HK1081436B - Hot melt tts for administering rotigotine - Google Patents

Description

Hot melt transdermal therapeutic system for the administration of D2 facilitator

Introduction:

the invention relates to a Transdermal Therapeutic System (TTS) comprising an adhesive matrix containing D2-promotor (Rotigotin), characterized in that the adhesive matrix comprises a heat-fusible adhesive, in which the active ingredient D2-promotor ((-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol) is dispersed, said active ingredient being partially or completely dissolved.

The invention further relates to a method for producing a TTS comprising an adhesive matrix containing a D2 promotor as active ingredient, characterized in that the components of the adhesive matrix are melted and homogenized without solvent at a temperature of 70 to 200 ℃, preferably 120 to 160 ℃, before application and lamination.

Finally, the present patent application also relates to the use of D2 promotor in a binding matrix for the production of TTS by the hot-melt process.

Various TTSs for the administration of D2 facilitator are known in the art.

WO94-07468 discloses a system comprising an active ingredient in a two-phase matrix. The two-phase matrix is composed of a hydrophobic polymer containing dispersed therein a silicate for absorbing a hydrophilic drug salt, and an organic solvent is additionally used therein. The matrix was prepared by drying the dispersion at 70 ℃. The content of D2 promoter in the matrix is 2-5 wt%.

However, this system has a series of drawbacks:

(1) the preparation process is multi-step and expensive. The active substance salt must first be dissolved in water or in an aqueous solvent mixture, then mixed with the silicate, and then mixed with the emulsifier to emulsify the final aqueous solution containing the polymer dissolved in an organic solvent, usually heptane, ethyl acetate or toluene, for example in a silicone binder. The resulting emulsion is difficult to handle.

(2) The use of organic solvents which have to be completely removed in the production of the TTS ensures sufficient storage stability and reproducible release of the TTS and avoids skin irritation. Therefore, the production cost is greatly increased. The process is not continuous until the step of binding the mass with the active ingredient.

(3) The use of organic solvents requires more stringent safety measures to avoid environmental pollution and damage to the workers involved in the production of TTS. The equipment for solvent recovery/separation, personal protection measures, and measures to dispose of the solvent are expensive.

(4) On the one hand, the active ingredient loading is limited due to the solubility of D2 facilitator in the respective solvent system. On the other hand, separation of the solvent during production leads to a concentration, during which the matrix system containing the active ingredient can become supersaturated and undesirably crystallised. The maximum amount of active ingredient that can be incorporated into the matrix is therefore limited. Lower active ingredient loadings in turn limit the matrix release capacity per unit time and/or shorten the useful life due to premature depletion of the active ingredient.

(5) The thickness of the substrate that can be obtained during the production process is limited to about 100 μm (corresponding to about 100 g/m)²) So that complete removal of the solvent required for production can be ensured upon drying. If a thickness of the bond matrix exceeding about 100 μm is desired, it must be present in a plurality of layered structures. But this is expensive and increases the cost.

(6) Silicate or silica left in the patch can constitute a diffusion barrier for the active ingredient, adversely affecting the release of the active ingredient. In addition, the water absorption capacity of the plaster is affected. The porous structure formed by the dissolution of the water-soluble matrix component at the interface with the skin results in a poor controlled release of the active ingredient.

WO99/49852 describes a TTS which comprises an acrylate-or silicone-based binding system and contains D2 promotor in the form of the free base. The same solvents which have to be removed again during production are used in the production of both systems, which is accompanied by the disadvantages and limitations described above under (2) to (5).

The two matrices described in WO99/49852 also have the following disadvantages in terms of loading and release of D2 facilitator:

silicone matrix: the loading of the matrix may be about 15% by weight in view of the emulsion or solution containing the active ingredient. Thus limiting the loadability of the silicone matrix containing the active ingredient. D2 promotes increased loading of hormones, such as in the preparation of patches for multi-day administration, by only covering additional matrix layers, which requires multiple steps and adds significant cost to the process.

Acrylate matrix: with solvent coating, the acrylate matrix can be loaded with up to about 40 wt% of D2 promoter. However, in this matrix, the increase in the capacity of the matrix to accommodate the D2 facilitator is in conflict with the decrease in the release capacity on the skin, due to the lower distribution coefficient of the active ingredient compared to silicone systems. To obtain sufficient plasma levels of D2 promotor (Plasmaspiegel D2 promotor) from this system, on the one hand, very high loadings are required. On the other hand, higher amounts of active ingredient remain after the use of the patch, which increases the production costs of such systems and is undesirable on the basis of the safety of the medicament.

It is therefore an object of the present invention to provide a TTS of D2 facilitator, and which system is capable of eliminating various disadvantages and limitations due to the use of solvents. In particular, the D2 facilitator-TTS should be loaded with a relatively large amount of D2 facilitator while providing the greatest possible flexibility and yet release the D2 facilitator in therapeutically relevant amounts.

The above problems have now been solved by firstly providing a TTS having an adhesive matrix containing a D2 promotor and characterized in that the adhesive matrix is produced by a hot-melt process such that the adhesive matrix contains a hot-melt adhesive and in that the partially or completely dissolved active ingredient D2 promotor ((-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol) is dispersed in the adhesive.

Description of the drawings:

fig. 1a and b compare the penetration of D2 facilitator through rat skin (HMS) from hot melt-silicone-TTS and from solvent-based silicone-TTS, respectively. FIG. 1a shows the release from the TTS at D2 facilitator contents of 9% by weight each. FIG. 1b shows the effect of higher D2 promoter loading on the penetration of D2 promoter from hot melt TTS through rat skin.

Fig. 2 shows the effect of wax content on penetration of D2 promoter from hot melt-silicone-TTS through rat skin at a constant active loading of 9 wt%.

Fig. 3a and b show the effect of D2 promoter loading on the penetration of D2 promoter from silicone-based hot melt TTS through rat skin in the presence of 15% wax (3a) or 5% wax (3 b).

Fig. 4 shows the effect of matrix weight on the penetration of D2 facilitator from silicone-based hot melt-TTS through rat skin.

Fig. 5a and b show the effect of the content of the internal phase component (PVP) on the cumulative permeation (5a) or linear permeation (5b) of D2 facilitator from the hot melt-TTS through the rat skin. Fig. 5c shows the effect of PEO concentration on the cumulative permeation of D2 facilitator from silicone-hot melt-TTS through human skin.

Fig. 6a compares the 72 hour cumulative penetration of D2 facilitator through human skin from hot melt-silicone-TTS and from solvent-based silicone-TTS, respectively. Fig. 6b shows the 7-day cumulative permeation of D2 facilitator from the hot-melt-silicone-TTS through human skin. Fig. 6c shows the 7-day cumulative permeation of D2 facilitator through human skin from hot-melt-silicone-TTS containing 5% ceresin or 5% ceresin.

FIG. 7 shows the cumulative permeation of D2 promoter through rat skin from hot-melt TTS containing various hot-melt adhesives.

Fig. 8 shows the cumulative penetration of D2 promotor from the extruder and silicone-based hot-melt TTS through the rat skin, and the system also contained different internal phase components and a content of 9% D2 promotor.

Fig. 9 shows the cumulative permeation through rat skin of EVA-based hot melt TTS made from an extruder with different D2 promoter content for D2 promoter. Fig. 9a compares the cumulative penetration of D2 facilitator through human skin from EVA-based hot melt TTS and solvent-based silicone-TTS, respectively.

Fig. 10 shows an example of a TTS structure with an adhesive matrix (1) containing an active ingredient, a backing layer (2) inert to the adhesive matrix ingredient and a protective film (3) which is peeled off before use.

Description of the invention:

it has now surprisingly been found that D2 promotor can be processed excellently in the hot-melt process, that D2 promotor remains stable when heated to at least 160 ℃ for a short period of time, and that it can also be incorporated homogeneously into the matrix produced by the hot-melt process and can also be released continuously and at the therapeutically desired rate from the hot-melt matrix.

In particular, the inventors have now surprisingly found that a D2 facilitator which is susceptible to oxidation remains stable in the hot melt process, even when the temperature is raised to about 160 ℃. Although the D2 promoter is susceptible to oxidative decomposition at higher temperatures in an oxygen-containing atmosphere, it is believed to be surprisingly stable in the hot, cohesive melt and can generally be present in the matrix in a purity of over 98%, typically over 99% (measured by HPLC at 220nm and 272 nm; see tables 2, 3 and 4).

