HK1069534B - Transdermal therapeutic system (tts) with fentanyl as active ingredient - Google Patents

Description

Transdermal Therapeutic System (TTS) containing fentanyl as active substance

The invention relates to a Transdermal Therapeutic System (TTS) containing the active substance fentanyl.

Fentanyl and fentanyl analog derivatives, for example: sufentanil (sulfontanyl), carfentanil (carfenntanyl), lofentanil (lofenntanyl) and alfentanil (Alfentanyl) are very effective analgesics. Their low dosage and their physicochemical properties such as n-octanol/water distribution coefficient, melting point and molecular weight enable them to be delivered transdermally in effective amounts, whereas their pharmacokinetic properties such as rapid metabolism and a narrower therapeutic index are desirable for transdermal delivery.

TTS, which is in fact fentanyl as the active substance, has been on the market for many years. This system is the so-called reservoir system (Reservoir system). By reservoir system is understood a transdermal therapeutic system which encapsulates a liquid or gel-like formulation containing an active substance in a sachet formed by an impermeable film and an active substance-permeable film. The impermeable film acts as a backing layer to avoid the exudation of the liquid or gel-like active substance preparation from the side of the capsular bag facing away from the skin. The permeable membrane acts to regulate the rate of release of the active substance from the capsular bag to the skin side. On this side, the membrane is additionally provided with an adhesive layer for fixing the entire transdermal therapeutic system to the skin.

In this particular case (TTS), fentanyl is dissolved in a mixed solution of ethanol and water. Further details of this system can be found in patent applications US 4,588,580 or DE 3526339, both of which are described in detail.

However, reservoir systems have a major disadvantage in that the capsules containing the active agent formulation leak (e.g. by simple mechanical damage, cutting or tearing, bursting of the seams, etc.) so that large areas of the skin come into contact with the active agent, as a result of which the dose is absorbed too far. Especially when fentanyl and fentanyl analogs are usedThis disadvantage can be fatal with derivatives, since overdosing can rapidly lead to respiratory depression and thus to fatal events. Many such lethal or moribund events have been described in Clinical pharmacopokinet.2000,38(1)，59-89。

it is an object of the present invention to provide a transdermal therapeutic system containing the active substance fentanyl and/or fentanyl analog derivatives which offers increased safety to the user against the absorption of unexpectedly high doses.

This object is achieved by providing a transdermal therapeutic system comprising: a back layer, an active material layer and a protective layer removed before use. The active material layer is composed of a polymer incorporating a plurality of liquid microreservoirs. Such microreservoirs contain the active substance.

It has been found that the active substance is contained in a liquid formulation of the active substance layer, which layer never leaks even when subjected to mechanical damage (cutting, tearing, abrasion, etc.). The user is thus not exposed to the risk of uncontrolled or accidental overdosing of the release by accidental or premature breakage of the active substance layer.

Purely by appearance, this transdermal therapeutic system does not differ from the second main type of TTS (matrix system).

In the TTS according to the invention, the internal active substance layer structure can only be detected under a microscope. The liquid microreservoirs are embedded (preferably self-adhering) in the active substance layer in the form of small droplets. (such droplets are of an approximately spherical configuration) transdermal therapeutic systems in which an active substance layer is built up in this way are referred to hereinafter as "microreservoir systems".

Such liquid microreservoirs have an average diameter of about 5 to 50 μm. However, they must be less than the thickness of the active material layer, otherwise the active material liquid will spill out. The size of the microreservoirs can be influenced by the selection of appropriate liquids and the adjustment of certain preparation parameters.

As with the matrix system, the microreservoir system of the present invention in its simplest form consists of a three-layer construction: a backing layer impermeable to the active substance, a self-adhesive layer containing microreservoirs and a protective layer which is removed before use. The system is shown in FIG. 1.

However, in some cases even microreservoir systems must limit the amount of active agent released by the transdermal therapeutic system over a certain period of time. This can be achieved by a membrane which adjoins the skin side of the active substance layer and which can additionally carry an adhesive layer for attachment to the skin. The skin side adhesive layer can be prepared by adding a limited amount of active substance, and after application of the microreservoir system, the active substance of the adhesive layer is released to the skin and thus to the living being in a manner which cannot be controlled by the membrane. The aim of this method is to shorten the time to reach a therapeutic amount of plasma (the so-called "lag-time"). The microreservoir system with membrane is shown in figure 2.

