Thermofusible tts for applying rotigotin

FIELD: medicine.

SUBSTANCE: the suggested transdermal therapeutic system (TTS) includes adhesive matrix that contains biologically active substance - rotigotin. The adhesive matrix contains thermofusible contact glue, the latter consists of contact glue, the mixture of different contact glues or contact glue with a plastifier and at 160°C is of dynamic viscosity being 100 Pa·sec, not more. TTS has been obtained due to hot fusion technique: before stratifying the adhesive matrix its components should be fused and homogenized without usage of solvents at 70-200°C. According to the present innovation TTS has got high degree of filling with rotigotin which is released out of thermofusible matrices constantly and at therapeutically desirable rate. Rotigotin in case of carrying out the technique of hot fusion keeps its stability at heating up to 160°C. There is no necessity in applying, removing, regenerating or burning up organic solvents and providing corresponding safety measures during TTS manufacturing.

EFFECT: higher efficiency.

24 cl, 10 dwg, 10 ex, 4 tbl

 

The invention relates to a transdermal therapeutic system (TTS)comprising containing rotigotine adhesive matrix, wherein the adhesive matrix contains a hot-melt contact adhesive, in which the dispersed partially or fully dissolved biologically active substance rotigotine [(-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl)amino]-1-naphthol].

In addition, the invention concerns a method of obtaining TTC with an adhesive matrix containing the biologically active substance rotigotine, characterized in that before applying or layering components of the adhesive matrix is subjected to melting and homogenization without the use of solvents at a temperature of from 70 to 200°C, preferably from 120 to 160°C.

Finally, the invention relates to the application of rotigotine to obtain adhesive matrix TTC by hot melting.

The prior art various TTC to apply rotigotine.

In WO 94-07468 described system, a two-phase matrix which contains salt biologically active substances. Two-phase matrix comprises a hydrophobic polymer dispersed in it for silicate absorption of hydrophilic salt drug substances, while the additional use of organic solvents. The matrix is obtained by drying the dispersion at 70°C. the Content of retigo is in the matrix is 2-5 wt.%.

However, the described system has a number of drawbacks.

(1) receive multi-phase and labor-intensive. Salt biologically active substances should be dissolved in water or water-containing solvent mixture, and then mixed with the silicate, then mixed with an emulsifier, so that at the final stage to emulsify the aqueous solution and dissolved in an organic solvent (usually, heptane, ethyl acetate or toluene) polymer, for example, silicone adhesive. Treatment of the obtained emulsion is difficult.

(2) Use of organic solvents, which upon receipt TTC can be completely removed in order to provide sufficient stability during storage and the reproducibility of the release of biologically active substances, and to prevent skin irritation. This leads to increased production costs. To the stage containing the biologically active substance of the adhesive mass, the process is executed periodically by the way.

(3) When handling organic solvents should take special precautions to prevent the harmful effects of solvents on the environment and engaged in the production of TTC staff. Purchase of equipment for regeneration and selection of solvents and implementation of measures to protect personnel and the elimination of the moves solvents require significant expenditures.

(4) management studies filling adhesive matrix biologically active substance is limited by the solubility of rotigotine used in the solvent system. In addition, when removing the solvents in the process of obtaining the matrix is the concentration of biologically active substances that may be accompanied by saturation of the matrix and unwanted crystallization of biologically active substances. Thus, the maximum number of biologically active substances that can be introduced into the adhesive matrix is limited. Low content of the matrix, in turn, causes a reduction in the number released per unit of time biologically active substances and/or reduce the viability of the matrix, due to the premature release of biologically active substances.

(5) in the process of drying the adhesive matrix to ensure complete removal used to obtain the solvent, the maximum thickness of the matrix at the stage of its receipt is limited to 100 μm (which roughly corresponds to the mass of 100 g/m2). The adhesive matrix of a thickness exceeding 100 μm can be obtained only in a few process steps. And this is due to increasing labor and production costs.

(6) Remaining in the patch silicate or silicon dioxide plays the role of a barrier diff is Ziya biologically active substances and which may adversely affect its release. In addition, these components have an effect on the water absorption of the patch. The pore formation on the border with the skin surface of the adhesive matrix, due to leaching of water soluble components, can lead to poorly controlled release of biologically active substances.

In WO 99/49852 described TTC with rotigotine in the form of a free base containing contact adhesive on acrylic or silicone-based. To create adhesives and other types may also use solvents that must be removed in the manufacturing process of TTC, which is also associated with the specified in paragraphs (2)to(5) disadvantages and limitations.

In addition, both described in WO 99/49852 adhesive matrix has the following disadvantages concerning their filling rotigotine and his release.

Silicone matrix. The degree of filling silicone adhesive matrix rotigotine, which can be achieved with the use of containing a biologically active substance emulsion or solution, does not exceed 15 wt.%. Thus, the filling of the silicone matrix of the biologically active substance is limited to a certain limit. To improve the filling of the matrix rotigotine, for example, with the aim of obtaining patches multi-day actions is possible only by applying additional adhesive layers, however, this requires the implementation of the Oia several technological operations, that leads to an increase in the complexity and cost of production TTC.

Acrylate matrix. The degree of filling of acrylate adhesive matrix rotigotine when it is applied from a solvent can be up to 40 wt.%. Although acrylate matrix and is able to absorb more rotigotine than silicone, but the use of acrylate matrices with higher filling is limited by reducing their ability to transport rotigotine to the skin compared to silicone systems, due to unfavorable values of the distribution coefficient of biologically active substances in the acrylate matrix. On the one hand, to provide a high level released from acrylate systems rotigotine in plasma requires a very high degree of filling of the adhesive matrix. But, on the other hand, after applying this patch, it will remain relatively large amounts of unclaimed biologically active substances, which increases the manufacturing cost of such systems and it is undesirable from the point of view of reliability of the use of drugs.

The purpose of the present invention consisted in the creation of containing rotigotine TTC eliminating the disadvantages and limitations caused by the use of solvents. In particular, should be both pecena the possibility of obtaining a TTS containing rotigotine, variable in a broad range, including IDT high degrees of filling, as well as the possibility of release rotigotine in therapeutically effective amounts.

The above problems are solved thanks to the first IDT, including containing rotigotine adhesive matrix, wherein the adhesive matrix is obtained by hot melting and, consequently, contains a hot-melt contact adhesive, in which the dispersed partially or fully dissolved biologically active substance rotigotine [(-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl)amino]-1-naphthol].

Drawings

On figa and 1B compares the penetration of rotigotine through the skin of the mouse of the hot-melt silicone TTS and silicone TTS-based solvents. On figa shows the release of rotigotine of TTC with content rotigotine 9 wt.%. On figb shows the effect of increasing the degree of filling of the hot-melt TTS-rotigotine its penetration through the skin of the mouse.

Figure 2 shows the effect of wax content on the penetration of rotigotine through the skin of the mouse of the hot-melt TTS based on silicone with constant filling rotigotine comprising 9 wt.%.

On figa and 3b shows the influence of the degree of filling rotigotine its penetration through the skin of the mouse of the hot-melt TTS based on silicone containing 15% (Fig 3 is) and 5% (figb) wax.

Figure 4 shows the influence of the weight of the adhesive matrix on the penetration of rotigotine through the skin of the mouse of the hot-melt TTS based on silicone.

On figa and 5B shows the effect of the content of polyvinylpyrrolidone (PVP) as vnutrivennogo component on a cumulative (figa) and linear (figb) penetration of rotigotine through the skin of the mouse of the hot-melt TTS. Fig 5B shows the effect of the content of polyethylene oxide (PEO) on the cumulative penetration of rotigotine through human skin from the hot-melt TTS based on silicone.

On figa shows observed within 72 hours of cumulative penetration of rotigotine through human skin from the hot-melt TTS silicon-based compared to silicone TTS-based solvents. On figb shows observed within 7 days of cumulative penetration of rotigotine through human skin from the hot-melt TTS based on silicone. On FIGU shows observed within 7 days of cumulative penetration of rotigotine through human skin from the hot-melt TTS based on silicone containing, respectively, 5% wax and 5% of ceresin.

7 shows the cumulative penetration of rotigotine through the skin of the mouse of the hot-melt TTS with variable contact adhesives.

On Fig shows the cumulative penetration of rotigotine through the skin of the mouse from the obtained hot-melt extruder TT is based on silicone with different nutrigenie components and content rotigotine 9%.

Figure 9 shows the cumulative penetration of rotigotine through the skin of the mouse from the obtained hot-melt extruder TTC on the basis of a copolymer of ethylene with vinyl acetate (EVA) with different content of rotigotine. On figa shows the cumulative penetration of rotigotine through human skin from the hot-melt TTS based on EVA compared to silicone TTS solvent-based.

Figure 10 shows an example of the structure of TTC with containing the biologically active substance is an adhesive matrix (1), inert to the components of the adhesive matrix inverse layer (2) and removed before applying the TTC protective film (3).

Description of the invention

Unexpectedly it was found that rotigotine perfectly suitable for processing by hot melting, stable by brief heating to temperatures at least up to 160°may be homogeneous distributed produced by hot melting adhesive matrix and is released from the hot-melt matrices constantly and therapeutically desirable speed.

In particular, the inventors have unexpectedly discovered that sensitive to oxidation rotigotine when implementing the method of the hot melt retained its stability when heated even up to 160°C. Despite the fact that rotigotine at elevated temperatures in oxygen-containing of atmosf the re prone to oxidative degradation, being in a hot melt glue he showed remarkable stability, and the degree of purity in the adhesive matrix rotigotine consistently exceeded 98%, generally accounting for more than 99% (measured by HPLC, the wavelengths of 220 and 272 nm; see tables 2, 3 and 4).

Rotigotine injected into gomogenizirovannogo molten adhesive matrix, preferably in the solid state, and thus, it melts only once in the hot matrix. After a short homogenization containing rotigotine matrix is cooled, so in General rotigotine exposed to a period which is less than 5 minutes, preferably less than 4, 3 minutes or even less than 1 minute. Further rotigotine resides in the composition of the solidified melt adhesive matrix. During these processes rotigotine largely protected against harmful environmental influences (light, oxygen).

The hot melt can be obtained TTC with a degree of filling rotigotine greater than 40 wt.% (calculated on the weight of the adhesive matrix).

Thus, the TTS according to the invention, obtained by hot melting, they possess a number of advantages compared with the known from the prior art TTS obtained using solvents.