The D2 facilitator is preferably introduced into the homogenized matrix melt in the solid state, such that the D2 facilitator first dissolves in the hot matrix. After a short period of uniform mixing, the binding matrix containing the D2 facilitator is cooled, such that the D2 facilitator is typically subjected to thermal stress in less than 5 minutes, preferably less than 4, 3, or even less than 1 minute. The D2 promoter is then present in the coagulated melt. The D2 facilitator can be further protected against environmental influences (light, oxygen) during this process.

TTS produced by the hot-melt process in this way has a relatively high D2 promoter loading of more than 40% by weight, based on the weight of the substrate.

Overall, the TTS produced by the hot-melt method according to the invention has a series of advantages over the solvent-based TTS known from the prior art:

● because the D2 facilitator can be incorporated directly into the binding melt, those problems associated with solvents do not arise when processing higher concentrations of active ingredients. The result is that a significantly higher concentration (up to 40% by weight or more) of the D2 promoter can be simply incorporated into the TTS than is present on the silicone matrix in a solvent-based process in which the D2 promoter concentration is no longer incorporated as a solution since it exceeds about 15% by weight. This makes it possible to introduce an unusually high content of D2 promotor in the case of a relatively thin substrate and also in one process step.

The ● layer thickness may vary over a wide range. Thus, a weight of more than 100g/m can be obtained in one process step without difficulty²Even more than 200g/m²The substrate of (1). The result is that in combination with higher D2 facilitator concentrations,the content of D2 promoter in TTS matrix can be up to 8mg/cm²And even more. In contrast, silicone TTS prepared by solvent-based processes cannot be obtained in a single production step at more than 1.5mg/cm²D2 of (a) facilitates element loading.

● the use, removal, recovery or eventual combustion of organic solvents in the production of TTS can be omitted.

● the hot melt technique enables continuous production of the TTS matrix and continues from the point where its individual components can be weighed until lamination. This production process in fact offers the following advantages:

production time is significantly shortened.

The feed amount may be determined by the duration of the production facility. This avoids the need to replace larger pieces of equipment, and the resulting scaling up, which causes problems and/or additional cost for validation testing.

● can be manufactured as a GMP integrated product on a compact facility requiring little space.

● the release of the D2 facilitator from the binding matrix can be delayed by the use of suitable emollients, such as waxes and/or optional incorporation of an internal phase. By designing the structure of the TTS accordingly, it is possible to produce a TTS which continuously releases the D2 facilitator in a therapeutic amount-dependent manner over a period of several days, for example over 5, 6 or 7 days.

It is therefore an object of the present invention to provide a Transdermal Therapeutic System (TTS) comprising an adhesive matrix containing D2 facilitator, characterized in that the adhesive matrix contains a heat-fusible adhesive.

Another object of the present invention is to provide a Transdermal Therapeutic System (TTS) comprising an adhesive matrix containing a D2 facilitator, characterized in that the adhesive matrix contains a heat-fusible binder in which the active ingredient D2 facilitator ((-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol) is dispersed, either partially or completely dissolved.

In another embodiment of the invention, the heat fusible bonding matrix does not contain D2 facilitator, but rather contains a D2 facilitator prodrug, i.e., a compound, such as an ester, which is capable of breaking down or metabolizing into a therapeutically effective amount of D2 facilitator in the patient, e.g., by the action of esterases in the blood or skin. Preferably, the prodrug releases D2 prokinetin in an amount such that a steady state therapeutically effective concentration of D2 prokinetin is achieved in the plasma. The concentration is preferably between 0.05 and 20ng/ml, more preferably between 0.1 and 10ng/ml and most preferably between 0.2 and 5 ng/ml.

It is a further object of the present invention to provide a TTS comprising a bonding matrix containing a D2 promoter prepared by the hot-melt process, wherein the bonding matrix is prepared by introducing the D2 promoter in the molten state or more preferably in the solid state into a solvent-free bonding matrix hot melt at 70-200 ℃. The D2 promoter is preferably introduced into a solvent-free hot melt at 100-170 ℃, more preferably 120-160 ℃ and particularly preferably 130-150 ℃ and the melt is preferably processed and cooled within 5 minutes, more preferably within 3 minutes, 2 minutes or most preferably within at most 1 minute after addition of the D2 promoter.

The term "transdermal therapeutic system" means an agent or device suitable for transdermal administration of an active ingredient through the skin of a mammal, particularly through the skin of a human, in a therapeutically relevant amount.

The term "hot melt process" means that heat energy is applied to the melt of the components of the bonding matrix, in particular to the melt of the heat-fusible binder and optionally the internal phase, so that the use of solvents can be dispensed with for the preparation of the bonding matrix. The term "hot melt" also includes within this application another method of processing at a temperature below the melting point of the D2 facilitator, such that the D2 facilitator can exist in a solid state in the bond melt.

The term "solvent-free" is used in this application to mean that the bonding matrix is prepared without the use of solvents that must also be removed during the manufacturing process.

The term "heat-fusible adhesive" means here an adhesive which is pressure-sensitive when applied to the skin and which can be processed by hot-melt processing at temperatures of from 70 ℃ to 200 ℃, preferably from 100 ℃ to 170 ℃, particularly preferably from 120 ℃ to 160 ℃, very particularly preferably from 130 ℃ to 150 ℃. Here, the "heat-fusible binder" may be constituted by a binder which is heat-fusible by itself or a mixture of various binders. In addition, the "hot-fusible binder" may also comprise a mixture of binders with suitable softeners.

Such hot-melt adhesives preferably have a dynamic viscosity of at most 150pa.s, preferably at most 120pa.s, particularly preferably less than 100pa.s, very particularly preferably less than 80pa.s, even less than 60pa.s, at 160 ℃, in particular at temperatures of from 130 ℃ to 150 ℃.

Among the adhesives which are not themselves heat fusible are, for example, commercially available silicone adhesives. The silicone adhesive is excessively viscous, i.e. has a dynamic viscosity of more than 150ps at the above-mentioned processing temperatures.

Various methods are described in the patent literature for rendering the viscosity of silicone adhesives hot-meltable by mixing in suitable additives (softeners). Examples of such softeners suitable for silicones are glycerol monolaurate OR lauryl acetate as described in EP835136, waxes of the formula R-c (o) -OR' as described in EP360467, alkyl methyl siloxane waxes as described in EP524775, siliconized polyether waxes as described in EP663431 OR organic waxes as described in US RE 36754.

In general, the amount of softening agent added to the silicone binder is from 1 to 30% by weight, based on the total mixture of the heat-fusible binder mixture. Preferred softeners are organic waxes as described in US RE36754, such as ozokerite, ceresin, paraffin, candelilla, carnauba, beeswax or mixtures of these waxes, of which ozokerite and ceresin are particularly preferred.

Premanufactured heat-fusible silicone adhesives, in particular mixtures of silicone adhesives with ozokerite or ozokerite, are commercially available from Dow Corning, Michigan. If 10% by weight of ozokerite wax is added to the silicone binder, the dynamic viscosity of the resulting binder mixture at a processing temperature of 160 ℃ can, for example, be reduced from above 150Pa.s to below 50 Pa.s. The silicone-based adhesive mixture can be processed very well by the hot-melt method in the temperature range from 100 ℃ to 200 ℃, in particular from 120 ℃ to 160 ℃.

It has surprisingly been found that a heat-fusible silicone adhesive is excellently suited for the transdermal administration of D2 facilitator.

The object of the present invention is therefore to provide a Transdermal Therapeutic System (TTS) comprising an adhesive matrix containing a D2 facilitator, characterized in that the adhesive matrix contains a heat-fusible binder in which the active ingredient D2 facilitator ((-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol) is dispersed, and in that the heat-fusible binder contains a suitable mixture of a silicone-based binder and at least one softening agent.

Another aspect of the invention is a TTS comprising a binding matrix and the matrix comprises:

(a) 50-99% by weight of a binder mixture consisting of

(i)70-99 wt% of an amine resistant silicone binder

(ii) 1-30% by weight of a suitable softening agent

(b) 1-40% by weight of a D2 facilitator or a D2 facilitator prodrug.

In a preferred embodiment of the invention, the silicone-based heat-fusible binder

(a) 70-99% by weight of an amine-resistant silicone binder, and

(b) from 1 to 30% by weight, preferably from 3 to 15% by weight, particularly preferably from 4 to 10% by weight, of an organic wax, and this wax is particularly preferably selected from ozokerite, ceresin, paraffin, candelilla, carnauba, beeswax or mixtures of these waxes, with ozokerite being particularly preferred, and ozokerite being particularly preferred.

Fig. 1a compares the in vitro permeability of D2 promoter resulting from the silicone-based hot-melt TTS of such a simple construction with the respective therapeutically effective and solvent-based silicone TTS known from the prior art.