Suitable active substances include: derivatives of fentanyl and/or fentanyl analogs, preferably sufentanil, carfentanil, remifentanil and alfentanil are considered. Preferably, the active substance is in the form of the free base, which may also be used as a pharmaceutically acceptable salt or as a mixture of the free base and a pharmaceutically acceptable salt of the base. Examples of salts include hydrogen chloride, hydrogen bromide, sulfates, bisulfates, citrates and tartrates.

As noted above, fentanyl and fentanyl analog derivatives have a narrow therapeutic index. The rate at which the active agent is released must therefore be very precisely controlled for transdermal therapeutic systems containing fentanyl or fentanyl analogs.

It has been found in studies that these polymers or polymer mixtures which impart cohesion to the active substance layer and in which the microreservoirs are embedded must meet certain requirements with regard to the dissolution capacity of the active substance and the miscibility with the liquid from which the microreservoirs are formed. Accordingly, the dissolution capacity for the active substance should be suppressed so that most of the active substance is located within the microreservoirs rather than within the polymer itself. In addition, the polymer should be substantially immiscible with the fluid forming the microreservoirs. This measure ensures firstly that the microreservoirs are formed and secondly that the dissolution capacity of the active substance in the polymer phase is not too high.

Suitable polymers are hydrophilic polymers, preferably with pressure sensitive adhesive properties. Such polymers include polyisobutylenes and siloxanes (polysiloxanes). Amine-resistant polysiloxanes have proven particularly suitable. Solubility studies have shown that the solubility of the active substances in such polymers is very low. For example, fentanyl in base form has a solubility in such polymers of less than 0.5% by weight.

Such amine-resistant polymers are produced by manufacturers such as Dow Corning under the name BIO-PSA. The viscosity of such polymers can range from non-tacky to moderately strong to strong, where the appropriate viscosity can also be adjusted by various types of mixing and/or addition of low molecular weight substances such as silicone oils.

Amine-resistant polysiloxanes have the advantage that they do not have free siloxanol groups and therefore do not lead to condensation reactions in the presence of alkaline active substances or salts of alkaline active substances, which have an adverse effect on the adhesive strength. In addition, its interaction with the polar groups of the active substance molecules is also small.

Solvents for the polymer include low polarity and/or hydrophobic solvents. Amine-resistant polysiloxanes can be provided in a variety of solvent systems. The solvents most suitable for the preparation of the transdermal therapeutic systems of the present invention are n-heptane and similar hydrocarbons, the microreservoir liquid being poorly miscible with such solvents.

Thus, during preparation, the solution of the active substance in the microreservoir liquid is dispersed in the polysiloxane solution so that the microreservoir size in the composition to be coated can be controlled by the stirring conditions. In this context, dispersion is a system consisting of a continuous phase (consisting of a polymer) and microreservoirs (consisting of liquid droplets) which are not in contact with one another.

The liquid (the important component constituting the microreservoir) should be at least partially miscible with water and organic solvents. And thus may also be referred to as an amphoteric.

Furthermore, the liquid should have a good dissolving power for the active substance in order to accommodate the required amount of active substance, which corresponds to 30-300g/m, in a conventional TTS active substance layer thickness of approximately 30-300 μm²Coating weight of (2).

Dipropylene glycol, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, 1, 3-butanediol, 2-dimethyl-4-hydroxymethyl-1, 3-dioxolane, 2-pyrrolidone and N-methylpyrrolidone have proven particularly suitable. In addition to the use of the abovementioned substances alone, it is of course also possible to use mixtures thereof.

Table 1 shows the measured saturation solubility of fentanyl in various different liquids suitable for use as microreservoirs.

Table 1: saturated solubility of fentanyl in different liquids

Micro reservoir fluid	Solubility [% g/g]
		1, 3-butanediol	10
Dipropylene glycol	18
		Transcutol	25
Diethylene glycol diethyl ether	26
		N-methyl pyrrolidone	26

^＊Diethylene glycol monoethyl ether

Accordingly, the solubility of fentanyl in the base form is about 20-50 times higher in the microreservoir fluid than in the polysiloxane polymer. This solubility is far enough to allow the necessary amount of active substance to be embedded in a microreservoir matrix with a thickness below 200 μm and an acceptable area size system.