Because rotigotine you can not enter orestano in melt adhesive, fall away due to the presence of solvents problems of processing of highly concentrated biologically active substances. The result is a simple way to enter into the TTC significantly large number of rotigotine (up to concentrations greater than 40 wt.%) in comparison with involving the use of solvents way to get TTS based on silicone, which does not allow you to enter more than 15 wt.% rotigotine. By implementing a single process operation by hot melting cannot enter the strikingly large number of rotigotine and part of a relatively thin adhesive matrix.

- The thickness of the adhesive matrix can be varied within a wide range. Thus, by implementing a single process operation is possible without any problems to make the adhesive matrix, weighing more than 100 g/m2and even more than 200 g/m2. Hence, at higher concentrations rotigotine in SMV its content in the adhesive matrix can achieve 8 mg/cm2or even higher. In contrast, the method of obtaining TTC silicon-based, involving the use of solvents, does not allow for the filling of the matrix rotigotine more than 1.5 mg/see

- There is no need to use, remove, re is enerali or the oxidation of organic solvents and ensuring appropriate security measures in the production of TTC.

Technology hot melt will allow you to get the adhesive matrix TTC continuous way, from weighing the individual components to the direct layering of glue. This technology provides the following advantages:

- significant reduction in the duration of the technological process,

- volume of produced batches of TTC can be set in accordance with the duration of operation of the production plant, thus avoiding the replacement of equipment on a larger, usually accompanied by problems of increasing scale (scale-up) and/or additional certification costs.

Products in accordance with a guaranteed minimum price (GMP) can be produced on compact plants that can be placed in small areas.

- Through the use of appropriate plasticizers, for example, waxes and/or, if necessary, carried out by the introduction of the internal phase may be provided a prolonged release of rotigotine of the adhesive matrix. With proper execution TTC this allows you to get system, releasing a therapeutically effective amount of rotigotine in several, for example, 5, 6 or 7 days.

Thus, the subject invention is TTS, including containing rotigotine adhesive matrix, trichomania fact, what adhesive matrix contains a hot-melt contact adhesive.

Another object of the invention is TTS, including containing rotigotine adhesive matrix, wherein the adhesive matrix contains a hot-melt contact adhesive, in which the dispersed partially or fully dissolved biologically active substance rotigotine [(-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl)amino]-1-naphthol].

In another embodiment, a hot melt adhesive matrix instead of rotigotine contains the predecessor of rotigotine, i.e. the connection, for example, ester, which is cleaved or metabolised in the patient's body, for example, in the blood or the skin under the influence of esterase with the formation of a therapeutically effective amount of rotigotine. When this precursor preferably should release as many rotigotine to plasma was created stationary therapeutically effective concentration of this substance. This concentration is preferably corresponds to the interval from 0.05 to 20 ng, particularly preferably from 0.1 to 10 ng and even more preferably from 0.2 to 5 ng rotigotine per ml of plasma.

Another object of the invention is TTS, including obtained by hot melting, containing rotigotine adhesive matrix, and the adhesive matrix is obtained by introducing a melt of the military or preferably solid rotigotine in solvent-free heated to 70-200mm f°melt adhesive matrix. Rotigotine is preferably introduced in a solvent, heated to 100-170°S, especially preferably up to 120-160°and even more preferably up to 130-150°With the melt, which is subjected to processing and cooling is not more than 5 minutes, preferably not more than 3, for 2 minutes or particularly preferably not more than 1 minute after injection of rotigotine.

Under transdermal therapeutic system means a pharmaceutical product or device suitable for transdermal application of a biologically active substance in a therapeutically effective amount through the skin of a mammal, in particular human skin.

In this case, the hot melt means the method comprising the use of thermal energy for melting the constituent parts of the adhesive matrix, in particular for melting hot melt contact adhesive and, if necessary, entered into the composition of the internal phase, which allows obtaining the adhesive matrix, you can refuse the use of solvents. In this application, the term "hot melt" is used to describe a variant of the method, providing for operation at temperatures below the melting point of rotigotine, i.e. when molten the first adhesive is injected solid rotigotine.

In this application, the term "solvent-free" means that to obtain the adhesive matrix do not use any solvents, subject to subsequent removal during the implementation of the method of obtaining TTC.

Under hot-melt contact adhesive contact adhesive means, with a sensitivity to the squeeze placed on the skin and is suitable for processing by hot melting at a temperature of from 70 to 200°C, preferably from 100 to 170°S, particularly preferably from 120 to 160°and even more preferably from 130 to 150°C. When this hot-melt contact adhesive may consist of only a contact adhesive or a mixture of different contact adhesives, each of which by itself has thermoplasty. Alternatively, the hot melt contact adhesive may also be a mixture of contact of the adhesive with an appropriate plasticizer.

Such hot-melt contact adhesive at 160°and, in particular, at a temperature of from 130 to 150°has a dynamic viscosity of not more than 150 PA·s, preferably not exceeding 120 PA·s, especially preferably less than 100 PA·s, even more preferably less than 80 PA·or even less than 60 PA·C.

Contact adhesives, which themselves do not have thermoplasty are, for example, the market is cnie silicone adhesives. At the above temperature processing such silicone adhesives have a too high viscosity, i.e. their dynamic viscosity is more than 150 PA·C.

In the patent literature describes various ways of modifying the viscosity of silicone adhesives by mixing them with appropriate additives (plasticizers) in order to give the adhesives of thermoplasti. Examples of such plasticizers for silicone adhesives are monolaurate glycerin or laurolactam (EP 835136), wax formula R-C(O)-OR' (EP 360467), alkylarylsulfonate wax (EP 524775), siloxane polyester wax (EP 663431) or organic wax (US RE36754).

In General, plasticizers is introduced into the composition of a silicone adhesive in the amount of 1-30 wt.% calculated on the total hot melt adhesive mixture. The preferred plasticizers are organic wax, for example, described in US RE 36754, in particular, ozokerite, ceresin, paraffin wax, candelilla wax, Carnauba wax, beeswax, or a mixture of these waxes, and particularly preferred are ozokerite and ceresin.

Hot-melt silicone adhesives factory manufacturing, in particular, mixtures of silicone contact adhesives with ceresin or ozokerite can be provided by the company Dow Corning (Michigan). For example, by adding to the silicone contact glue 10 wt.% of ceresin could fell the ü measured at a temperature of processing 160° C dynamic viscosity with a value in excess of 150 PA·with (original glue), to the extent of less than 50 PA· (a mixture of silicone contact adhesive with ceresin). This mixture is well processed by hot melting in the temperature interval from 100 to 200°With, in particular from 120 to 160°C.

Unexpectedly it was found that the hot-melt silicone contact adhesive ideal for transdermal application of rotigotine.

Thus, the object of the present invention is TTS, including containing rotigotine adhesive matrix, wherein the adhesive matrix contains a hot-melt contact adhesive, in which the dispersed biologically active substance rotigotine [(-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl)amino]-1-naphthol], and hot-melt contact adhesive contains a proper blend of silicone contact adhesive, at least one plasticizer.

Another object of the invention is TTS, including adhesive matrix, which contains

(a) 50-99 wt.% a mixture of contact adhesive, consisting of

(I) 70-99 wt.% resistant to amines silicone glue,

(II) 1-30 wt.% appropriate plasticizer,

(b) 1-40 wt.% rotigotine or predecessor of rotigotine.

In one preferred embodiment, a specified melt to the stroke adhesive based on silicone consists of

(a) 70-99 wt.% resistant to amines silicone glue and

(b) 1-30 wt.%, preferably 3-15 wt.% and even more preferably 4-10 wt.% organic wax, which is particularly preferably selected from the group comprising ozokerite, ceresin, paraffin wax, candelilla wax, Carnauba wax, beeswax, or a mixture of these waxes, and even more preferred waxes include mineral waxes, and in particular, ceresin.

As shown in figa, with such a simple design hot-melt TTS based on silicone provides the penetration speed of rotigotine in vitro, comparable to that known from the prior art therapeutically effective silicone TTS solvent-based.

As shown in figb, due to the higher filling rotigotine hot-melt silicone TTS according to the invention achieved a much higher rate of penetration in vitro in comparison with the known from the prior art clinically effective silicone adhesives, solvent-based.

In this application under the hot-melt TTS refers to the system, the adhesive matrix which is obtained by hot melting, i.e. by melting the hot-melt contact adhesive and, optionally, additional components in the absence of solvent.

It has been unexpectedly discovered that h is about adding waxes, in particular, organic waxes, in particular mineral wax or ceresin, affects the penetration of rotigotine through the skin of the mouse in vitro of the hot-melt silicone TTS. As shown in figure 2, the rate of penetration of rotigotine with increasing content of the wax is reduced. This experimental fact can be explained by a partial distribution of rotigotine in wax, and the resulting slowdown effect his release.

The specified property of the wax is of particular importance when creating TTC intended for use within a few days, for example, within 7 days. This patch multi-day actions should be heavily filled with rotigotine, however, there is the danger of the so-called effect of dose-dumping, that is, premature release of excess rotigotine in the initial phase of application of the TTC. In this regard, the composition of TTC it is expedient to introduce a component that regulates the release of biologically active substances. This component may be membrane from the back side of the adhesive matrix and regulating the release of biologically active substances. However, the creation of such membranes is associated with increased material costs and increased complexity of manufacturing TTC. Therefore, instead of using additional membrane preferably the introduction of the Matri what s proper components, able to slow down the release of rotigotine.

Because unexpectedly discovered that the presence of wax in the adhesive layer slows down the release of biologically active substances, the variation of the content of the wax not only allows you to adjust the dynamic viscosity of contact adhesive, but also provides unexpected additional ability to control the release of biologically active substances.

With the increasing content of wax dynamic viscosity silicone contact adhesive first decreases sharply (to the wax content of about 5 wt.%), however, in the future, only gradually decreases. The wax content in the silicone contact adhesive in the range of 4-10 wt.% corresponds suitable for the processing of dynamic melt viscosity, and the wax will have a minor effect on the release of rotigotine. Further increasing the concentration of the plasticizer provides additional effect of slowing the release of rotigotine.

As shown in figa and 6b, by adding 5 wt.% organic wax to TTC with a relatively high degree of filling rotigotine (about 25 wt.%) the rate of penetration of rotigotine through human skin becomes comparable with the speed characteristic of the TTC-based solvents with less content (9 wt%). This provides the possibility of obtaining TTC is a prolonged release of biologically active substances, what is happening, for example, during the period exceeding 7 days (see figb and 6b).