FIG. 1b shows the in vitro permeation rates achieved for the hot-melt silicone TTS of the invention at correspondingly higher loadings, which are significantly higher than those of the clinically effective solvent-based silicone patches known from the prior art.

The term "hot-melt TTS" is intended in the present application to mean a TTS whose adhesive matrix is produced by the hot-melt process, i.e. by melting the hot-melt adhesive and, if appropriate, further components without solvent.

It has now surprisingly been found that the addition of waxes, in particular organic waxes such as ozokerite or ceresin, also has an effect on the in vitro penetration of the D2 promoter from the hot-melt silicone TTS through the rat skin. As shown in fig. 2, the permeability of D2 facilitator decreased as the concentration of wax increased. This phenomenon can be illustrated by the partial dispersion of the D2 facilitator in the wax and the hysteresis effect caused thereby.

These properties of the waxes are of great importance, in particular, in the development of TTS which are used for a number of days, for example, more than 7 days. Such a patch for multi-day administration requires a high D2 facilitator loading, but the risk is that too much D2 facilitates release ("overdose") during the initial period of use. It is therefore desirable to incorporate an ingredient into the TTS which controls the release of the active ingredient. It may be a film coated on the underside of the substrate which controls the release of the active ingredient, but this film leads to increased material costs and makes the TTS structure expensive. It is therefore desirable to introduce a suitable retarding component into the matrix without an additional membrane.

Since it has now surprisingly been found that the release of the active ingredient can be retarded by incorporating a certain amount of wax into the matrix, a change in the amount of wax not only allows control of the dynamic viscosity of the binder, but surprisingly also allows selective control of the release of the active ingredient.

As the wax content increases to about 5 wt%, the dynamic viscosity of the silicone adhesive decreases dramatically first and then only slightly. Thus, at wax contents of 4 to 10% by weight, the dynamic viscosity of the silicone adhesive can be adjusted to a value suitable for hot-melt processing, with minimal effect on the release of D2 promoter. Retarding effects can also occur if the wax concentration is higher.

Figures 6a and 6c show that the human skin permeation rate obtained by adding 5 wt% of organic wax to TTS loaded with a higher amount of D2 promoter (here about 25 wt%) is comparable to the typical rate of addition to solvent-TTS loaded with a smaller amount (9 wt%), respectively. This makes it possible to prepare TTS with longer active ingredient release times, for example over 7 days (FIGS. 6b and 6 c).

The effect of the wax on the rheology of the TTS is also unexpected. If an organic wax is used as a softening agent for the silicone adhesive, the dynamic viscosity of the adhesive mixture decreases at higher temperatures, so that the silicone-based adhesive mixture can be processed excellently in the hot-melt process. At the same time, however, it is surprising that the rheological properties, such as cohesion, of the silicone are not significantly affected at room temperature, so that the problems which usually occur with heat-fusible adhesives, such as cold flow on the skin of a patient, are not reproduced.

In principle, silicone adhesives known from patch technology can be considered as silicones. The preferred silicone adhesive is an amine resistant and pressure sensitive polyorganosiloxane adhesive. The silicone binder is in most cases polydimethylsiloxane, but in principle other organic groups, such as ethyl or phenyl groups, can also be present instead of methyl groups. Generally, the amine-resistant silicone adhesive is characterized in that it contains no or only very little free silanol groups, since the Si-OH groups are alkylated. These binders are described in EP 180377. Particularly preferred binders are condensates or mixtures of silicone resins with polyorganosiloxanes, as described in US RE 35474.

Such silicone adhesives are commercially available, for example, from Dow Corning as Bio-PSAQ7-4300 or Bio-PSA Q7-4200. Thermally fusible silicone adhesives composed of a mixture of PSA 7-4300 and an organic wax such as ozokerite or ceresin are also commercially available from Dow Corning.

The amount of the active ingredient D2 prohibitin may be from 1 to over 40% by weight based on the total weight of the adhesive layer, and wherein the D2 prohibitin can also be present as a salt or free base. Preferably, the D2 facilitator is present in the form of a free base in the binding matrix. In addition, D2 ghrelin may also exist as a prodrug, such as a D2 ghrelin ester or a D2 ghrelin carbamate.

In contrast to solvent-based silicone adhesives containing amounts of active ingredient of up to 15% by weight, the adhesive matrix can be loaded with greater amounts of D2 promoter without additional technical expenditure for hot-melt TTS. This allows for greater flexibility in adjusting the permeability and duration of release of the hot melt TTS.

As shown in fig. 3a and 3b for the example of silicone-based hot melt-TTS, higher permeation through mammalian skin and longer duration of D2 promoter release were obtained with increasing loading of D2 promoter. If the TTS is applied to human skin, a higher D2 promoter loading, in particular a longer D2 promoter release time, is obtained, whereas the penetration through human skin is only slightly increased starting from a D2 promoter content of about 8-9%.

The concentration of D2 facilitator or D2 facilitator prodrug in the adhesive layer is preferably from 4 to 40 wt.%, more preferably from 9 to 30 wt.%, most preferably from 9 to 25 wt.% or from 15 to 25 wt.%, and for 7-day administration the patch is preferably from 20 to 40 wt.%, particularly preferably from 25 to 35 wt.%, all based on the total weight of the adhesive layer.

In the Kuheuter model, it was tested whether silicone-based hot melt-TTS with higher D2 promoter loadings (> 15 wt%) could be compatible with skin. For this purpose, the cellular activity and the PGE were tested after application of the corresponding D2 promoter-Hot melt TTS (5% ceresin, 2% PEO, 25-30% D2 promoter)₂-a synthetic body.

The cellular activity after application of the TTS of the invention was not significantly different from that of untreated skin, whereas PGE₂The complex is slightly elevated at the beginning, but no longer detectable after 5 hours of coating. In contrast, significant cell lethality (more than 50% after 5 h) was shown after treatment of skin with 10% SDS solution, and PGE was also observed as a marker of inflammatory response₂The synthesis is markedly elevated (> 60% after 5 h). It can be concluded that the hot-melt TTS according to the invention, which is suitable for the application of D2 promoter for a plurality of days, does not cause any significant skin irritations despite the high D2 promoter loading.

As another factor that can control the rate and duration of D2 facilitator release, the thickness of the layer of the binding matrix is varied. Fig. 4 shows the effect of the matrix weight on the in vitro permeability of D2 facilitator through rat skin in the example of hot-melt silicone TTS.

The thickness of the bonding matrix can be adjusted in a wide range in only one process step, since the limiting factors for the layer thickness brought about by the solvent method are eliminated. The layer thickness may be between 30 and 300. mu.m, preferably between 50 and 150. mu.m, particularly preferably between 50 and 120. mu.m.

The weight of the binding matrix of the TTS of the invention is preferably 30 to 300g/m²Particularly preferably in the range from 50 to 150g/m²Most preferably from 50 to 120g/m²To (c) to (d); while for 7-day administration, the patch is preferably 70-200g/m²Particularly preferably 80 to 180g/m²And 100 to 160g/m²。

The content of D2 promoter in the matrix is preferably 0.4mg/cm, depending on the duration of TTS application²-8mg/cm²。

For TTS administered for 1 day, the preferred loading is 0.4 to 1.5mg/cm²Particularly preferably 0.4 to 0.8mg/cm²。

The average required dose for treatment of adults is about 6mgD2 facilitator/day. Thus, an average of about 42mg of active ingredient per TTS is required for a patch to be administered 7-days. For safety reasons, transdermal systems for clinical use can only utilize an average of about 50-60% of TTS reservoirs. Therefore, a TTS for 7-day administration preferably contains at least 70mg to 84mg of active ingredient.

For a patch for 7-day administration, the TTS size is preferably 10-30cm²Particularly preferably 15 to 25cm²And the corresponding preferred D2 facilitator loadings are listed in the table below:

patch size cm	Minimum D2 promoter content mg/cm
		10	7.0-8.4
15	4.7-5.6
		20	3.5-4.2
25	2.8-3.4
		30	2.3-2.8

Therefore, in the patch to be administered 7-day, the content of D2 facilitator or D2 facilitator prodrug is preferably about 2mg/cm²To 8mg/cm²Particularly preferably about 2.8mg/cm²To 5.6mg/cm²And most preferably about 3.1 to 5.6mg/cm²。

TTS with such a high D2 promoter content for administering D2 promoters in a therapeutically relevant dose has not been known in the prior art, but can be achieved only by varying the loading and layer thickness of the hotmelt-TTS. For a patch to be administered 7-day containing a relatively high amount of D2 facilitator, a relatively thin matrix having a layer thickness of 80-200 μm, preferably 80-180 μm, particularly preferably 80-160 μm can be prepared with a D2 facilitator loading rate of up to 40% by weight or more.