The high fentanyl solubility microreservoir liquid and the simultaneous low fentanyl solubility polysiloxane polymer also result in a substantial portion of the fentanyl being dissolved in the microreservoirs rather than in the polymer phase.

Before the application of the TTS according to the invention, more than 50% of the total active substance in the TTS is preferably in the microreservoir, otherwise the active substance layer would be too thick due to poor solubility in the polymer and the application properties of the resulting system would be impaired.

The total concentration of active substance in the active substance layer is only between 2 and 5 wt.%, i.e. approximately the saturation concentration of active substance in the polymer. This means that the thermodynamic activity of the active substance is maximal, i.e. slightly less than or equal to 1, despite the low concentration.

The microreservoir portion in the active material layer can be up to 40% by weight, however, advantageously no more than 30% by weight.

It has proven advantageous to add substances to such liquids which increase their viscosity. The substance may here relate to a polymer which is capable of forming a gel with a liquid. Illustrative and also useful in the examples are ethyl cellulose and hydroxypropyl cellulose. This measure can improve the dispersion of the liquid in the polymer solution and also can make the diameter of the microreservoir smaller.

For microreservoir systems according to the invention with membranes, microporous membranes or so-called dispersion membranes (verteilungsmmembrans) can be used. Microporous membranes may provide fine pores or channels. The active substance is essentially transported through such pores or channels and must therefore be filled with a medium (e.g., liquid, gas, gel or other material) in which the active substance can diffuse. The release (permeation rate) of the active substance is mainly determined by the number of pores, the internal surface area, the pore size and the physicochemical properties of the pores or channel fillers.

The dispersion membrane does not have any pores, i.e. the active substance must diffuse through the membrane material itself. Thus, when such membranes are used, the thickness of the membrane, the solubility of the active substance and the diffusion coefficient in the membrane material all determine the release of the active substance. Particularly suitable dispersion films have proven to be based on ethylene and vinyl acetate copolymers (EVA). Such films are available in a variety of different thicknesses and different compositions. Typically the thickness ranges between 20-150 μm and the Vinyl Acetate (VA) content is between 2-25 wt%.

Since VA content affects the solubility of the active substance in EVA polymers and the diffusion coefficient, it is another important membrane property parameter in the application of membranes of such materials. In the examples, a film having a thickness of 50 μm and a VA content of 9% by weight was used. The use of such membranes can increase the permeation rate by using thinner membranes or membranes with higher VA content. Of course, using a thicker film and reducing the VA content has the opposite effect.

In particular in the case of systems which are not controlled by membranes, the amount of active substance absorbed, i.e. actually absorbed through the skin into the blood circulation, by the TTS released also depends on the permeability of the skin. In particular the outermost skin layer, the stratum corneum, forms the main barrier to penetration of active substances. This barrier effect can be reduced by the use of so-called enhancers, which increase the absorption of the active substance. Fortifiers are well known to the skilled person and to avoid repetition of the description in the present disclosure, see for example: osborne and Jill J.Henke, "Skin proportions in the technical problem" published by the ViroTex Corporation and the Internet http:// www.pharmtech.com/technical/osborne.

It is particularly advantageous for the transdermal therapeutic systems according to the invention to use fatty acids, fatty acid esters, fatty alcohols or glycerol esters as enhancers, especially when fentanyl is used as active substance.

For the preparation of the active substance layer, the active substance is dissolved in a microreservoir-forming liquid and this solution is dispersed in a polymer solution. This dispersion is applied to a suitable substrate, typically a polyester film containing an adherent coating, and the polymer solvent is dried off. The drying conditions should be selected to remove no or only a small portion of the microreservoir solvent. It has been shown that the liquid and the solvent are preferably chosen such that the boiling point of the solvent selected is at least about 30 deg.f, particularly preferably at least 50 deg.f, below the boiling point of the liquid.

The dried matrix film is bonded to the back layer of the system (typically a thin film impermeable to the active substance, having a thickness of about 15-30 μm) and the monolithic laminate thus obtained is then compression molded to obtain the individual transdermal therapeutic systems.

The preparation of corresponding microreservoir systems with membranes is somewhat complicated, but the coating and lamination and adhesion processes are not different from the preparation of known systems with the same coating sequence. The preparation of microreservoir systems with and without membranes will be described in detail in the examples.