Unexpected was the effect of wax on rheological properties of TTC. The use of organic wax as a plasticizer silicone contact adhesive provides a reduction of the dynamic viscosity of the corresponding mixture at elevated temperatures, making adhesives based on silicone perfectly suitable for processing by hot melting. This rheological characteristics of silicone at room temperature, in particular, its cohesive strength, unexpectedly remain almost unchanged, and the typical problems associated with the use of hot-melt contact adhesives, such as cold fluidity on the skin of patients are not available.

As silicones in principle suitable known from the technology of patches silicone contact adhesives. Preferred silicone contact adhesives are resistant to amines, sensitive to the squeeze organopolysiloxane adhesives. Silicone contact adhesives are often polymethylsiloxane that instead of methyl groups in principle, of course, can contain other organic substituents, for example, ethyl or through groups. Resistant to amines silicon is s contact adhesives in General are characterized by what they do not contain any free silanol groups or contain only a small number of groups such as Si-OH-groups was previously performed alkylation. Such adhesives are described in EP 180377. Especially preferred silicone adhesives are condensate or a mixture of silicone polymer with polyorganosiloxane described, for example, in US RE 35474.

Such silicone contact adhesives are commercially available products, for example, by the company Dow Coming under the trade name Bio-PSA Q7-4300 or Bio-PSA Q7-4200. In addition, the company Dow Coming releases a hot-melt silicone adhesives, representing a mixture of PSA 7-4300 with organic waxes, in particular mineral wax or ceresin.

The content is used as a biologically active substance rotigotine calculated on the total weight of the adhesive matrix can be from 1 to more than 40 wt.%, rotigotine may be present in the form of a salt or free base. Preferred is the presence of rotigotine in the adhesive matrix in the form of free base. As an alternative to the possible presence of rotigotine in the adhesive matrix in the form of the corresponding predecessor, for example, complex ether or carbamate.

Unlike silicone contact adhesives, solvent-based, containing a maximum of 15 wt.% biologically sports the substance, the composition of the adhesive matrix hot-melt TTS without additional technical costs can be entered much larger number of rotigotine. Thanks to this feature much more opportunities to regulate the speed of penetration of rotigotine and the duration of its release from hot-melt TTS.

As shown in figa and 3b for example, the hot-melt silicone TTS, due to the increase of the degree of filling rotigotine can be increased as the speed of penetration of rotigotine through the skin of the mammal, and the duration of its release. When fixing TTC on the skin, increasing the degree of filling of the adhesive matrix rotigotine leads, in particular, to increase the duration of its release, while the rate of penetration of rotigotine through the skin, since its content of 8-9%, increases very slightly.

The preferred content of rotigotine or predecessor of rotigotine in the adhesive matrix is 4-40 wt.%, in particular, 9-30 wt.%, most preferably 9-25 or 15-25 wt.%, as for the patch to a seven-day period of use 20-40 wt.%, in particular, 25-35 wt.% calculated on the total weight of the adhesive matrix.

Using as a model the udder of the cow, carried out the experimental verification of the compatibility of the hot-melt TTS silicon-based high content roti is a otin (more than 15 wt.%) with the skin. With this purpose, we measured cell viability, as well as the synthesis of PGE2after applying the corresponding containing rotigotine hot-melt TTS (5% ceresin, 2% REO, 25-30% of rotigotine).

The activity of the cells after the application of TTS according to the invention compared with Naturhotel such treatment skin change significantly, while the synthesis of PGE2in the initial period was slightly increased, and after 5 hours after the application of TTC was discontinued. Compared with the results after treatment of the skin with a solution of sodium dodecyl sulfate concentration of 10% was found a significant increase in the activity of the cells (more than 50% after 5 hours) and a significant increase in the synthesis of PGE2(more than 60% in 5 hours), testified to the occurrence of inflammatory reactions. Hence it can be concluded that the hot-melt TTS according to the invention, suitable for use with rotigotine for several days, despite the high content of rotigotine not cause significant irritation to the skin.

Additional speed and duration of the release rotigotine provides the variation of the thickness of the adhesive matrix. Figure 4 on the example of the hot-melt silicone TTC shown in vitro the influence of the weight of the adhesive matrix on the penetration of rotigotine through the skin of the mouse.

Thickness to eeway matrix can be flexibly adjusted over a wide interval, realizing the only technological operation of the adhesive, because there are no restrictions on the thickness inherent in the method, involving the use of solvents. The thickness of the adhesive matrix may be from 30 to 300 μm, preferably from 50 to 150 μm and particularly preferably from 50 to 120 μm.

The weight of the adhesive matrix TTS according to the invention is preferably from 30 to 300 g/m2, particularly preferably from 50 to 150 g/m2and even more preferably from 50 to 120 g/m2and for patches with a seven-day period of use preferably from 70 to 200 g/m2, particularly preferably from 80 to 180 g/m2and from 100 to 160 g/m2.

The preferred content of rotigotine in the adhesive matrix, depending on the envisaged duration of application of the TTC varies from 0.4 to 8 mg/cm2.

The preferred filling TTC with a one-day validity is from 0.4 to 1.5 mg/cm2, particularly preferably from 0.4 to 0.8 mg/cm2.

therapeutic dosage of rotigotine for adults average about 6 mg/day. Therefore, TTC with a seven-day validity period must contain an average of about 42 mg of biologically active substances. Given the need for reliable therapeutic effect, when applied clinical transdermalsystem assumption, that exhaustion is subject to an average of only 50-60% of the biologically active substances from share TTC. Thus, TTC with a seven-day expiration preferably contains at least 70 to 84 mg of biologically active substances.

Thus, the preferred content TTC with a seven-day expiration preferred area of 10-30 cm, and particularly preferred area of 15-25 cm2is:

The area of the patch, cm2The minimum content of rotigotine, mg/cm2
107,0 an 8.4
154,7-5,6
203,5-4,2
252,8-3,4
302,3-2,8

Therefore, the content of rotigotine or predecessor of rotigotine in the patch with a seven-day validity period is preferably from 2 to 8 mg/cm2especially preferably from 2.8 to 5.6 mg/cm2and even more preferably from 3.1 to 5.6 mg/cm2.

TTC according to the prior art intended to apply rotigotine in therapeutically effective dosage and having such a high content of rotigotine, until recently, were not known, and receipt of such TTS was only possible thanks to the VA is jiroemon content and varying the thickness of the adhesive layer of the hot-melt TTS. Moreover, a high degree of filling rotigotine (more than 40 wt.%), required for TTC with a seven-day period of validity, may be provided for relatively thin adhesive matrix, the thickness of which is 80-200 μm, preferably 80-180 μm, particularly preferably 80-160 μm.

Thus, the object of the present invention are TTC for applying rotigotine in therapeutically effective amount, wherein the content of rotigotine in the adhesive matrix is at least 2.0 mg/cm2preferably at least 2.8 mg/cm2especially preferably, Manisha least 3.1 mg/cm2or, at least, 3.4 mg/cm2. While preferred are TTC containing adhesive matrix with a degree of filling rotigotine more than 20 wt.% and weighing less than 200 g/m2for example, from 80 to 180 g/m2and particularly preferably from 80 to 160 g/m2(which corresponds to the thickness of the matrix 80-200 µm).

In the adhesive layer (also referred to as adhesive matrix) along with rotigotine and a mixture of contact adhesive, if necessary, can be introduced component that performs the function of the internal phase.

This vnutriplitnyi component is used, in particular, as hydrotropes a solubilizer and an inhibitor of crystallization and promotes uniform distribution of biologically active the substances in the adhesive matrix. In addition, vnutriplitnyi component is designed to improve moisture absorption fixed at the skin patch.

For use in hot melt is particularly suitable such nutrigenie components, the melt which is at a temperature below 170°has a dynamic viscosity of not more than 150 PA·s, preferably less than 120 PA·s and 100 PA·and particularly preferably less than 80 PA·C.

If the dynamic viscosity vnutrivennogo component at the desired treatment temperature is too low, then, if necessary, to him you must first add the appropriate plasticizer, such as glycerol. In some cases, plasticizing properties may possess and use as biologically active substances rotigotine. For example, for the introduction of polyvinylpyrrolidone (PVP) in the extruder can be prepared prior to the melt mixture of PVP with rotigotine.

Such nutrigenie components preferably selected from the group including

(a) a hydrophilic or amphiphilic polymers

(b) a hydrophilic or amphiphilic copolymers,

(C) a mixture of (a) and/or (b) with a pharmaceutically acceptable plasticizers,

(g) condensates of glycerol and fatty acids or polyols,

(d) appropriate mixture of components (a)to(g).

Nutrigenie components suitable for use in the vehicle according to the invention, can be selected, for example, from the group comprising polysaccharides, substituted polysaccharides, polyethylene oxide, polyvinyl acetate, PVP, PVP with an appropriate plasticizer, polyethylene glycol, polypropyleneglycol, acrylates, copolymers consisting of PVP and (poly)vinyl acetate, copolymers of ethylene with vinyl acetate, and polyvinyl alcohol containing an appropriate plasticizer, such as glycerin.

Preferred nutrigenie components are PVP, plasticized PVP, polyethylene oxide (PEO), polyvinyl acetate (PVA)and copolymers consisting of PVP and vinyl acetate.

Vnutriplitnyi component is introduced into the adhesive layer in an amount of 0-40 wt.% calculated on the total weight of the adhesive layer. Preferably introduced 2-25 wt.% vnutrivennogo component.

Unexpectedly, it was found that at constant content rotigotine and, if necessary, the used plasticizer vnutriplitnyi component not only helps to increase the solubility of rotigotine, and thus its uniform distribution in the adhesive matrix, but with the increasing content of rotigotine can also provide slow or linearization his release.

On figa and 5B for example, hot-melt TTS based on silicone shows the effect of PVP content on penetration of rotigotine through the skin of the mouse in vitro. When increasing the content of the PVP observed linearization penetration of rotigotine (figa), that should explain a significant reduction in the release of biologically active substances at the initial stage (figb). On FIGU shows the effect of the concentration of PEO in the penetration of rotigotine through human skin silicone hot-melt TTS.

Found the slowing effect vnutrivennogo component can be used, for example, when creating a hot-melt TTS with a high content of biologically active substance to be used as such a substance rotigotine evenly in a therapeutically effective amount would be released over a long period of time, comprising, for example, at least 4, 5, 6 or 7 days.