It is therefore an object of the present invention to provide a TTS for the administration of a therapeutically relevant amount of a D2 agonist, characterized in that the content of D2 agonist in the binding matrix is at least 2.0mg/cm²Preferably at least 2.8mg/cm²In particular at least 3.1mg/cm²Or at least 3.4mg/cm². The D2 promoter loading in the TTS preferably comprises a matrix with a D2 promoter loading of more than 20 wt.% and a matrix weight of less than 200g/m²E.g. having a weight of 80 to 180g/m²Particularly preferably 80 to 160g/m²(corresponding to a layer thickness of about 80-200 μm).

In addition to the D2 facilitator and binder mixture, an optional ingredient may be added as an internal phase to the bonding layer (also referred to as the bonding matrix).

Such internal phase components particularly preferably act as a solution medium and crystallization inhibitor and aid in the uniform distribution of the active ingredient in the binding matrix. The inner phase component can further serve to increase the hygroscopicity of the patch on the skin.

The internal phase components which are particularly suitable for the hot-melt process should have a dynamic melt viscosity of at most 150pa.s, preferably less than 120pa.s, 100pa.s and very preferably less than 80pa.s at temperatures below 170 ℃.

If the dynamic viscosity of the internal phase component is too low at the desired processing temperature, a suitable softening agent, such as glycerol, must be added in advance, if appropriate. In some cases, the active ingredient D2 facilitator may also have softening properties. This is the case, for example, with polyvinylpyrrolidone, so that for the metered addition of PVP a pre-melt of PVP and D2 prohormone can be produced in an extruder.

Such internal phase components are preferably selected from the following groups

(a) Hydrophilic or hydrophilic-lipophilic polymers

(b) A hydrophilic or a hydrophilic-lipophilic copolymer,

(c) a mixture of (a) and/or (b) and a pharmaceutically acceptable emollient

(d) Condensation products of glycerol with fatty acids or polyhydroxy compounds

(e) Suitable mixtures of components (a) to (d).

The internal phase components suitable for use in the TTS of the invention may be selected from the group consisting of, for example: polysaccharides, substituted polysaccharides, polyethylene oxide, polyvinyl acetate, polyvinyl pyrrolidone (PVP), PVP with suitable softeners, polyethylene glycol, polypropylene glycol, acrylates, copolymers of polyvinyl pyrrolidone and (poly) vinyl acetate, copolymers of ethylene and vinyl acetate and with suitable softeners such as glycerol, polyvinyl alcohol.

Preferred internal phase components are PVP, PVP with softeners, polyethylene oxide (PEO), polyvinyl acetate (PVA), and copolymers of PVP and vinyl acetate.

The internal phase components are added to the tie layer in an amount of 0 to 40 weight percent, based on the total weight of the tie layer. Preferably 2-25 wt% of the internal phase ingredients are added.

It has now surprisingly been found that, at a constant amount of active ingredient, the internal phase component and possibly also the emollient not only promote dissolution of the D2 facilitator and thus homogeneous distribution thereof in the matrix, but also retard or linearize the release of the D2 facilitator as the amount increases.

Fig. 5a and 5b show the effect of PVP content on the in vitro penetration of D2 prokinetic through rat skin in the case of silicone-based hot melt TTS. As PVP content increased, D2 promoted penetration also appeared to be linearized (fig. 5a), which can be attributed to a significant decrease in the initial active ingredient release rate. Fig. 5c shows the effect of different concentrations of PEO on the penetration of D2 facilitator from silicone-hot melt-TTS through human skin.

In hot-melt TTS, for example, with very high active ingredient loadings, this blocking effect of the internal phase ingredients can be exploited, thereby producing patches which release the active ingredient D2 facilitator uniformly in therapeutically relevant amounts and over a longer period of time, for example at least 3 days, at least 4, 5, 6 or 7 days.

Since the average daily dose was 6mg of D2 prokinetic, a steady state permeation rate of 250 μ g D2 prokinetic per hour was required. For an area of 10 to 30cm²In the case of TTS, this means that the desired permeability is 8.3-25. mu.g/cm²/h。

In an in vitro permeation test on human skin, when the D2 facilitator loading is about 23-25% by weight and the patch weight is 54-84g/m²When the content of the D2 promoter is 1.2-2.1mg/cm²When using the silicone-based hot-melt TTS according to the invention, a matrix is obtained which is at least 3 days or more and is 12-16. mu.g/cm²Continuous permeability per hour (see FIG. 6 a).

The permeation rates fluctuate within the order of magnitude of the clinically relevant permeation rates of the silicone-based comparative TTS produced by the solvent method. The permeation curve of the comparative TTS used is drastically reduced after about 48 hours due to the depletion of the active ingredient storage, whereas the higher loading of the hotmelt TTS is not depleted after 72 hours.

In the human skin model used as described in example 9, when the D2 facilitator loading was 25 wt% and the matrix weight was 85g/m²In time, after an initial lag period, the in vitro steady state permeation rate through human skin can be maintained at about 15 μ g/cm using the hot melt TTS of the present invention²H and over 7 days (FIG. 6 b). This result was verified in further experiments and it was demonstrated that ceresin and ceresin are of equal value (fig. 6 c).

It is therefore an object of the present invention to provide a TTS in which the binding matrix contains at least 20% by weight, preferably more than 25% by weight, of D2 promotor or D2 promotor prodrug as active ingredient and which produces at least 8 μ g/cm over a period of at least 5, 6 or 7 days in an in vitro penetration test with human skin as in example 9²H, preferably at least 10. mu.g/cm²Continuous permeability in/h.

Another object of the present invention is to provide a hot-melt TTS which contains at least 20% by weight, preferably at least 25% by weight, of D2 promotor as active ingredient in the adhesive layer and which produces at least 8. mu.g/cm in a period of time exceeding at least 7 days in an in vitro penetration test with human skin as in example 9²Permeability per hour.

Furthermore, for the first time a TTS is provided which is capable of delivering D2 facilitator through mammalian skin, in particular human skin, over a period of at least 5, 6 or 7 days and at an hourly permeability of 200-300 μ g.

It is therefore an aspect of the present invention to provide a TTS, preferably a hot-melt TTS, particularly preferably a silicone-based hot-melt TTS, and which is suitable for continuous administration of D2 facilitator over a period of at least 5, 6 or 7 days with a steady state permeation rate of 200 and 300 μ g/day.

The term "steady state" means in this patent application a dynamic equilibrium which can be adjusted after an initial lag period after the first application of the device according to the invention.

The term "steady state permeability" means a permeability in dynamic equilibrium that can be adjusted after the onset of the lag phase.

In a preferred embodiment of the present invention, the permeability rates mentioned in the patent application are constant permeability rates.

The term "constant permeability" is used in this patent application to mean a steady state permeability at which D2 facilitator penetrates human skin at an average permeability and the respective variability CV of the permeability over time is at most 30%, preferably at most 20% or even at most 10%, and wherein CV is determined according to the equation CV ═ (sd: x) x 100% (see "Parameters for comparative-free Pharmacokinetics", Shaker press, asian, 1999, Berechnung Cawello (ED) on page 112). Average permeation rate of daily dose when administered at daily dose: 24 (mg/hr) and a CV of 30%. It will be clear to the skilled person that a constant permeation rate can be adjusted after the initial penetration period ("lag period") after the first application of the device. Therefore, the lag phase need not be considered in calculating the constant permeation rate.

Another object of the present invention is to provide a TTS for transdermal administration of D2 facilitator comprising an active ingredient-containing layer, characterized in that

(a) Active ingredient-containing layer

(a1) Containing at least 20% by weight, preferably at least 25% by weight, of D2 facilitator,

(a2) containing at least 2.0mg/cm²Preferably 2.8mg/cm²Particularly preferably at least 3.1mg/cm²Or at least 3.4mg/cm²The amount of D2 facilitator of (a),

(a3) optionally containing an organic wax and/or an internal phase component in an amount to retard the release of the active ingredient, and

(b) after application of the TTS to the skin of the patient, D2 facilitator is released through the skin at a steady state permeation rate of 100-.

It is a further object of the present invention to provide a TTS containing the D2 promotor, preferably a hot-melt TTS containing the D2 promotor, particularly preferably a silicone-based hot-melt TTS containing the D2 promotor,

(a) the binding matrix contains at least 20 wt.%, preferably at least 25 wt.% of D2 facilitator,

(b) the bonding matrix contains at least 2.0mg/cm²Preferably 2.8mg/cm²Particularly preferably at least 3.1mg/cm²Or at least 3.4mg/cm²D2 promoter amounts of (A) and (B)

(c) The D2 facilitator is released to the patient at a steady state rate of at least 100-.