Three transdermal therapeutic systems provided by the present invention, namely microreservoir systems with and without membranes, were studied for permeation using human epidermis and Franz diffusion cells well known to those skilled in the art. The compositions and results are summarized in tables 2-5, the preparation of which is described in detail in the examples.

Table 2: microreservoir system compositions without membranes

^＊High bond strength amine resistant silicone adhesives

^＊＊Diethylene glycol monoethyl ether

Table 3: results of permeation studies of formulation A, B and C

^＊Average value of n-3

Table 4: composition with system for controlling membranes

^＊High bond strength amine resistant silicone adhesives

^＊＊Diethylene glycol monoethyl ether

Table 5: formulation D, E and results of F penetration study

^＊Average value of n-3

Comparing the permeation results of the microreservoir systems with and without membrane, it was found that the membrane system had a lower active substance permeation after 72 hours, despite the same composition of the active substance-containing layer. This phenomenon is due to the controlling effect of the membrane, which limits the release of the active substance to a maximum value, irrespective of the specific properties of the various skins.

The figures (fig. 3 and 4) also show that by using a membrane, the osmotic form is linear and thus the in vivo absorption of the active substance is made uniform during use. This is particularly evident in the case of formulation C, which shows the highest permeation rate.

TTS on the market () There were 4 intensities with mean release rates of 25, 50, 75 and 100 μm/h. The surface area of the system can be easily calculated by referring to these figures and the results of the permeation study. The results are summarized in table 6.

Table 6: calculation of surface area of formulation A-F System

The calculated surface areas all fall within the acceptable range. The size of the microreservoir system with a membrane can be made smaller by using a thinner membrane or a membrane with a higher VA content, in which case, however, the membrane has less effect in controlling the release of the active substance.

The microreservoir system provided by the invention therefore exhibits very good permeation rates, does not contain a control membrane, results in a small area of TTS and is suitable for application. At the same time there is absolutely no risk of the patient excessively absorbing the active substance as a result of leakage.

When the microreservoir system is provided with a membrane, the patch will be larger, but still acceptable, by the membrane (membrane control that limits the release of the active substance).

In summary, microreservoir systems for fentanyl and fentanyl analog derivatives thus represent a significant advance over known prior art in terms of application comfort and patient safety.

The following preparation examples describe the preparation of microreservoir systems with and without membranes.

Example 1: microreservoir system for 1, 3-butanediol liquid (formulation A)

1g of fentanyl base was dissolved in 9g of 1, 3-butanediol thickened with 3% hydroxypropylcellulose. To this solution 54.8g of an n-heptane solution of 73% strength of an amine-resistant silicone adhesive (BIO-PSA 4301, Dow Corning) were added and the active substance solution was dispersed in the silicone adhesive solution with rapid stirring. The dispersion was then applied with a doctor blade to an adhesively coated film, here a protective layer (Scotchpak 1022, 3M) removed before use, in a thickness such that after removal of the n-heptane, drying was carried out at 30 ℃ for 15 minutes, the coating weight was 135g/M². The dried film layer was bonded to an active substance impermeable backing layer (Scotchpak1220, 3M) and the resulting integrated laminate was compression molded into a finished transdermal therapeutic system.

Example 2: microreservoir system for dipropylene glycol liquid (formulation B)

1g of fentanyl salt was dissolved in 4.6g of dipropylene glycol thickened with 2% hydroxypropyl cellulose. To this solution was added 30.5g of a 73% strength amine-resistant silicone adhesive in n-heptane (BIO-PSA 4301, Dow Corning), and the active substance solution was dispersed in the silicone adhesive solution with rapid stirring. The dispersion was then applied with a doctor blade to an adhesively coated film, here a protective layer (Scotchpak 1022, 3M) removed before use, in a thickness such that after removal of the n-heptane, drying was carried out at 30 ℃ for 15 minutes, the coating weight was 85g/M². The dried film layer was bonded to an active substance impermeable backing layer (Scotchpak1220, 3M) and the resulting integrated laminate was compression molded into a finished transdermal therapeutic system.