When the average daily dosage of rotigotine 6 mg required fixed speed current (stedy-state fluxrate) is 250 µg/H. This means that the flow speed for the TTS in size from 10 to 30 cm2should be 8,3 25 mg/cm2/PM

In experiments in vitro to study the penetration of rotigotine through human skin from the hot-melt TTS based on silicone according to the invention with a degree of filling 23-25 wt.% and weight 54-84 g/m2that is , with content rotigotine in the adhesive layer of 1.2-2.1 mg/cm2managed to ensure constant flow speed rotigotine 12-16 mg/cm2/h over a period of at least three days (see figa).

PR is the flow speed rotigotine on the order differs from clinically effective speed current for comparative TTC based on silicone, obtained using solvents. If the curve of penetration of rotigotine of comparative TTC after about 48 hours there is a break due to exhaustion of the reserve biologically active substances, the corresponding resource more highly filled hot-melt TTS has not been exhausted, and after 72 hours.

According to an in-vitro human skin model experiment (example 9) using hot-melt TTS according to the invention with an adhesive matrix weight 85 g/m2and filling rotigotine 25 wt.% after an initial induction period allows for a 7 days to provide a fixed flow speed rotigotine through human skin, comprising about 15 mg/cm2/h (figb). This result was confirmed in an additional experiment (pigv), and used as wax, ceresin and ozokerite had equivalent efficacy.

Thus, the subject invention is TTS, the adhesive matrix which as a biologically active substance contains rotigotine or predecessor of rotigotine in the amount of at least 20 wt.%, preferably more than 25 wt.%, and which when tested penetration of biologically active substances through human skin in vitro according to example 9 provides a constant velocity of its current, preferably the leaves, at least 10 µg/cm2/h over a period of at least 5, 6 or 7 days.

Another object of the invention is hot-melt TTS, the adhesive layer which contains as a biologically active substance rotigotine in the amount of at least 20 wt.%, preferably at least 25 wt.%, and which when tested penetration of rotigotine through human skin in vitro according to example 9 provides a constant speed of its current component, at least 8 mg/cm2/h over a period of at least 7 days.

In addition, for the first time the TTC, which allows you to apply rotigotine through the skin of a mammal, in particular human skin with a flow rate of 200-300 μg/h over a period of at least 5, 6 or 7 days.

Thus, the object of the present invention is TTC, preferably hot-melt TTS, particularly preferably hot-melt TTS based on silicone, suitable for permanent use rotigotine over a period of at least 5, 6 or 7 days, fixed flow rate of 200-300 mg/day.

The term "stationary" (steady-state) in the context of this application refers to a dynamic equilibrium that occurs after an induction period, cinausero after first applying to the skin of the devices according to the invention.

Under stationary flow speed (steady-state fluxrate) is the current velocity in the dynamic equilibrium established after the initial induction period.

In one preferred embodiment of the invention described in this application, the speed of the current are constant speed of the current.

Under constant flow speed in the context of this application refers to a stationary flow speed rotigotine (steady-state fluxrate), in which he is transported through the skin of a person with average speed, characterized by individual internal instability over time (CV)up to 30%, preferably 20% or even 10%, and the CV is determined by the equation CV=(sd:x)×100% (see calculation Cavallo (ED) in "Parameters for Compartment-free Pharmacokinetics", Shaker Verlag, Aachen, 1999, s.112). With a daily dose of rotigotine transported at an average speed of current (daily dose divided by 24, in mg/h) and an indicator of instability CV, constituting 30%. Professionals it is clear that the constant speed of the current is set only upon completion of the initial phase (induction period lag-phase), coming directly after the first overlay adaptation on the skin. Therefore, the induction period in the calculation of the constant speed of the current is ignored.

Another object of the present invention is TTS transdermal the applications of rotigotine, includes containing a biologically active material layer, characterized in that

(a) containing a biologically active material layer contains

(A1) at least 20 wt.%, preferably at least 25 wt.% rotigotine,

(A2) at least 2.0 mg/cm2preferably 2.8 mg/cm2especially preferably, at least about 3.1 mg/cm2or, at least, 3.4 mg/cm2rotigotine,

(A3) optionally, an organic wax and/or vnutriplitnyi component in the quantity, slow down the release of biologically active substances, and

(b) after the application of TTC to the skin of the patient rotigotine penetrates through it for a period of at least 5 days, preferably at least 7 days, fixed speed DC component of 100-500 μg/h, preferably 200-300 mcg/h

Another object of the invention is containing rotigotine TTC, preferably containing rotigotine hot-melt TTS and particularly preferably containing rotigotine hot-melt TTS based on silicone, characterized in that

(a) the content of rotigotine in the adhesive matrix comprises at least 20 wt.%, preferably at least 25 wt.%,

(b) contents of rotigotine in the adhesive matrix is at least 2.0 mg/cm2preferably 2.8 mg/cm2special is preferably about, at least, 3.1 mg/cm2or at least 3.4 mg/cm2and

(C) rotigotine penetrates the patient's skin over a period of at least 5, 6 or 7 days with the stationary current velocity, component, at least 100-500 µg/h, preferably 200-300 mcg/h and even more preferably 230 to 270 µg/h

Model Tanojo used to measure the velocity of the current through human skin in vitro (Tanojo, J Contr. Release 45, 1997, cc.41-47), in the standardization containing rotigotine silicone TTS-based solvents, has established itself as a very convenient model for the prediction of the speed of the current, determined from clinical studies in vivo. Unlike some others, used to compare models of human skin, defined using models Tanojo in vitro, the rate of current through human skin perfectly correlated with the speed of current levels of rotigotine in plasma and clinical settings, for example, an indicator UPDRS achieved in clinical in vivo studies (phase III).

Thus, on the basis of the results obtained using the described in example 9 of the model, it can be concluded that the hot-melt TTS according to the invention suitable for use with rotigotine for several days in therapeutically effective amounts and in vivo.

Moreover, in clinical practice sorostitute of rotigotine preferably set so to his constant therapeutic level in the plasma of the patient corresponded to the interval from 0.4 to 2 ng/ml of blood. For this current rotigotine through the patient's skin should be 100-400 µg/h, preferably 200-300 mcg/h (corresponds to a flow rate of 10-15 µg/cm2/h for TTC area of 20 cm2), particularly preferably 230 to 270 µg/h and even more preferably about 250 μg/h Cause deviations from standard dosages can be, in particular, the specific Constitution of the patient. As shown in figb, when using the TTS according to the invention, this flow rate can be observed during the period of 7 days.

Thus, for the first time the TTC for continuous transdermal application of rotigotine that after applying to the human skin for at least 5, 6 or 7 days induces rotigotine, providing its concentration in plasma is in the range of from 0.4 to 2 ng/ml.

Another object of the present invention is TTC, preferably hot-melt TTS, particularly preferably hot-melt TTS based on silicone, suitable for permanent use rotigotine a patient for a period of at least 5, 6 or 7 days, and after at least 80%, preferably at least 90% and especially predpochtitel is about, at least 95% of the time, selected from the above values, the level of rotigotine plasma circulatory system of the patient corresponds to the interval from 0.4 to 2 ng/ml of blood.

These options apply to the TTS according to the invention, containing precursors rotigotine, for example, esters or carbamates of rotigotine. The application of appropriate amounts of such predecessor is followed by its cleavage in the skin and/or blood and the release of free rotigotine.

Other components, which in principle can be contained in the adhesive layer, in particular, antioxidants, stabilizers, enhancers stickiness, preservatives or stimulants penetration, known to specialists. Benefits derived as a result of adding such components to a regulated claims the main components of the adhesive layer can be set in each case by performing the relevant practical experiment. Thus, these embodiments of the invention without somenone be its object.

In one preferred embodiment, a hot-melt TTS according to the invention do not contain stimulants penetration of biologically active substances.

Thus, one implementation of the invention is to thermoplas the th TTC, including the adhesive layer, which contains:

(a) 50-99 wt.% hot-melt contact adhesive

(b) 1-40 wt.%, preferably 5-30 wt.%, particularly preferably 9-30 wt.% and even more preferably 15-25 wt.% or 20-30 wt.% rotigotine,

(C) 0-40 wt.%, preferably 2-25 wt.%, particularly preferably 5-25 wt.% vnutrivennogo component, preferably selected from the group comprising polysaccharides, substituted polysaccharides, polyethylene oxide, polyvinyl acetate, plasticized or not plasticized polyvinylpyrrolidone, polyethylene glycol, polypropyleneglycol, acrylates, copolymers consisting of polyvinylpyrrolidone and (poly)vinyl acetate, copolymers of ethylene with vinyl acetate, and polyvinyl alcohol, plasticized, for example, glycerin,

(d) 0-10 wt.%, preferably 0-5 wt.% and particularly preferably 0-3 wt.% other auxiliary substances, for example, amplifiers stickiness, antioxidants, stabilizers, stimulants, penetration,

moreover, the hot melt contact adhesive (a) is preferably a mixture consisting of

(I) 70-99 wt.% resistant to amines silicone glue,

(II) 1-30 wt.% appropriate plasticizer, in particular, waxes, particularly preferably organic wax and even more preferably wax or ceresin.

Hot-melt TTS may consist of only the adhesive matrix, however, along with containing rotigotine adhesive matrix TTC as an additional component parts may preferably be impervious to contain biologically active substances and inert with respect to the components of the adhesive matrix inverse layer (2)and remove before use TTS protective film (3)covering the adhesive matrix (1) (see figure 10). Specialists and other known variants of design of TTC, for example, optionally comprising a membrane that is designed to regulate the current of biologically active substances, and/or additional adhesive film (overtape). Especially preferred is depicted in figure 10 "monolithic" design TTC.

Rotigotine is a dopamine agonist. Therefore, the TTS according to the invention, in particular suitable for the treatment of diseases caused by disorders of dopamine metabolism, in particular for the treatment of Parkinson's disease or syndrome Akroma.

Thus, the subject invention is a method of therapy associated with impaired dopamine metabolic diseases, in particular Parkinson's disease or syndrome Akroma, characterized in that the skin of the patient record containing rotigotine hot-melt TTS according to the invention.

Another object of the invention is a trade package that includes one or more containing p is tikotin hot-melt TTS according to the invention, as well as the instructions for use TTC.

To date, the prior art only such methods of obtaining containing rotigotine TTC, according to which contains rotigotine adhesive matrix obtained by removing the solvents from the containing silicone or acrylate dispersions. Thanks to the present invention for the first time, available way receipt containing rotigotine TTC by hot melting without using solvents.