It has been shown that an in vitro model according to Tanojo (J Contr. Release 45(1997)41-47) for measuring the permeation rate through human skin, after standardisation of a solvent-based silicone TTS containing D2 prohibitin, is a very good model for predicting the in vivo permeation rates to be confirmed in clinical studies. Unlike some other comparative in vitro models of human skin used, the in vitro permeation rate through human skin determined in the model according to Tanojo can be correlated with the permeation rate, plasma levels and clinical parameters obtained in the clinical study (phase III), such as the OPDRS-number.

Therefore, as can be deduced from the results obtained from the model described in example 9, the hot-melt TTS of the present invention is also suitable for administration of the D2 facilitator in vivo for a plurality of days and in a therapeutically relevant amount.

In clinical practice, it is preferred to adjust the permeation rate such that a continuous therapeutic plasma level of 0.4 to 2ng/mL of blood is obtained in the patient. For this purpose, it is required that D2 prokinetic flux per hour penetrate the skin of the patientIs 100-400. mu.g, preferably about 200-300. mu. g D2 promotor (corresponding to 10-15. mu.g/cm)²Per 20cm of h²TTS), particularly preferably 230-. The deviation from the standard dose may be determined in particular by the constitution of the patient. As shown in FIG. 6b, one can obtain TTS of the present invention administered for more than 7 days and such permeation rate.

Thus, firstly, there is provided a TTS for the continuous transdermal administration of D2 facilitator and, after application to human skin, D2 facilitator produces a mean plasma concentration of 0.4 to 2ng/ml D2 facilitator over a period of at least 5, 6 or 7 days.

A further aspect of the present invention is to provide a TTS, preferably a hot-melt-TTS, particularly preferably a silicone-based heat-capacity-TTS, which is suitable for continuous administration of D2 facilitator to a human for a period of at least 5, 6 or 7 days, and which is adapted to adjust the plasma level in the patient's blood circulation to a value of 0.4 to 2ng D2 facilitator per mL of blood after a selected period of at least 80%, preferably at least 90%, particularly preferably at least 95%.

The foregoing also applies to TTS of the invention containing a prodrug of D2 facilitator, such as an ester or carbamate. After administration of a corresponding amount of the prodrug, D2 prokinetic is released from the prodrug into the skin and/or blood due to decomposition.

Further components which can in principle also be included in the adhesive layer, such as antioxidants, stabilizers, adhesion promoters, preservatives or permeation promoters, are known to the skilled worker. Whether it is necessary in each case to add these components to the essential components of the invention, as defined in the claims, can be determined computationally by routine experimentation. Thus, these embodiments are clear to the present disclosure.

In a preferred embodiment of the invention, the hot-melt TTS according to the invention contains no penetration enhancer.

One embodiment of the invention is therefore a hot-melt TTS comprising an adhesive matrix, and the adhesive matrix comprises:

(a)50-99 wt.% of a heat-fusible binder,

(b)1 to 40 wt.%, preferably 5 to 30 wt.%, particularly preferably 9 to 30 wt.%, most preferably 15 to 25 wt.% or 20 to 30 wt.% of D2 facilitator,

(c)0 to 40 wt.%, preferably 2 to 25 wt.%, particularly preferably 5 to 25 wt.% of an internal phase component, and which is preferably selected from polysaccharides, substituted polysaccharides, polyethylene oxide, polyvinyl acetate, polyvinylpyrrolidone with or without softener, polyethylene glycol, propylene glycol, acrylates, copolymers of polyvinylpyrrolidone and (poly) vinyl acetate, copolymers of ethylene and vinyl acetate and polyvinyl alcohols with softener such as glycerol,

(d)0-10 wt.%, preferably 0-5 wt.%, most preferably 0-3 wt.% of other auxiliaries, such as tackifiers, antioxidants, stabilizers, permeation promoters.

Wherein the thermally fusible binder (a) is preferably a mixture of

(i)70-99 wt% of an amine resistant silicone binder,

(ii) from 1 to 30% by weight of a suitable softening agent, in particular a wax, particularly preferably an organic wax, most preferably ozokerite or ceresin.

The hotmelt TTS may consist of an adhesive matrix only, preferably a backing layer (2) which is impermeable to the active ingredient and inert to the matrix components, in addition to the adhesive matrix containing the D2 promoter, and a protective film (3) which covers the adhesive matrix (1) and is to be removed before use, as further components (see fig. 10). Other variants of the TTS structure are also known to the person skilled in the art, for example they can additionally comprise a film layer for controlling the flux of active ingredient and/or additional adhesive tapes ("overlap tape"). Particularly preferred is a "monolithic" TTS structure as shown in fig. 10.

D2 facilitator is a dopamine antagonist. The TTS according to the invention is therefore particularly suitable for the treatment of diseases which are associated with a disturbed dopamine metabolism, particularly preferably for the treatment of Parkinson's disease or restless legs.

The object of the present invention is therefore to provide a method for treating disorders of dopamine metabolism, in particular Parkinson's disease or restless leg syndrome, which is characterized in that the skin of a patient is coated with a hot-melt TTS according to the invention containing D2 promotor.

Another object of the present invention is to provide a packaged good containing one or more of the D2 promoters-containing hot-melt TTS of the present invention and instructions for its use.

The prior art has disclosed only a method for producing TTS containing D2 promotor, in which a binding matrix containing D2 promotor is obtained by separating the solvent from a solvent-containing silicone-or acrylate-based dispersion. The invention for the first time proposes a solvent-free hot-melt process for the preparation of TTS containing the D2 promoter.

It is therefore an aspect of the present invention to provide a TTS for producing a bonding matrix containing a D2 promoter as active ingredient, characterized in that the components of the bonding matrix are melted and homogenized without solvent at a temperature of 70 to 200 ℃, preferably 100 to 200 ℃, particularly preferably 120 to 160 ℃ before lamination to a film. The most preferred working temperature in the extruder is between 130 and 150 ℃.

It has surprisingly been found that after melting, the D2 promoter is stably present in a variety of matrices without the addition of stabilizers or antioxidants. HPLC measurements with UV detection at 220nm and 272nm show that the purity of the active ingredient can generally be up to more than 98% and often more than 99% without the addition of antioxidants (tables 2-4; examples 4, 6, 7).

One aspect of the present invention therefore consists in the use of a D2 promoter in the production of TTS, characterized in that the D2 promoter is incorporated into the adhesive layer of the TTS by the hot-melt process.

The D2 promoter can in principle be introduced into the matrix in the form of a pre-melt or in the form of a solid into a hot matrix melt and fused.

In a preferred embodiment, the D2 promotor is melted at a temperature of 100 to 200 ℃, preferably 120 to 160 ℃, particularly preferably 130 ℃ to 150 ℃, by metering the solid D2 promotor into the matrix melt, and this melting process can optionally be carried out without addition of stabilizers and antioxidants.

In a particularly preferred embodiment, the D2 promoter is melted by adding it to the matrix melt in solid form while the matrix melt containing the D2 promoter is calendered onto a film and cooled after rapid mixing. The D2 promotor is preferably only subjected to temperatures of from 100 ℃ to 200 ℃, preferably 120 ℃ and 160 ℃, particularly preferably 130 ℃ and 150 ℃ for up to 5 minutes, particularly preferably less than 4, 3, 2 or even less than 1 minute.

A further aspect of the invention is therefore the use of D2 promotor for the production of TTS at temperatures of 120 to 160 ℃, preferably 130 to 150 ℃ in a hot-melt process which makes it possible to produce adhesive substrates containing D2 promotor with a purity of at least 98%, preferably 99% (measured at 220nm and 272 nm).

In a further embodiment of the invention, the adhesive layer of the TTS is melted at a very low temperature of 70-75 ℃, i.e. at a temperature just below the melting point of the D2 promoter. Thus, in this embodiment the D2 facilitator is first present in solid form in the matrix. For this embodiment it is necessary to use an adhesive which is heat-fusible and suitable for processing at a temperature of 70 ℃, while on the other hand the dynamic viscosity of the adhesive mixture cannot be adjusted too low in order to avoid a cooling flow of the adhesive layer on the skin. A relatively high shear force must therefore be applied in the process.

It is therefore also an aspect of the present invention to prepare the TTS in a hot-melt process, and in which the adhesive layer melts at a temperature below the melting point of the D2 promoter, i.e. at a temperature below 75 ℃, and the D2 promoter is metered into the melt in solid form.