Example 3: microreservoir system of Transcutol liquid (formulation C)

1g of fentanyl base (base) was dissolved in 3g of Transcutol thickened with 4% ethylcellulose. To this solution 22g of a 73% strength n-heptane solution of an amine-resistant silicone adhesive (BIO-PSA 4301, Dow Corning) were added and the active substance solution was dispersed with rapid stirring in the silicone adhesive solution. The dispersion was then applied with a doctor blade to an adhesively coated film, here a protective layer (Scotchpak 1022, 3M) removed before use, in a thickness such that the coating weight after removal of the n-heptane, at 15 minutes drying at 30 ℃ was 65g/M². The dried film layer was bonded to an active substance impermeable backing layer (Scotchpak1220, 3M) and the resulting integrated laminate was compression molded into a finished transdermal therapeutic system.

Examples 4 to 6: microreservoir system with membranes (formulations D, E and F)

The dispersion was applied with a squeegee to an adhesively coated film, here a protective layer (Scotchpak 1022, 3M) removed before use, to a thickness of 20g/M coating weight after removal of n-heptane and drying at 30 ℃ for 15 minutes². The dried film layer was bonded to a film (EVA, 50 μ M, 9% VA, 3M).

The protective layer was removed from the laminate obtained in examples 1 to 3, and a laminate composed of an active material layer and a back layer was bonded to this film. The resulting integrated laminate (formulations D, E and F) was then compression molded into a finished transdermal therapeutic system.

The components shown in the figures are as follows:

1 ═ back layer

Active substance layer with microreservoirs

3-micro reservoir

Control film (4 ═ control film)

Layer in contact with skin 5 ═ layer

6-removable protective layer

Claims (16)

1. Transdermal therapeutic system comprising an active substance-impermeable back layer, an active substance layer, a skin-side adjoining film layer, optionally an adjoining adhesive layer and a protective layer which is removed before use, wherein the active substance is fentanyl and/or a fentanyl analog derivative and/or a salt of a fentanyl salt and/or a fentanyl analog derivative and the active substance layer comprises a polymer or a polymer mixture with microreservoirs dispersed therein, and the skin-side film layer is composed of an ethylene-vinyl acetate copolymer which constitutes a film layer having a vinyl acetate fraction of from 2 to 25% by weight and a thickness of from 20 to 150 μm, which improves the safety against accidental administration of excessively high doses of the active substance.

2. The transdermal therapeutic system of claim 1, wherein the microreservoir comprises up to 40% by weight of the active material layer.

3. A transdermal therapeutic system according to claim 1 or claim 2 wherein when the membrane layer does not have adhesive properties, there is an adhesive layer between the membrane layer and the protective layer.

4. The transdermal therapeutic system according to claim 1 or 2, wherein the polymer or polymer mixture is selected from the group consisting of polyisobutylene and silicone.

5. The transdermal therapeutic system of claim 1 or claim 2, wherein the polymer is an amine-resistant silicone.

6. The transdermal therapeutic system of claim 1 or claim 2, wherein the microreservoir comprises a fluid.

7. The transdermal therapeutic system according to claim 1 or 2, wherein the active agent is completely dissolved in the microreservoir.

8. A transdermal therapeutic system according to claim 1 or claim 2 wherein at least 50% of the active agent in the transdermal therapeutic system is contained within the mini-reservoir.

9. The transdermal therapeutic system of claim 6, wherein the fluid comprises: dipropylene glycol, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, 1, 3-butanediol, 2-dimethyl-4-hydroxymethyl-1, 3-dioxolane, 2-pyrrolidone or N-methylpyrrolidone, or a combination thereof.

10. The transdermal therapeutic system of claim 6, wherein the liquid comprises a viscosity increasing additive.

11. The transdermal therapeutic system of claim 10, wherein the additive is ethyl cellulose or hydroxypropyl cellulose.

12. The transdermal therapeutic system of claim 6, wherein the concentration of active agent in said active agent layer is less than 5% by weight.

13. The transdermal therapeutic system of claim 12, wherein the concentration of active agent in said active agent layer is less than 4% by weight.

14. A transdermal therapeutic system according to claim 6, wherein the weight of the active substance layer per unit area is between 30 and 300g/m²In the meantime.

15. The transdermal therapeutic system of claim 6, wherein the active material layer further comprises a substance that enhances the rate of permeation through human skin.

16. Transdermal therapeutic system according to claim 15, characterized in that the substances belong to the group of fatty acids, fatty acid esters, fatty alcohols and glycerides.