Thus, the object of the present invention is a method of obtaining a TTS containing adhesive matrix with rotigotine as a biologically active substance, characterized in that the component parts of the adhesive matrix before layering on the film is subjected to melting and homogenization without the use of solvents at a temperature of from 70 to 200°C, preferably from 100 to 200°and particularly preferably from 120 to 160°C. an Even more preferred operating temperature in the extruder corresponds to the interval from 130 to 150°C.

When this unexpectedly discovered that rotigotine retains its stability after melting in a variety of adhesive matrices and without the addition of stabilizers or antioxidants. According to the results of measurement by HPLC with UV-detection at wavelengths of 220 and 272 nm with a purity of biological the key active ingredients and without added antioxidants systematically exceeds 98%, but in the General case, more than 99% (table 2-4; examples 4, 6, 7).

Thus, one of the objects of the invention concerns the application of rotigotine to get TTS, characterized in that rotigotine injected into the adhesive layer TTC by hot melting.

Mainly in the adhesive matrix, you can enter the pre-molten rotigotine, however, it may be introduced into the hot molten matrix, where the subsequent melting, and in the solid state.

According to one preferred variant implementation of the invention solid rotigotine injected into the molten adhesive matrix with a temperature of 100 to 200°C, preferably from 120 to 160°and particularly preferably from 130 to 150°and, if necessary, in the melt can be introduced rotigotine that do not contain additional stabilizers or antioxidants.

According to one particularly preferred variant implementation of the invention, the melt is introduced in the solid state of rotigotine occurs in hot melted adhesive matrix, and contains rotigotine melt glue after a short homogenization are calandrinia on film and cooling. Thus rotigotine preferably subjected to temperatures being in the range from 100 to 200°C, preferably from 120 to 160°With whom particularly preferably from 130 to 150° With, within a period not exceeding 5 minutes, particularly preferably less than 4, 3, 2 minutes or even less than 1 minute.

Thus, another subject of the invention is the use of rotigotine to obtain TTC by hot melting at a temperature of from 120 to 160°and particularly preferably from 130 to 150°With, moreover, the use of hot melt provides the receiving adhesive matrix with rotigotine, the degree of purity of which, measured at 220 and 272 nm, is at least 98%, preferably 99%.

According to another variant implementation of the invention the adhesive layer TTC melted at very low temperature (70-75°C), i.e. slightly below the melting point of rotigotine. Therefore, under this option the first rotigotine remains in the adhesive matrix in the solid state. To implement this option, you should use hot-melt contact adhesive suitable for processing at 70°but, at the same time, avoid ludoteques adhesive layer on the skin, the dynamic viscosity of the mixture of contact glue should not be too low. Therefore, implementation of this method requires the use of fairly large effort shift.

Thus, the object of the invention to provide TTC by hot melting, and the adhesive layer, for example, is up to melting at temperatures below the melting point of rotigotine, that is below 75°and rotigotine injected into the adhesive melt in the solid state.

When industrial production TTC adhesive layer preferably get in the extruder. While individual components of the adhesive layer can be introduced into the extruder, for example, in dvuhseriynyy extruder through different supply lines separately or in the form of a previously prepared mixture. The appropriate mixture is stirred for controlling the heating in the extruder, and it can be subjected to processing in a continuous process and subsequent layering.

Because hot-melt contact adhesive at room temperature is in the solid state, it shall be pre-melting. It can be done, for example, dosing of the melt, consisting of a container with controlled heating, in which pre-melt hot-melt contact adhesive, for example, silicone hot-melt contact adhesive is carried out at a temperature of from 70 to 200°C, preferably from 100 to 170°S, particularly preferably from 120 to 160°and even more preferably from 130 to 150°C. the dosing System of the melt can be feed continuously, and therefore, it can be flawlessly integrated in a continuous the technological scheme. The dosing system suitable for volumetry is a mini, and for gravimetric dosing of the melt.

Rotigotine has a solubility in the hydrophobic adhesives, for example, silicones only in trace, and therefore should be subjected to dispersion. The viscosity of the molten rotigotine extremely low, therefore the implementation process can be significant difference between the viscosity values of the contact adhesive and biologically active substances. For optimal distribution of biologically active substances in the adhesive matrix in the technological scheme of the extrusion, if necessary, can be included static mixers, providing homogeneous mixing of the adhesive matrix. Suitable static mixers can be, for example, devices supplied by Sulzer Chemtech GmbH. As shown by microscopic examination of the adhesive matrix, the use of such mixers can reduce the size of the pear-shaped particles of biologically active substances or vnutriplitnykh domains to average values which are less than 20 microns.

This provides the following benefits :

First, avoid the formation of excessively large accumulations of biologically active substances in the adhesive matrix, which can cause uneven current biologically active substances, violations desinsection equilibrium adhesive matrix or recrystallization of biologically active substances. Secondly, it avoids the concentration of biologically active substances on the boundary surface between the adhesive matrix and the skin, which can cause skin irritation and/or protonation of biologically active substances and as a consequence decrease the speed of the current due to reverse diffusion of the protonated base.

In this regard, the maximum size of microscopii should not be more than 80%, preferably more than 60%, especially preferably more than 50% of the thickness of the adhesive matrix.

The average size of microscopii preferably not more than 40%, especially preferably 30% of the thickness of the adhesive matrix.

Thus, when the thickness of the adhesive matrix component, for example, 50 μm, the internal phase is in it, preferably in the form of droplets with an average size of up to 20 μm, preferably not more than 15 μm.

On Fig shows the penetration of rotigotine through mouse skin in vitro from different hot-melt TTS based on silicone, obtained in the extruder by extrusion from the melt, and TTC contain variable nutrigenie components.

Along with contact adhesives based on silicone in the composition containing rotigotine hot-melt TTS according to the invention in principle can include other contact hot-melt adhesives.

Hot-melt contact adhesives known in the prior art. When the apostrophes such adhesives are adhesives based on block copolymers of styrene (so-called contact adhesives type SXS), the polymer chain which consist of end elastomeric polystyrene blocks located between the elastomeric blocks. The elastomeric blocks can consist, for example, from parts of polyethylenimine, polyethylenepropylene, polybutadiene or polyisoprene.

Such adhesives are described, for example, in US 5559165 and US 5527536, and they have good adhesive properties, ease of obtaining and processing and good compatibility with the skin. Contact adhesives type SXS are commercially available products (e.g., Duro Tak 378-3500 company National Starch &Chemical) or can be obtained on the equipment for the extrusion of melt in the process of direct production containing a biologically active substance patch. To do this through a separate metering devices in the extruder enter the appropriate number (at least, the following components): a block copolymer of styrene (for example. Shell Kraton GX1657 or Kraton D-1107CU), resins (e.g., Keyser Mackay Regalite R1090, Regalite R1010 or Regalite R1100) and oil (for example, Shell Ondina 933 or Ondina 941), and subjected to mixing and melting. At the final stage in the extruder is formed to contact the glue add a biologically active substance, and the resulting mass layer on the film. Typical mass ratio between the polymer resin and oil is, for example, 10:120:20 or 100:200:50. By varying this ratio properties of the contact adhesive type SXS can be aligned with the desired characteristics TTC (gluing ability, minimal cold fluidity, the duration of adhesion, the parameters of the release of biologically active substances and so on).

Since the adhesives of the type SXS prone to oxidation into the corresponding adhesive matrix is preferably introduced antioxidants. An example of a suitable commercially available antioxidant is IrganoxR(CIBA).

Another example is the hot-melt contact adhesives based on copolymers of ethylene and vinyl acetate (contact adhesives EVA). Such contact adhesives are described, for example, in US 4144317. The pin adhesives EVA have good adhesive characteristics, ease of obtaining and processing and good compatibility with the skin. The pin adhesives EVA can be purchased, for example, the firm Beardow Adams (13/BA).

Using hot-melt contact adhesives as type SXS, and EVA can be obtained containing rotigotine TTC with hot-melt adhesive matrix, releasing a therapeutically effective amount of rotigotine (Fig.7).

In figures 9 and 9a shows the penetration of rotigotine through the skin of the mouse and human skin in vitro from hot-melt TTS based on EVA with variable content rotigotine obtained in the extruder by means of extrusion of the races of the lava.

Thus, the subject invention is TTS, including containing rotigotine adhesive matrix, wherein the adhesive matrix contains a hot-melt contact adhesive, in which the dispersed partially or fully dissolved biologically active substance rotigotine [(-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl)amino]-1-naphthol], and hot-melt contact adhesive is a contact adhesive type SXS or EVA.

Thus, one implementation of the invention is a hot-melt TTS, including the adhesive layer, which contains:

(a) 50-99 wt.% hot-melt contact adhesive

(b) 1-40 wt.%, preferably 5-30 wt.%, particularly preferably 9-30 wt.% and even more preferably 15-25 wt.% rotigotine or predecessor of rotigotine,

(C) 0-40 wt.%, preferably 2-25 wt.%, particularly preferably 5-25 wt.% vnutrivennogo component, preferably selected from the group comprising polysaccharides, substituted polysaccharides, polyethylene oxide, polyvinyl acetate, plasticized or not plasticized polyvinylpyrrolidone, polyethylene glycol, polypropyleneglycol, acrylates, copolymers consisting of polyvinylpyrrolidone and (poly)vinyl acetate, copolymers of ethylene with vinyl acetate, and polyvinyl alcohol, plasticized, for example, glycerin,

(d) 0-10 wt.%, preferably the 0-5 wt.% and particularly preferably 0-3 wt.% other auxiliary substances, for example, amplifiers stickiness, antioxidants, stabilizers, stimulants, penetration, and hot-melt contact adhesive (a) is preferably selected from the group including

(A1) contact adhesive EVA,

(A2) contact adhesive type SXS or

(A3) a mixture consisting of

(I) 70-99 wt.% resistant to amines silicone glue,

(II) 1-30 wt.%, preferably 3-15 wt.% and even more preferably 4-10 wt.% appropriate plasticizer, preferably organic wax and especially preferably of ceresin or ozokerite,

with contact glue EVA (A1) and contact glue type SXS (A2), if necessary, can be added plasticizers, and if you use contact adhesive type SXS, and antioxidant.

If hot-melt contact adhesive, for example, contact adhesive type SXS or EVA need to be aligned with specific technological requirements, it is up to him if necessary, can be also added additional components of the prescription, for example, additional plasticizers, amplifiers stickiness, antioxidants, amphiphilic polymers, etc.

It was found that in comparison with various other hot-melt contact adhesives contact adhesive based on silicone provides a better efficiency of the release of rotigotine of TTC. The reduction in the release of rotigotine what about therapeutically ineffective level of the hot-melt TTS type SXS and EVA comes to a point in time, when the adhesive matrices of these TTS still nonliberalized to 30 wt.% rotigotine. In contrast, the reserve rotigotine in hot-melt TTS based on silicone can be almost completely exhausted.