For the industrial production of TTS, the adhesive layer is preferably produced in an extruder. The individual components of the adhesive layer may be fed separately or jointly into different feed tubes of an extruder, for example a twin-screw extruder. The resulting mixture is mixed in an extruder under controlled heating conditions and can be processed continuously and finally laminated.

Since the hot-meltable binder is present in a solid consistency at room temperature, it needs to be pre-melted, which can be achieved by, for example, a melt-metering system. The system consists of a controlled-heating container in which a heat-fusible adhesive, for example a heat-fusible silicone adhesive, is pre-melted at a temperature of from 70 ℃ to 200 ℃, preferably from 100 ℃ to 170 ℃, particularly preferably from 120 ℃ to 160 ℃, very particularly preferably from 130 ℃ to 150 ℃. The melt metering system allows continuous feeding and can therefore be integrated without problems with a continuous system. The dosing system may be adapted for volumetric dosing or gravimetric dosing.

The D2 facilitator is only sparingly soluble in hydrophobic binders such as silicone and must therefore be dispersed therein. The viscosity of the molten D2 promoter is very low, so that there is a significant viscosity difference between the cement and the active ingredient during processing. In order to achieve an optimal distribution of the active ingredient in the binding matrix, a static mixer ensuring a homogeneous blending of the binding matrix may optionally be incorporated into the extruder process. Suitable static mixers are available, for example, from Sulzer Chemtech GmbH. In this way, the droplet size of the active ingredient or the internal phase region can be reduced to an average size of less than 20 μm, as shown when microscopic testing of the binding matrix is performed.

The above scheme has multiple advantages:

on the one hand, it is thus possible to suppress the formation of larger active ingredient reservoirs in the matrix, which could otherwise lead to uneven flux of the active ingredient, impair the adhesive/cohesive balance of the bonding matrix or recrystallization of the active ingredient.

On the other hand, the active ingredient enrichment at the adhesive matrix/skin surface is suppressed, which often causes skin irritation and/or protonation of the active ingredient, as a result of which the permeability rate is reduced by the reverse diffusion of the protonated base.

Thus, the maximum dimension of the microreservoir should be no more than 80%, preferably 60%, and particularly preferably no more than 50% of the thickness of the bonding matrix. The average size of the microreservoirs is preferably less than 40%, particularly preferably less than 30%, of the thickness of the matrix.

The internal phase in the binder matrix is therefore preferably present in the form of droplets having an average particle diameter of 20 μm or less, preferably not more than a maximum of 15 μm, based on a matrix thickness of 50 μm.

Fig. 8 shows the in vitro permeation of D2 promotor through rat skin from different silicone-based hot melt TTSs prepared in an extruder via melt extrusion, while using different internal phase ingredients.

In addition to the silicone-based adhesive systems, other thermally fusible adhesives are also conceivable in principle for use in the inventive hot-melt TTS containing the D2 promoter.

Heat-fusible binders are known from the prior art. For example, a hot-melt binder ("SXS-binder") based on styrene block copolymers may be used and is based on a polymer of non-elastomeric styrene blocks at the ends and an elastomeric block in the middle. The elastomeric block may be comprised of, for example, polyvinylbutene, polyethylenepropylene, polybutadiene, or polyisopropene.

Such adhesives are described, for example, in US5559165 and are characterized by good adhesive properties, simple preparation and processing and good compatibility with the skin. SXS-adhesives are either commercially available (e.g., from National Starch & Chemical under the designation Duro Tak 378-3500) or can be prepared using hot melt extrusion equipment during the manufacture of the active ingredient-containing patches. To this end, corresponding amounts (at least the following components) of a styrenic block copolymer (e.g., Shell Kraton GX1657 or Kraton D-1107CU) and a resin (e.g., Keyser Mackay Regalite R1090 or Regalite R1010 or Regalite R1100) and an oil (e.g., Shell Ondina993 or Ordina941) are added to the extruder from various addition points, mixed and melted. In the last step, the active ingredient is added to the coherent body thus obtained in an extruder and the mass is laminated to a film. Exemplary weight ratios that are commonly used are polymer to resin to oil, for example, 100: 120: 20 or 100: 200: 50. By varying these amounts, the SXS-binder can be made to have properties which all meet the requirements of the TTS for the desired properties (adhesion, minimum cooling flow, adhesion duration, release profile of the active ingredient, etc.).

Due to the oxidizing action of SXS-binders, it is preferred to add an antioxidant to the SXS-based binder matrix. An example of such a commercially available and suitable antioxidant is Irganox^R(CIBA)。

Another example is an adhesive based on vinyl acetate copolymers ("EVA-adhesive"). Such EVA adhesives are described, for example, in US 4144317. EVA adhesives are characterized by good adhesion, ease of preparation and processing, and good skin compatibility. EVA adhesives are available from, for example, Beardow Adams (13/BA).

TTS containing the D2 promoter and containing a hotmelt adhesive matrix and releasing the D2 promoter in relevant amounts were prepared using both a hotmelt SXS type binder and a hotmelt EVA type binder (FIG. 7).

FIGS. 9 and 9a show the in vitro permeation of D2 promotor from EVA-based hot-melt TTS with different D2 promotor contents through murine skin or through human skin, and which was prepared by melt extrusion in an extruder.

It is therefore an object of the present invention to provide a transdermal delivery system (TTS) comprising an adhesive matrix containing a D2 facilitator, characterized in that the adhesive matrix contains a heat-fusible binder and in which the partially or completely dissolved active substance D2 facilitator ((-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol) is dispersed, and in that the heat-fusible binder is of the SXS type or of the EVA type.

One embodiment of the invention is therefore a hot-melt TTS comprising an adhesive matrix having the following composition:

(a)50-99 wt% of a hot-melt adhesive,

(b)1 to 40 wt.%, preferably 5 to 30 wt.%, particularly preferably 9 to 30 wt.%, most preferably 15 to 25 wt.% or 20 to 30 wt.% of D2 ghrelin or prodrug of D2 ghrelin,

(c)0 to 40 wt.%, preferably 2 to 25 wt.%, particularly preferably 5 to 25 wt.% of an internal phase component, and which is preferably selected from polysaccharides, substituted polysaccharides, polyethylene oxide, polyvinyl acetate, polyvinylpyrrolidone with or without softener, polyethylene glycol, propylene glycol, acrylates, copolymers of polyvinylpyrrolidone and (poly) vinyl acetate, copolymers of ethylene and vinyl acetate and polyvinyl alcohols with softener such as glycerol,

(d)0-10 wt.%, preferably 0-5 wt.%, most preferably 0-3 wt.% of other auxiliaries, such as tackifiers, antioxidants, stabilizers, permeation promoters.

Wherein the heat-fusible binder (a) is preferably selected from

(a1) An EVA (ethylene-vinyl acetate) adhesive,

(a2) SXS-binder or

(a3) A mixture consisting of

(i)70-99 wt% of an amine resistant silicone binder,

(ii) from 1 to 30% by weight, preferably from 3 to 15% by weight, particularly preferably from 4 to 10% by weight, of a suitable softening agent, preferably an organic wax, particularly preferably ozokerite or ceresin, it being possible optionally for softening agents and, if SXS binders, antioxidants to be added to the EVA binders (a1) and SXS binders (a2) to be present.

If the binders which are themselves heat-fusible, for example of the SXS or EVA type, are made to meet certain processing requirements, it is also possible to optionally add thereto further acceptable components, such as further softeners, thickeners, antioxidants, hydrophilic-lipophilic polymers, etc.

The highest efficiency of the TTS containing the silicone-based hotmelt adhesive is evident by a comparison of the release of the D2 promoter from the different hotmelt adhesives. The release of the D2 facilitator from SXS-and EVA-based hot melt TTS decreases to a level that is no longer therapeutically effective at the time when about 30 wt% of the D2 facilitator is also present in the adhesive matrix. In contrast, silicone-based hot-melt TTSs are almost completely consumed.

The hot-melt TTS containing D2 promoter as described above, based on silicone adhesives, is therefore most preferred.

