an indication of 1/1000 second. At an angle of inclination of 35 ° using a 18 mm diameter stainless steel ball bearing, the averaged values from 6 experiments were found in Figure 1 for the indicated run times.

For all three types of adhesives, measurements with increasing crosslinking agent concentration showed a correlated decrease in run time. Thus, with silicone adhesives, with the addition of a crosslinking agent, the adhesion decreases in a way that would be expected from the theory for crosslinking and thereby reducing the creep ability of the polymer, and as is also seen in the known crosslinking polyacrylate example (A11-A14). This is particularly true for the amine-compatible silicone adhesive (S11-S14), but clearly also for the amine-compatible variant (S21-S24).

Furthermore, it has been found that crosslinking provides particularly pronounced effects in the concentration range up to 0.05% and also between 0.05% and 0.1% aluminum. The application of aluminum-based crosslinking agent (S31-S32) instead of titanium (S11-S12) has been shown to be equally effective with silicone adhesive agents (Fig. 2).

The shear strength of the produced adhesive adhesive films was further examined. In the non-crosslinked, fibrous, creep-capable polymers, a slow film flow occurs after the shear force is applied. If the film is not sheared quickly and thus torn off, a nearly constant flow rate can be observed at a constant shear force. On the other hand, in the three-dimensional cross-linking of the polymer chains, the viscosity fraction is almost lost and only elastic deformation can still occur. With increasing shear force, the polymer structure is finally ruptured and the entire film is finally ruptured.

Thus, for crosslinked and non-crosslinked adhesive film films, very different characteristics in relation to the shear behavior result. In order to investigate this behavior, 12 mm diameter round moldings were taken from the produced films. These round film pieces were fixed between 2 strips of PET-foil (Hostaphan RN 100; Hoechst) according to Fig. 3. After clamping the formulation into a commercially available

tensile testing machine (universal testing machine 81803 from Frank, Weinheim), the shearing force was recorded after the time needed to achieve a constant shear rate of 2.5 mm / min. The obtained force / time diagrams for just 6 individual measurements are shown in Figures 4 to 7.

For the reference polyacrylate, a constant shear force is established after a short time in the non-crosslinked state, which must be exerted to maintain a predetermined constant shear rate: the polymer flows (FIG. 4). In contrast, in the crosslinked network, the shear force increases rapidly under elastic deformation until ultimately the elastic film extensibility is exceeded and the film tears, whereby the shear force rapidly drops to zero (Fig. 5).

The silicone film without the addition of a crosslinking agent exhibits a behavior very similar to the non-crosslinked polyacrylate film in that, at a certain shear force, a predetermined shear rate is also maintained at a certain shear force. The forces required are only at a higher level, and the energy wall to move from rest to creep motion is more clearly expressed than for non-crosslinked polyacrylate (Fig. 6). This could be related to different chain lengths and different intermolecular interaction forces of both polymer types.

However, the characteristic change in the course of the silicone film containing the crosslinking agent is critical. Similarly to the cross-linked polyacrylate, a shear force is provided under elastic deformation, which eventually drops to zero when the film breaks (Fig. 7). It can be seen that the silicone adhesive polymer film is no longer able to flow after the addition of titanyl acetylacetonate as crosslinking agent.

Claims (11)

A method of making a cold flow reduced polysiloxane adhesive layer by applying and drying a one component polysiloxane adhesive adhesive solution on a suitable flat substrate, characterized in that a metal ion complex of the group of calcium, magnesium, zinc, aluminum, titanium is added to the applied organic adhesive solution. , zirconium or hafnium with a low molecular weight complexing agent, the metal ion being released from the complexing agent only under the conditions of heating and / or drying the adhesive solution. Method according to claim 1, characterized in that the metal addition is at least 0.005 wt. %, based on the dried adhesive mass. Method according to claim 1, characterized in that the metal is used in an amount of from 0.005 wt. % up to 0.5 wt. %, based on the dried adhesive mass. Process according to one or more of the preceding claims, characterized in that the organic complexing agent is substantially removed during drying. Method according to one or more of the preceding claims, characterized in that:. drying is carried out at a temperature between 20 ° C and 120 ° C. . Method according to one or more of the preceding claims, characterized in that the basis weight of the dried film is between 10 g / m ² and 300 g / m ² . Process according to one or more of the preceding claims, characterized in that the organic complexing agent is acetylacetone or that acetylacetone is involved in the formation of the complex. Method according to one or more of the preceding claims, characterized in that the metal involved in the complex is aluminum or titanium. Method according to one or more of the preceding claims, characterized in that the polysiloxane is essentially polydimethylsiloxane. 10. The method of claim 9, wherein the free silanol groups present in the polydimethylsiloxane are chemically inactivated by suitable end coatings and thereby become amine resistant. Medical patch characterized in that there is at least one layer of polysiloxane adhesive polymer in its layered structure which has been produced according to any one of the preceding claims.