Thus, as described above containing rotigotine hot-melt TTS with hot-melt contact adhesive based on silicone is the most preferred.

Experimental part

Comparative example.

Silicone TTS solvent-based

1.8 g of rotigotine (as free base) is dissolved in 2.4 g of ethanol and the solution is added to 0.4 g of the product Kollidon 90F, dissolved in 1 g of ethanol. The resulting mixture was added to a solution of silicone polymer [(8,9 g BioPSA 7-4201+8,9 g BIO-PSA 7-4301 (Dow Corning)] heptane concentration of 74%. After adding 2.65 g petroleum ether mixture for 1 hour, mixed with speed stirrer 700 rpm until a homogeneous dispersion. The mixture layer on a polyester film and dried at 50°C. the Mass of the obtained patch is 50 g/cm2.

Example 1. Receipt containing 15% rotigotine hot-melt TTS based on silicone in laboratory conditions

(a) Silicone hot-melt contact adhesive

Used hot-melt contact adhesives based on silicone containing a mixture of a silicone adhesive Bio-PSA 7-4300 (Dow Corning, mi) with Otokar the volume or ceresin as a plasticizer, the concentration is calculated on the total weight of the mixture of the contact adhesive was 5, 10 or 15% (adhesives purchased from Dow Corning).

(b) Obtaining TTC

8.5 g of a mixture of a contact adhesive based on silicone in accordance with paragraph (a) about 20 min was heated at 160°before the formation of a homogeneous melt. Added 1.5 g of rotigotine (as free base) and the resulting mixture was stirred for 5 min at 160°C. it was Then subjected to manual homogenization and layered heated to 120°With film (width of the gap of 250 μm). Chiseled samples TTC area of 5 cm2.

Example 2. Getting hot-melt TTS based on silicone with an internal phase

TTC was obtained analogously to example 1, and simultaneously with rotigotine was administered 0.5 g vnutrivennogo component.

Example 3. Getting hot-melt TTS based on silicone with varying parameters in laboratory conditions

TTC received mostly similar to examples 1 and 2. Various parameters, in particular, the type of wax, its content, the concentration vnutrivennogo component, the content of biologically active substances, the density of the IDT varied as indicated in table 1.

Table 1
Hot-melt TTS based on silicone
Code part and (recipes) The content of ceresin, [wt.%]The content of wax, [wt.%]Internal phase, type/ content [wt.%]theoretical content of rotigotine, [wt.%]The measured content of rotigotine (n=5), [wt.%]The weight of the adhesive layer (n=10), [g/m2]
2001103115-PVP/1098,51108
2001103215-PVP/299,2383
2001103515-PVP/21515,8166
2001103615-PVP/101515,56100
2001203815-PVP/29The concentration is**)123
2001204015-PVP/215The concentration is**)118
2001204215-PVP/225The concentration is**)114
2010304215-01515,2557
2003043 15-PVP/251514,04127
2010503815-098,7591
2010503915-PVP/299,0788
2010504015-PVP/1099,1491
201050415-098,08106
20105043-5098,03105
2010504415-01514,5078
2010504515-02525,2077
20106016-15098,1288
20107040-501513,7199
20107041-502524,7184
20109009- 1501513,2889
201090105-about1514,09107
20111059-5about2523,9554
20111058-5about15of 14.5754
20111057-5about98,6456
20109043-5about2522,69117
20105044-15about1514,4957
20103043-15about1514,0478
WE11682*)--PVP/298,8350
20107011*)--PVP/299,90110
*) Comparative example (solvent-based)

**) N.O.=not determined

The content of rotigotine and weight of the adhesive matrix op delali as follows. Carving out 10 samples of patch area of 5, 10 or 20 cm2, each of which weighed from the weighing result subtracted defined by weighing the average mass of pure film similar area (5, 10 or 20 cm2).

Example 4. Getting hot-melt TTS based on SXS or EVA in laboratory conditions

8.5 g of the hot melt contact adhesive type SXS (Duro-Tak 34-4230; National Starch &Chemical) or 8.5 g contact hot-melt adhesive EVA about 20 min was heated at 160°before the formation of a homogeneous melt. To the melt was added 1.5 g or 1.65 g rotigotine in the form of the base and the mixture was subjected to manual homogenization. It was then layered on the film, using a temperature-controlled (120° (C) roller device. Chiseled samples TTC area of 5 cm2(to determine the penetration of rotigotine) and 20 cm2(to determine the mass IDT). Values of the mass of the samples are shown in table 2.

Table 2
Code party (recipe)GlueThe content of the internal phase [wt.%]theoretical content of biologically active substances [wt.%]The measured content of biologically active substances [wt.%]Mass (n=10), [g/m2]The degree of purity (220/272 nm) [%]
SXS-1514,968594,9/94,3
20103048EVA-16,218,245898,1/99,7
20103047EVA-16,215,9612798,8/99,9

Example 5. Getting hot-melt TTS based on silicone with 15% of rotigotine and 5% of the internal phase in the extruder

A. prior to the melt mixture of silicone contact adhesive

The desired number described in example 1, a mixture of silicone contact adhesive was injected into the metering device Meltex GR 12-1 company Melzer and heated to 140°C. the mixture is Then volumetric they dosaged in the extruder.

B. Receiving the adhesive layer by hot melt

Used dvuhseriynyy extruder designed for small - and medium-scale production (firm Dr. Collin GmbH, 25×24D), as well as industrial dvuhseriynyy extruder ZSK25 firm Werner Pfleiderer (Stuttgart). The mode of extrusion: the rate of 5 kg/h, the temperature in the heating zones 120-140°C. For layering used laminator Melzer CL200.

Example 6. Getting hot-melt TTS based on silicone with varying parameters in the extruder

TTC received mostly analogously to example 5. While the TTS settings were varied as follows.

Table 3
No.Code party (recipe)ScaleStatic mixingThe content of ceresin, [wt.%]The content of the internal phase [wt.%]theoretical content of rotigotine, [wt.%]Measured

Noah contents of rotigotine (n=5), [wt.%]
The weight of the adhesive layer (n=10), [g/m2]The degree of purity of rotigotine (220/272 nm) [%]
120105025Large-15PVA/1098,8811799,3/99,7
220105025Large+15PVA/1097.16*)11799,3/99,9
320105018Large-15PVA/1099,169299,4/100
420105018Large+15PVA/109at 8.3686of 99.5/100
520109006Small- 15PVA/1098,808299,6
620109007Small-15PITA/1098,969898,3
720109008Small-15PEO/1097,2888of 99.1
820108030Large+15-2522,4318799,2/not defined
920105045Small-15-2525,27798,7/a 96.9
PVPA=copolymer of vinylpyrrolidone with vinyl acetate

Example 7. Getting hot-melt TTS based on EVA in the extruder TTC received mostly analogously to example 5. Received TTS had the following characteristics :

Table 4
Code party (recipe)ScaleThe content of the internal phase [wt.%]theoretical content of biologically active substances which, [wt.%],The measured content of biologically active substances (n=5), [wt.%]Mass (n=10), [g/m2]The degree of purity of rotigotine (220 / 272 nm) [%]
20103048Small-16,218,245898,1/99,7
20103047Small-16,215,9612798,8/99,9
20109019Large-98,629398,9/99,9
20109045Large-1515,0810499,4/not defined
20109020Large-20a 18.578996,1/not defined

Example 8. The current detection of biologically active substances on the skin model mouse

For current measurement of biologically active substances through the skin of the mouse was used skin thickness from 120 to 150 μm, taken from the abdomen and back of a hairless mouse. TTC with the square cut of 2.55 cm2recorded in horizontal diffusion cell from the stratum corneum skin samples. Directly following this, the acceptor chamber of the cell was filled thermostatic p and 32° With of 0.066 modernim phosphate buffer solution with a pH of 6.2, avoiding air bubbles, and thermostatically Wednesday release at a temperature of 32±0,5°C.

By the time of selection of the sample environment release was replaced with fresh, thermostated at 32±0,5°With the environment. Release rotigotine controlled by HPLC as described in example 10.

Example 9. The current definition of rotigotine on the model of human skin

Current rotigotine through human skin was determined basically as described in .Tanojo etc., J. Control Rel. 45, 1997, c.41-47.

For this selected human skin thickness of about 250 μm from the abdomen. Sample TTC area of 2,545 cm2recorded on the skin similar to a square, and the skin is adjoined to the acceptor-side silicon membrane (scheme 1). As acceptor phase used a buffered phosphate of 0.066 malarky physiological solution with a pH of 6.2 and a temperature of 32±0.5°C. Experiments were performed within 72 hours at the speed of a current of 5 ml/h, and every 3 hours taking samples. By the time of the sampling environment release was replaced with fresh, thermostated at 32±0,5°environment and HPLC was measured by the number of released rotigotine. The flow rate of rotigotine Q(t) was determined based on the contact area of the measuring cell (0,552 cm2) by the formula:

Q(t=µ g/cm 2=concentration of rotigotine in the amount of acceptor/0.552 cm2.

Example 10. Analytical determination of rotigotine

(a) Analytical determination of release of biologically active substances

Current bioactive substances prepared through the skin was determined by HPLC (RPC18 column LichroCART 75×4 mm, Superspher 60select) under the following conditions: 650 obtala water, 350 obtala acetonitrile, 0.5 to obtala methansulfonate; room temperature; wavelength of 272 nm; flow rate of 2 ml

(b) Analytical determination of the content of biologically active substances in the adhesive matrix

(B1) preparing a matrix

The adhesive matrix was mixed with 0.1% methansulfonate, and the mixture was shaken, centrifuged and performed the measurement.

(B2) Analytical determination of the content of biologically active substances

The content of biologically active substances were identified by means of isocratic HPLC under the following conditions:

solvent: 65 obtala water with 0.05% methansulfonate, 35 obtala acetonitrile with 0.05% methansulfonate;

column: LiChroCART, 75×4 mm, Superspher 60 RP-select B, 5 µm;

rate: 2 ml/min, column temperature 30°C;

UV detection (272 nm).

(B3) Analytical determination of the stability of biologically active substances

The degree of purity of rotigotine was determined by the method of gradient HPLC using aqueous and organic (acetonitrile) phase by adding to each of them with 0.05% methansulfonate. The initial content of the organic phase with 5%, for 35 minutes, it was increased to 60%.