Experimental part:

comparative example: solvent-based silicone TTS

1.8g of D2 promotor (free base) was dissolved in 2.4g ethanol and added to 0.4g Kollidon 90F (in 1g ethanol). This mixture was added to 74% silicone polymer-containing (8.9g BioPSA 7-4201+8.9g BIO-PSA 7-4301[ Dow Corning ]]) In heptane solution. After 2.65g of petroleum ether was added, the mixture was stirred at 700UpM for 1 hour to obtain a homogeneous dispersion. After lamination to polyester, it was dried at 50 ℃. The patch weight was finally 50g/cm²。

Example 1: silicone-based Hot melt TTS containing 15% D2 Probefacient was prepared on a laboratory scale

(a) Silicone-hotmelt adhesive

The silicone-based hotmelt adhesive used here contained the silicone adhesive Bio-PSA 7-4300(Dow Corning, Michigan) and was also admixed with a softener paraffin wax or ceresin in a concentration of 5%, 10% or 15% by weight (commercially available from Dow Corning) of the total weight of the adhesive mixture.

(b) Preparation of TTS

8.5g of a silicone-based binder mixture as described in (a) was heated for about 20 minutes to 160 ℃ until a homogeneous melt was formed. 1.5g of D2 facilitator (free base) was added and the mixture was held at 160 ℃ for an additional 5 minutes. The mixture was then mixed well by hand and laminated to a preheated film (120 ℃ C., gap width 250 μm). Finally cutting into 5cm²The block of (1).

Example 2: preparation of silicone-based Hot-melt TTS with internal phase

The procedure is as in example 1, but 0.5g of the internal phase component is admixed with the D2 promoter.

Example 3: preparation of Silicone-based Hot melt-processed Material on a laboratory Scale with varying parameters TTS

The TTS is prepared in principle as described in examples 1 and 2. Wherein various parameters such as type of wax, wax content, concentration of internal phase components, active ingredient content, patch thickness are varied as listed in the following table:

table 1: silicone-based hot-melt TTS

Batch number (Ch.B.)	White ceresin content [% w/w]	Content of ozokerite [% w/w]	Internal phase-form/content [% w/w]	Theoretical D2 content of promoter [% w/w]	Measured content of D2 promotor (n-5) [% w/w]	Weight of the adhesive matrix (n 10) [ g/m ]]
							20011031	15	-	PVP/10	9	8.51	108
20010132	15	-	PVP/2	9	9.23	83
							20011035	15	-	PVP/2	15	15.81	66
20011036	15	-	PVP/10	15	15.56	100
							20012038	15	-	PVP/2	9	n.d.	123
20012040	15	-	PVP/2	15	n.d.	118
							20012042	15	-	PVP/2	25	n.d.	114
20103042	15	-	0	15	15.25	57
							20103043	15	-	PVP/25	15	14.04	127
20105038	15	-	0	9	8.75	91
							20105039	15	-	PVP/2	9	9.07	88
20105040	15	-	PVP/10	9	9.14	91
							20105041	5	-	0	9	8.08	106
20105043	-	5	0	9	8.03	105
							20105044	15	-	0	15	14.50	78
20105045	15	-	0	25	25.20	77
							20106016	-	15	0	9	8.12	88
20107040	-	5	0	15	13.71	99
							20107041	-	5	0	25	24.71	84
20109009	-	15	0	15	13.28	89
							20109010	5	-	0	15	14.09	107
20111059	-	5	0	25	23.95	54
							20111058	-	5	0	15	14.57	54
20111057	-	5	0	9	8.64	56
							20109043	-	5	0	25	22.69	117
20105044	-	15	0	15	14.49	57
							20103043	-	15	0	15	14.04	78
WE11682)	-	-	PVP/2	9	8.83	50
							20107011)	-	-	PVP/2	9	9.90	110

Comparative example based on solvent; PVP ═ polyvinylpyrrolidone

The D2 promoter content and the weight of the binding matrix were determined as follows: punch 10 patches a to 5cm²、10cm²Or 20cm²And weighed individually, the weights being corrected subtractively by the average weight of the pure film (measured on equally sized blocks, i.e. 5, 10 or 20cm each)²Measured on the block of (a).

Example 4: preparation of SXS-or EVA-based Hot-melt TTS on a laboratory Scale

8.5g of SXS hot melt adhesive (Duro-Tak 34-4230; National Starch) was heated at 160 deg.C&Chemical) or 8.5g eva hot melt adhesive for about 20 minutes until a homogeneous melt is obtained. 1.5g or 1.65g of D2 prokinetic base was added and the mixture was mixed well by hand. Then laminated on a pre-thermostated (120 ℃ C.) chill roll. Cutting into 5cm²(for permeation experiments) and 20cm²(for determining patch weight). The weight of the matrix can be seen in table 2 below.

Table 2:

batch number (Ch.B.)	Binder	Internal phase/content [% w/w]	Content of theoretical active ingredient [% w/w]	The content of active ingredient [% w/w [ ]]	Weight (n is 10) [ g/m]	Purity% (220nm/272nm)
							20103041	SXS	-	15	14.96	85	94.9/94.3
20103048	EVA	-	16.2	18.24	58	98.1/99.7
							20103047	EVA	-	16.2	15.96	127	98.8/99.9

Example 5: silicone-based formulations were prepared in an extruder with 15% D2 facilitator and 5% internal phase Hot melt TTS

A. Preparation of a Pre-melt of a Silicone bonding mixture

The required amount of silicone adhesive mixture as described in example 1 was filled into an addition unit (Meltex GR12-1, Melzer Corp.) where the mixture was preheated to 140 ℃ and then metered volumetrically into the extruder.

B. Preparation of the bonding matrix by hot-melt method

Twin-screw extruders for small to medium production scale (dr. collin, 25 × 24D) and for large industrial scale (ZSK25, Werner Pfleiderer, stuttgart) were used. The operating conditions were 5kg/h, heating zone 120-. Lamination was performed using MelzerCL 200.

Example 6: production of a silicone-based Hot-melt TTS in an extruder with varying parameters

The TTS was prepared essentially as described in example 5. Wherein the parameters are varied as follows:

table 3:

number (C)	Batch number (Ch.B.)	Scale of	Static mixing	White ceresin content [% w/w]	Internal phase type/content [% w/w]	Theoretical D2 content of promoter [% w/w]	Measured content of D2 promotor (n-5) [% w/w]	Weight of substrate (n 10) [ g ]/m]	D2 promoter purity [% ]](220nm/272nm)
										1	20105025	Large scale	-	15	PVA/10	9	8.88	117	99.3/99.7
2	20105025	Large scale	+	15	PVA/10	9	7.16	117	99.3/99.9
										3	20105018	Large scale	-	15	PVA/10	9	9.16	92	99.4/100
4	20105018	Large scale	+	15	PVA/10	9	8.36	86	99.5/100
										5	20109006	Small-sized	-	15	PVA/10	9	8.80	82	99.6
6	20109007	Small-sized	-	15	PVPVA/10	9	8.96	98	98.3
										7	20109008	Small-sized	-	15	PEO/10	9	7.28	88	99.1
8	20108030	Large scale	+	15	-	25	22.43	187	99.2/n.d.
										9	20105045	Small-sized	-	15	-	25	25.2	77	98.7/96.9

PVA ═ polyvinyl acetate; PEO ═ polyethylene oxide

PVPVA-polyvinyl pyrrolidone-vinyl acetate copolymer

Example 7: preparation of EVA-based Hot-melt TTS in an extruder

TTS was prepared essentially as described in example 5, wherein the TTS had the following composition:

table 4:

batch number (Ch.B.)	Scale of	Internal phase/content [% w/w]	Amount of theoretical active ingredient [% w/w]	Measured active ingredient content (n ═ 5) [% w/w]	Weight (n is 10) [ g/m]	D2 promoter purity [% ]](220nm/272nm)
							20103048	Small-sized	-	16.2	18.24	58	98.1/99.7
20103047	Small-sized	-	16.2	15.96	127	98.8/99.9
							20109019	Large scale	-	9	8.62	93	98.9/99.9
20109045	Large scale	-	15	15.08	104	99.4/n.d.
							20109020	Large scale	-	20	18.57	89	96.1/n.d.

Example 8:determination of active ingredient flux in rat skin model

Abdominal and dorsal skin with a thickness of about 120 to 150 μm was used in the flux measurement experiment through the rat skin. In a horizontal diffusion cell, the die-cut surface was 2.55cm²The TTS of (a) was fixed to the stratum corneum layer of the abdominal and dorsal skin of hairless rats. The receptor compartment of the cell was then directly filled with phosphate buffer solution (0.066 mol) pre-thermostated to 32 ℃ at pH6.2 and without bubbles, and the release medium was thermostated to 32. + -. 0.5 ℃.

At the moment of sample removal, the release medium is replaced by a fresh medium thermostated to 32. + -. 0.5 ℃. D2 facilitator release was determined via HPLC as described in example 10.

Example 9: determination of D2 facilitator flux in human skin models

The flux of D2 promoietin across human skin was determined essentially as described in H.Tanojo et al, J.control Rel.45(1997) 41-47.