Column: LiChrospher 100 CN, 125×4.6 mm, 5 µm;

speed: 1.0 ml, column temperature 40°C;

UV detection (two wavelength: 272 and 220 nm).

(B4) Determining the dynamic viscosity

The dynamic viscosity was determined as described in RE 36754.

1. Transdermal therapeutic system (TTS)comprising the adhesive matrix containing a biologically active substance rotigotine [(-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl) ethyl) amino]-1-naphthol], wherein the adhesive matrix contains a hot-melt contact adhesive and hot-melt contact adhesive consists of a contact adhesive, a mixture of different contact adhesives or contact adhesives with a plasticizer and at 160°has a dynamic viscosity of not more than 100 PA·with TTS obtained by hot melting.

2. TTS according to claim 1, and rotigotine dispersed, partially or completely dissolved in the specified hot-melt glue.

3. TTS according to claim 1, and containing rotigotine adhesive matrix obtained by dosing rotigotine in solvent-free melt adhesive matrix at a temperature of from 70 to 200°C.

4. TTS according to claim 1, whereby the hot-melt contact adhesive consists of a mixture of resistant to amines silicone contact adhesive, at least one n is improper plasticizer.

5. TTS according to claim 4, whereby the plasticizer is an organic wax.

6. TTS according to claim 4, whereby the plasticizer is ceresin or ozokerite.

7. TTS according to claim 1, whereby the content of rotigotine in the adhesive layer is 4-40 wt.%.

8. TTS according to claim 1, whereby the content of rotigotine in the adhesive layer is 9-30 wt.%,

9. TTS according to claim 1, whereby the content of rotigotine in the adhesive layer is 20-40 wt.%.

10. TTC by one of the previous paragraphs, rotigotine is in the form of a Foundation.

11. TTS according to claim 1, and the adhesive matrix containing the biologically active substance further comprises vnutriplitnyi component wybrany from the group including

(a) a hydrophilic or amphiphilic polymers

(b) a hydrophilic or amphiphilic copolymers,

(C) a mixture of (a) and/or (b) with a pharmaceutically acceptable plasticizers,

(g) condensates of glycerol and fatty acids or polyols,

(d) appropriate mixture of components (a)to(g).

12. TTS according to claim 11, and nutrigenie components selected from the group comprising polysaccharides, substituted polysaccharides, polyethylene oxide, polyvinyl acetate, polyvinylpyrrolidone, copolymers consisting of polyvinylpyrrolidone and (poly)vinyl acetate, polyethylene glycol, polypropyleneglycol, copolymers of ethylene with vinyl acetate, esters of glycerin and fatty acids as well as mixtures on Ivanilova alcohol with glycerin.

13. TTS according to claim 1, wherein the adhesive matrix contains (a) 50-99 wt.% the specified contact hot-melt adhesive, (b) 4-40 wt.% rotigotine, (b) 0-40 wt.% vnutrivennogo component (d) 0-10 wt.% additional auxiliary substances.

14. TTS according to claim 11 or 13, and the specified hot-melt contact adhesive selected from the group comprising (A1) a contact adhesive based on a copolymer of ethylene with vinyl acetate (EVA), (A2) contact adhesive type SXS-based block copolymer of styrene or (A3) a mixture consisting of (I) 70-99 wt.% resistant to amines silicone adhesive, (II) 1-30 wt.% appropriate plasticizer.

15. Transdermal therapeutic system (TTS) for the transdermal application of rotigotine [(-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl)amino]-1-naphthol], while TTC includes containing rotigotine layer consisting of a contact adhesive, a mixture of different contact adhesives or contact adhesives with a plasticizer and at 160°With a dynamic viscosity of not more than 100 PA·C, characterized in that it contains (a) at least 20 wt.% rotigotine, (b) at least 2.0 mg/cm2rotigotine, (C) optionally, an organic wax and/or vnutriplitnyi component in the quantity, slow down the release of biologically active substances, while TTC obtained by hot melting.

16. TTC by § 15, and rotogate is transported through the skin with a stationary flow rate of 100-500 μg/h in the period constituting at least 5 days.

17. TTC by § 15, and rotigotine is transported through the skin of a person with a flow rate of 100-500 μg/h for 7 days.

18. TTC by § 15, and TTC induced in the plasma of the patient rotigotine in average concentrations of 0.4-2 ng/ml over a period of at least 5 days.

19. A method of obtaining a transdermal therapeutic system (TTS)comprising the adhesive matrix containing the biologically active substance rotigotine [(-)-5,6,7,8-tetrahydro-6- [propyl[2-(2-thienyl)ethyl)amino]-1-naphthol], characterized in that the adhesive matrix using hot-melt contact adhesive and hot-melt contact adhesive consists of a contact adhesive, a mixture of different contact adhesives or contact adhesives with a plasticizer and at 160°With a dynamic viscosity of not more than 100 PA·and before layering adhesive matrix components is melted and homogenized without the use of solvents at a temperature of from 70 to 200°C.

20. The method according to claim 19, characterized in that the melting and homogenization of the components of the adhesive matrix is carried out in an extruder.

21. The use of rotigotine to get way hot melting transdermal therapeutic system (TTS), in which rotigotine injected in solvent-free pre-melted adhesive is atrica at a temperature of from 70 to 200° And in the adhesive matrix, use hot-melt contact adhesive consisting of a contact adhesive, a mixture of different contact adhesives or contact adhesives with a plasticizer and at 160°With a dynamic viscosity of not more than 100 PA·C.

22. Use item 21, in which the hot melt implement at a temperature of from 120 to 160°C.

23. The application of article 22, in which rotigotine injected into the melt adhesive matrix in the solid state.

24. The application of article 22, which is determined by HPLC at 220 and 272 nm, the degree of purity of rotigotine that are received by way of a hot-melt adhesive matrix is at least 98%.



 

Same patents:

FIELD: medicine.

SUBSTANCE: the present innovation deals with obtaining a biologically active peptide fraction out of poultry blood serum being useful at some human and animal diseases and disorders. It is necessary to carry out electrostimulation of a bird's head at the mode of about 70-80 V for about 2-3 sec to sample blood and incubate it at 4-8°C for about 18-24 h, then the serum sampled should be irradiated with C0 60 at the mode of 25±5.0 kGy and extracted after irradiation with 0.5 mM solution of phenylmethane sulfonyl fluoride in distilled water at the ratio of 1:10 to be mixed at 5°C for 1 h and centrifuged at 12000 rot./min for 30 min, then the residue should be repeatedly centrifuged under the same conditions, supernatant should be filtered successively through the membrane at pore's diameter being 0.45 mcm and 10 kDa, and a target product being a peptide fraction at molecular weight up to 10 kDa should be lyophilized and kept at about 4-8°C. The suggested pharmaceutical composition is characterized by the fact that as an active substance it contains efficient quantity of peptides of molecular weight up to 10 kDa obtained to a certain technique and a pharmaceutically acceptable carrier or filler. The innovation enables to obtain new biologically active peptide fraction up to 10 kDa and develop its medicinal form.

EFFECT: higher efficiency.

2 cl, 2 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel derivative of 5-methoxy-8-aryl[1,2,4]-triazole[1,5-a]pyridine of the general formula (I): wherein R1 means hydrogen, halogen atom or lower alkoxy-group; R2 means -C(O)-phenyl wherein ring can be unsubstituted or substituted with one or two substitutes chosen from group consisting of halogen atom, lower alkyl, lower alkoxy-group or trifluoromethyl, or it means -C(O)-furanyl or -C(O)-thiophenyl wherein rings are not substituted or substituted with halogen atom, and its pharmaceutically acceptable salts. Proposed compounds can be used in treatment of diseases associated with adenosine A2 receptors. Also, invention describes a medicinal agent used in treatment of diseases associated with adenosine A2A receptors containing compound of the formula (I) and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of agent.

8 cl, 1 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes using the compound (R/S)-(-/+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or their salts for preparing a medicinal agent. This agent is used in treatment of extrapyramidal motor disorders, in particular, in treatment of unfavorable effects of anti-parkinsonic preparations and using (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman in combination with an anti-parkinsonic preparation for preparing the combined medicinal agent. Also, invention relates to a pharmaceutical composition for treatment of extrapyramidal disorders and a set of the same designation. Proposed compounds are able to prevent catalepsy caused by usual anti-dopaminergic preparations and they are strong agonists of 5-HT1A-receptors in combination with antagonism to dopamine D2-receptors and interaction with D3-receptors that provides positive effects on extrapyramidal system in treatment of dyskinesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzothiazole of the general formula (I): and their pharmaceutically acceptable acid-additive salts used as ligands of adenosine receptors and to a medicinal agent based on thereof. In compound of the general formula (I) R means phenyl, pyridine-2-yl, -C(O)-O-(lower)-alkyl, -C(O)-(lower)-alkyl, -C(O)-morpholinyl, -C(O)-NR'2, -(CH2)n-NR'2 or -(CH2)n-O-(lower)-alkyl; R' means hydrogen atom or (lower)-alkyl. Compounds can be used in treatment and prophylaxis of diseases mediated by adenosine receptors A2A and A1, for example, in Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease.

EFFECT: valuable medicinal properties of compounds.

15 cl, 3 sch, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nicotine- or isonicotine-benzothiazole of general formulas (IA) and (IB) their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. In compounds of general formula (IA) and (IB) R1 means phenyl, piperidine-1-yl or morpholine; A means -O-; R means -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)n-O-lower alkyl, lower alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R''), -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidinyl or (C4-C6)-cycloalkyl; R'' mean(s) independently of one another hydrogen atom or lower alkyl; n= 1 or 2; A means -N(R')-; R means lower alkyl, (C4-C6)-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R'')2; R' and R'' mean independently of one another hydrogen atom or lower alkyl; n = 1 or 2; or A means -CH2-; R means -N(R'')-(CH2)m-O-lower alkyl, -N(R'')2, S-lower alkyl, or R means azethidinyl, pyrrolidinyl or piperidinyl that are substituted optionally with hydroxy-group or lower alkoxy-group; or R means morpholinyl, -N(R'')-(CH2)m-(C4-C6)-cycloalkyl, -N(R'')-(CH2)m-C(O)-O-lower alkyl, -O-(CH2)m-O-lower alkyl or alkoxy-group; R'' mean(s) independently of one another hydrogen atom or lower alkyl; m = 1, 2 or 3; or A means -S-; R means lower alkyl, or A-R mean in common piperazinyl substituted with alkyl, -C(O)-lower alkyl or oxo-group, or group A-R means piperidinyl substituted with lower alkoxy-group or hydroxy-group, or group A-R means morpholinyl substituted with lower alkyl, or group A-R means (C4-C6)-cycloalkyl, azethidine-1-yl optionally substituted with hydroxy-group or lower alkoxy-group, or group A-R means thiomorpholinyl-1,1-dioxo-group, tetrahydropyrane or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Proposed compounds can be used in treatment of diseases mediated by adenosine A2A-receptors, for example, Alzheimer disease, some depressive states, toxicomania and Parkinson's disease.

EFFECT: valuable medicinal properties of compounds and agent.

37 cl, 10 sch, 109 ex

Fumaric acid amides // 2290946

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents, namely, to using fumaric acid amides of the formula (I): These compounds are used in preparing a medicinal agent designated for treatment of autoimmune diseases, response reactions "transplant against host", treatment of diseases mediated by NfkappaB, and to fumaric acid amides of the formula (I) and to a medicinal agent comprising fumaric acid amide of the formula (I) taken in the dose corresponding to 1-500 mg of fumaric acid as measured for a single dose and designated for treatment abovementioned diseases. Fumaric acid amides and a medicinal agent comprising thereof are characterized by absence of systemic adverse effect of body and resistance against hydrolysis that allows avoiding their multiply dosing.

EFFECT: valuable medicinal properties of agents.

19 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I) wherein radicals R1, R2 and alk have values given in claim 1 of the invention claim. Compounds prepared by a method by claim 6 are important antagonists of 5-HT2A-receptors and can be sued in treatment psychosis, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's diseases, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's chorea, nutritional disturbances, such as bulimia, nervous-psychic anorexia, premenstrual syndrome and/or for the positive effect on obsessive-compulsive disorder.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

12 cl, 12 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine that are partial agonists of D2 receptors and can be used in treatment of the central nervous system disorders, in particular, Parkinson's disease. Invention describes derivatives of benzoxazolone of the formula (1): wherein R means group of the formula (a) or (b) , and their salts. Also, invention describes a method for preparing compounds of the formula (1), pharmaceutical composition based on compounds of the formula (1), method for treatment of Parkinson's disease and method for treatment of the central nervous system disorders, such as schizophrenia, anxiety state and depression based on compounds of the formula 91). Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: improved methods for treatment, valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention proposes a medicinal preparation for treatment of extrapyramidal disorders (Parkinson's disease, dyskinetic and choreic syndromes, in particular, Huntington chorea, dystonic syndromes, later dyskinesia, tremor, Gilles de la Tourette's disease, ballism, fatigue legs syndrome and Wilson's disease), and a pharmaceutical composition and a set for the same designation also. As a medicinal preparation invention proposes (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or its physiologically acceptable salt known early as a combined selective antagonist of dopamine D2 receptors and antagonist of serotonin receptor of 1A subtype. These properties and high affinity to D3 receptor show favorable effect on extrapyramidal and motor systems. Pharmaceutical composition and set comprise (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or its salt and a medicinal preparation against Parkinson's disease as active compounds. The compound (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman decreased extrapyramidal moving disorders caused by neuroleptics and enhanced their anti-parkinsonic effect, i. e. it shows property to diminish symptoms of Parkinson's disease and to enhance the general activity.

EFFECT: improved and valuable medicinal properties of compound and pharmaceutical composition.

26 cl, 10 ex

FIELD: medicine.

SUBSTANCE: method involves applying plaster having sealing protection layer and contact layer attached to mentioned protection layer. The contact layer is directly engageable with nail and optionally with surrounding skin areas. The contact layer is manufactured from adhesive material, agent for stimulating penetration through skin and/or nail, therapeutically effective quantity of pharmaceutically active antifungal agent and permissible additives.

EFFECT: enhanced effectiveness of treatment.

21 cl

FIELD: medicine.

SUBSTANCE: system is applicable to skin surface.

EFFECT: improved flexibility and wear resistance.

7 cl, 3 dwg, 5 tbl

FIELD: medicine.

SUBSTANCE: invention describes a percutaneous or permucous medicinal formulation used in treatment of nicotine dependence or elimination from the smoking habit. Proposed medicinal formulation comprises nicotine, nicotinic salt, a derivative of nicotine or substance enhancing effect of nicotine in combination with at least one additional substance effecting on the central nervous system. Oral dosing an additional substance effecting on the central nervous system excludes adverse effects and providing a simple and safety intake of drug for patients.

EFFECT: improved and valuable properties of formulation.

10 cl

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes a transdermal plaster for administration of fentanyl, alfentanyl, carfentanyl, lofentanyl, remifentanyl, sufentanyl or trifentanyl through skin and comprising a backing. Also, a reservoir is disposed on a backing and wherein proposed plaster displays an unregulated rate in administration of fentanyl, alfentanyl, carfentanyl, lofentanyl, remifentanyl, sufentanyl or trefentanyl through a patient skin in aims for analgesia for the prolonged time.

EFFECT: valuable medicinal properties of plaster.

85 cl, 4 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: preparation is characterized by rapidly degrading or water-soluble plate in the environment, mainly consisting of one or several polymers soluble in water, and at least one active ingredient. The dosage form matrix is hardened foam in which empty spaces or cavities are available as a result of foaming soluble polymers in water containing foam-stabilizing substance differing from the active component. The cavities are filled with gas, gas mixtures or, preferably, with air. Dosage form thickness is 50 μm-5 mm large. Dosage form surface is rough or irregular, preferably made corrugated or zoned. Method involves producing plate-shaped dosage forms, distinguished by water-soluble polymers solution-, dispersion medium - or melt-foaming stages realization. The foaming stage is carried out as, for example, foaming film-forming polymer solution or dispersion medium by introducing gas or gas mixtures into it after having preliminarily added foam-stabilizing substances or by carrying out dissolved gas decompression, when needed, after adding foam-stabilizing substances, or by adding hydrophobic solvent which does not mix up with solvent, used for preparing water-soluble polymer solution or a dispersion medium with emulsion being produced, that contains hydrophobic solvent as finely dispersed drops. The solvent is the removed producing in this way foamed matrix structure, or by adding fillers or filler combinations, capable of gassing, or foaming water-soluble polymer melt by introducing gas or gas mixtures into it, or by receiving gas in chemical way, or by decompressing dissolved gas if needed, after having preliminarily added foam-stabilizing substances. A plate for introducing drugs is described with active ingredient selected from group composed of nicotine and nicotine bitartrate.

EFFECT: enhanced effectiveness of treatment; wide range of functional applications.

9 cl

FIELD: cosmetics, medicine, pharmacy.

SUBSTANCE: invention relates to compositions used in topical applying and possessing improved water-retaining properties and improved releasing of active agent. Proposed cosmetic compositions contain from 5% to 70% of pentane-1,5-diol by mass and cosmetically acceptable carrier and under condition that this composition doesn't contain polysiloxane, volatile siloxane, phosphatidylcholine, creatine, carnitine, pantenol, pyruvic acid, lauric acid monoglyceride or myristic acid monoglyceride. Also, invention discloses corresponding methods for administration, plaster for attachment of indicated composition to skin and methods for prophylaxis or treatment of skin dryness state or maintaining skin in moisture state. Compositions for topical using and administration of pharmaceutical preparation possess the improved water-retaining properties, improved releasing active agent being without toxicity and skin irritation.

EFFECT: improved and valuable medicinal properties of compositions.

37 cl, 5 tbl, 1 dwg, 6 ex

FIELD: medicine, stomatology.

SUBSTANCE: invention relates to agents and method for whitening teeth. Agent for whitening teeth represents a film made of combined hydrophobic and hydrophilic layers. Hydrophilic layer comprises hydrogen peroxide or its complexes with organic, inorganic polymeric compounds and fluoride-containing compounds, and/or potassium nitrate. Accessory components are included in both hydrophilic and hydrophobic layers of film wherein the content of a whitening component is 1.2-1.5 mg/cm2 as measured for hydrogen peroxide, and the film thickness is 0.2-0.6 mm. For whitening teeth this film is glued on the moister frontal surface of teeth row by gums line for 2-4 h. Agent and method for whitening don't show irritating effect in mouth cavity tissues, injury of teeth or destruct teeth enamel.

EFFECT: improved and valuable properties of agent and method.

7 cl, 16 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to porous spongy cellulose material for its using in treatment of wounds and/or burns. Cellulose material comprises zinc, copper, selenium and/or iron bound with the matrix material and/or absorbed on its in the amount providing granulation and revascularization processes of the wound base wherein the amount of zinc, copper, selenium and/or iron is at least 0.1 mcg/g of dry material. The porous spongy cellulose material is effective by consumptions for its preparing and can be used easily in treatment of wounds and/or burns.

EFFECT: enhanced effectiveness and valuable medicinal properties of material.

12 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention proposes using percutaneous therapeutic system inducing high plasma levels of rotigotin for producing anti-parkinsonic medicinal agent and a method for treatment of Parkinson's disease. Proposed system involves rotigotin in the concentration from 0.1 to 3.15 mg/cm2 in form of free base and silicone representing a mixture of at least one pressure-sensitive stick silicone adhesive (Q7-4301) and at least one pressure-sensitive silicone adhesive with mean stickness (Q7-4201). This provides an average plasma concentration of rotigotin from 0.4 to 2.0 ng/ml for 24 h after its applying.

EFFECT: enhanced medicinal effectiveness of system.

10 cl, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: system is distinguished by reduced formation of oxidation decomposition products during transdermal therapeutic system storage time that is related to at least one active substance containing in given system capable of being oxidized with hyperoxides. The transdermal therapeutic system is characterized in that peroxidation number (POZ) sum of auxiliary substances in the drug containing one or several active substances relative to proportion selected according to transdermal therapeutic system formulation is not greater than 20.

EFFECT: reduced quantity of oxidation products.

11 cl

FIELD: medicine.

SUBSTANCE: the suggested compositions include taxol as a factor to inhibit the development of blood vessels and a pharmaceutically acceptable carrier. Also, it has been described the method of embolization of blood vessel dealing with the supply of therapeutically efficient quantity of the above-mentioned composition into the vessel mentioned. According to the innovation in question these compositions are nontoxic, thrombogenic, they don't change their form or physical properties during storage period before their application, they reveal no clotting signs at formation of large-sized particles in solution and after injection, they lead to slow release of the factor that inhibits the development of blood vessels.

EFFECT: higher efficiency.

18 cl, 22 dwg, 19 ex, 3 tbl

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