In this experiment, human skin having a thickness of about 250 μm was taken out from the abdomen. Then the area was 2545cm²The TTS of (a) was applied to the same area of human skin while the skin facing the recipient was placed on the silicone membrane (fig. 11). As the acceptor phase, PBS (0.066 mol) having a pH of 6.2 and a temperature of 32. + -. 0.5 ℃ was used. The experiment was run at a throughput of 5mL/h for 72 hours with samples taken every 3 hours. At the moment of sample withdrawal, the release medium was replaced by a fresh medium thermostated to 32 ± 0.5 ℃, and the amount of released D2 facilitator was determined via HPLC. To measure the area of the groove (0.552 cm)²) The permeation rate Q (t) was calculated according to the following formula:

Q(t)＝μg/cm²d2 ghrelin concentration receptor volume/0.552 cm²

Example 10: d2 promoter analysis

(a) Active ingredient release assay

The flux of the active ingredient through the skin sample is determined by HPLC: (RPC18 lichocart 75-4 Superspher 60select) and was performed under the following conditions: 650 parts by Volume (VT) water, 350VT acetonitrile, 0.5VT methanesulfonic acid; room temperature; wavelength: 272 nm; flow rate 2ml

(b) Analysis of active ingredients in matrices

(b1) Processing of substrates

The binding matrix was mixed with 0.1% methanesulfonic acid, shaken, centrifuged and measured.

(b2) Analysis of active ingredient content

The content of active ingredient was determined by isocratic HPLC under the following conditions:

dispersing agent: 65 parts by volume of water containing 0.05% of methanesulfonic acid; 35 parts by volume of acetonitrile containing 0.05% of methanesulfonic acid

Column: LiChrocarT 75X 4mm, Supersperser 60RP-select B5 μm

Flow rate: 2mL/min, column temperature: 30 deg.C

UV detection (272nm)

(b3) Analysis of active ingredient stability:

the purity of D2 promotor was determined by gradient-HPLC using an aqueous phase and an organic phase (acetonitrile) each supplemented with 0.05% of methanesulfonic acid. Initially 5% organic fraction, increased to 60% organic fraction over 35 minutes.

Column: LiChrospher100CN, 125 mm. times.4.6 mm, 5 μm

Flow rate: 1.0mL, column temperature 40 deg.C

UV detection (2 wavelengths, 272 and 220nm)

(b4) Dynamic viscosity determination

The dynamic viscosity was determined as described in RE 36754.

Claims (31)

1. Transdermal therapeutic system comprising an adhesive matrix containing the active ingredient (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol, characterized in that the adhesive matrix contains a thermally fusible adhesive, which consists of an adhesive or a mixture of different adhesives or a mixture of an adhesive and a softener and has a dynamic viscosity of at most 100pa.s at 160 ℃, which is pressure-sensitive when applied to the skin and can be processed in a hot-melt process at a processing temperature of 70 ℃ to 200 ℃, wherein the components of the adhesive matrix are solvent-free melted and mixed homogeneously at a temperature of 70 ℃ to 200 ℃ before lamination to a film, wherein (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is present in the bonding matrix in an amount of 4 to 40 weight percent.

2. Transdermal therapeutic system according to claim 1, wherein (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is dispersed partly or completely dissolved in the heat-fusible binder.

3. Transdermal therapeutic system according to claim 1 or 2, wherein the adhesive matrix containing (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is prepared by metering (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol into a solvent-free adhesive matrix melt at a temperature of 120 ℃ to 160 ℃.

4. Transdermal therapeutic system according to claim 1 or 2, wherein the heat-fusible adhesive consists of a mixture of an amine-resistant silicone adhesive and at least one softening agent, wherein the softening agent is selected from the group consisting of glycerol monolaurate, lauryl acetate and organic waxes.

5. The transdermal therapeutic system of claim 4, wherein the emollient is an alkyl methyl silicone wax or a silicone-alkylated polyether wax.

6. The transdermal therapeutic system of claim 4, wherein the organic wax is ceresin.

7. The transdermal therapeutic system of claim 4, wherein the organic wax is ozokerite.

8. Transdermal therapeutic system according to claim 1 or 2, wherein (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is present in the adhesive matrix in an amount of 9 to 30% by weight.

9. Transdermal therapeutic system according to claim 1 or 2, wherein (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is present in the adhesive matrix in an amount of 20 to 40% by weight.

10. Transdermal therapeutic system according to claim 1 or 2, wherein (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is present as a salt or as a free base.

11. Transdermal therapeutic system according to claim 1 or 2, wherein the adhesive matrix containing the active ingredient additionally contains an internal phase component in the form of droplets selected from the group consisting of polysaccharides, substituted polysaccharides, polyethylene oxides, polyvinyl acetates, polyvinyl pyrrolidones, copolymers of polyvinyl pyrrolidones and (poly) vinyl acetates, polyethylene glycols, polypropylene glycols, copolymers of ethylene and vinyl acetates, glycerol-fatty acid esters and mixtures of polyvinyl alcohols and glycerol.

12. Transdermal therapeutic system according to claim 1 or 2, characterized in that the adhesive matrix comprises

(a)50 to 99 wt.% of the heat-fusible binder,

(b) 4-40% by weight of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol,

(c)0-40 wt% of an internal phase component as claimed in claim 10,

(d)0-10 wt.% of other auxiliaries.

13. Transdermal therapeutic system according to claim 1 or 2, wherein the thermally fusible adhesive is selected from the group consisting of

(a1) An adhesive based on an ethylene vinyl acetate copolymer,

(a2) hot-melt adhesives based on styrene block copolymers or

(a3) A mixture of

(i)70-99 wt% of an amine resistant silicone binder,

(ii) 1-30% by weight of a suitable softening agent.

14. Transdermal therapeutic system according to claim 1 or 2, wherein a prodrug of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is used or added instead of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol.

15. The transdermal therapeutic system of claim 14, wherein the prodrug of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is an ester or carbamate of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol.

16. Transdermal therapeutic system according to claim 1, wherein the transdermal therapeutic system comprises a layer containing (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol, characterized in that the layer containing active ingredient

(a) Comprising at least 20% by weight of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol,

(b) having a density of at least 2.0mg/cm²(-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino]-1-naphthol and

(c) optionally, at least 4 wt% of an organic wax and/or an internal phase component as claimed in claim 10 is included in an amount to retard the release of the active ingredient.

17. Transdermal therapeutic system according to claim 16, wherein a prodrug of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is used or added instead of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol.

18. The transdermal therapeutic system of claim 17, wherein the prodrug of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is an ester or carbamate of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol.

19. A method for the preparation of a transdermal therapeutic system comprising an adhesive matrix according to claim 12 containing (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol as active ingredient, characterized in that the components of the adhesive matrix are solvent-free melted and mixed homogeneously at a temperature of 70 ℃ to 200 ℃ before lamination to the membrane.

20. The method of claim 19, wherein the components of the bonding matrix are melted and uniformly mixed in the extruder.

21. The method of claim 19 or 20, wherein the hot melt process is carried out at a temperature of 120 ℃ to 160 ℃.

22. A method according to claim 19 or 20, wherein (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is incorporated in solid form in the melt of the binding matrix.

23. The method according to claim 19 or 20, wherein (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol present in the binding matrix prepared by the hot-melt method has a purity of at least 98% by HPLC at 220nm and 272 nm.

24. A method according to claim 19 or 20, wherein a prodrug of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is used or added in place of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol.

25. The method of claim 24, wherein the prodrug of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is an ester or carbamate of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol.

Use of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol in the preparation of a transdermal therapeutic system by hot-melt process, characterized in that (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is introduced into the adhesive matrix of a transdermal therapeutic system as claimed in claim 12 in a solvent-free prefusion at a temperature of 70 ℃ to 200 ℃.

27. Use as claimed in claim 26, wherein the hot melt process is carried out at a temperature of 120 ℃ to 160 ℃.

28. Use according to claim 26 or 27, wherein (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is incorporated in the melt of the binding matrix in solid form.

29. Use according to claim 26 or 27, wherein (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol present in a binding matrix prepared by a hot-melt method has a purity of at least 98% by HPLC at 220nm and 272 nm.

30. Use according to claim 26 or 27, wherein a prodrug of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is used or added instead of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol.

31. The use as claimed in claim 30, wherein the prodrug of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol is an ester or carbamate of (-) -5, 6, 7, 8-tetrahydro-6- [ propyl (2- (2-thienyl) ethyl) amino ] -1-naphthol.