SI9200262A - Transdermal penetration accelerator - Google Patents

Abstract

Formulation to increase transdermal permeability pharmaceuticals or other biologically of active substances, characterized by the penetration content of the accelerator parts of lanolin derivatives per se or mixed with isopropyl alcohol esters with long-chain fatty acids and / or polyethylene glycols fatty alcohols of longer chains than penetration the accelerator as well as the process for their production.

Description

Penetration is an accelerating substance

FIELD OF THE INVENTION

Field of the invention to which the invention relates are lanolin derivatives as a penetration promoting agent and their use in formulations containing pharmaceutical substances or other biologically active substances.

A technical problem

The invention relates to lanolin derivatives alone or in admixture with isopropyl-1-alcohol esters with long-chain fatty acids and / or

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92-9200262 Long-chain polyethylene glycol ethers of fatty alcohols as penetration of an accelerating substance in formulations containing pharmaceutical substances or other biologically active substances.

Transdermal administration offers a number of advantages for a multiplicity of pharmaceutical substances or other biologically active substances:

- Skin is indefinitely accessible

- no change of the medium occurs in the case of oral use

- surgery is easy and comfortable

- a single dose is sufficient, rather than repeated daily doses

- Positive psychological effects are noted

- continuous therapy is possible over a long period of time

- constant plasma levels are guaranteed over a long period

- therapy can be discontinued at any time

- the plasma level, which is initially too high, as in the case of intravenous administration, is prevented, resulting in negligible secondary action

- lower risk of overdose or underdose

- controlled release of the active substances, especially those with a low therapeutic index, is guaranteed.

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Background of the art 'ž ¹¹ si

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Some pharmaceuticals that, due to their high initial effect, their low dosage and their high .j '·' ki 'f / 1' k

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Although effective ala-9200262 were considered ideal, in many cases they have such a low permeability to the skin that the value of therapeutic plasma cannot be reached. In the case of all these pharmaceutical substances, the so-called penetration enhancers need to be added. This line describes the multiple substances listed in the following patent specifications:

US 4 299 826, US 4 343 798, US 4 046 886, US 4 130 643, US 4 405 616, US 4 335 115, US 4 130 667, US 3 903 256, US 4 379 454, US 3 527 864, US 3 952 099, US 3 896 238, US 3 472 931.

In addition to being able to fulfill their specific functions, penetration of the promoting substance must have the following properties: even if they remain on the skin for a long time, under absorption conditions, the skin must suffer, be allergic and be compatible with the active substances involved.

Accelerators known from the literature can be classified into different chemical classes:

1. primary and secondary alcohols f

1.1. Short-chain primary alcohols C ₂ to C ₈

1.2. Long chain primary alcohols C ₄ to C | ₆

1.3. Secondary alcohols C3 to C ₅

2. Anionic surfactants, such as Na - dodecyl sulfate, = 7 -: - 7 i ^ · ..: in YU -t.j.T Ljubljana, Klagenfurt (el .: 0611576 535 Telex 32-167 YU ADV;

Ρ-9200262

3. Saturated and unsaturated fatty acids

4. Azons and derivatives (1-alkyl azacycloheptan-2-one, 1-alkyl azacycloalkanones)

5. amides such as N, N-diethyl-3- methyl-benzamide (DEET), N, N-diethyl-metoluamide

6. Alkyl N, N-dialkyl aminoacetate ¹

7. Macrocyclic ketones and lactones

8. Pyrrolidones

9. Esters such as ethyl acetate, isopropyl perrystate, glycerin monolaurate, diethyl sebacate, propylene glycol esters of saturated fatty acids f

10. Terpenes such as limonene, menthol and cineole

11. Phosphatides

12. Organic acids such as citric acid, salicylic acid, etc.

13. Cationic surfactants and amines.

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The existence of so many substances of all possible chemical structures, all of which are claimed to have accelerated penetration effects, makes an amazing single mechanism work. Therefore, there are several mechanisms or a combination of these in the discussion.

1. Effect of solvents on active substance and skin lipids

2. Effect on membrane lipid structure

3. Effect on Keratin and on the Protein Structure of the Skin Given the many skin interactions and the different chemical properties exhibited with respect to the active substance concerned, it is very difficult to predict the penetration enhancement properties of all these so-called accelerators with respect to the active substance.

It can be said from previous experience that penetration of an accelerating substance is only very rarely in line with the characteristics required by pharmaceuticals or groups of pharmaceuticals.

Description of the solution to a technical problem with examples of implementation

It is an object of the invention to provide penetration enhancers that are tolerated by the skin, are compatible with the active substance in question, do not produce allergies that are - readily available and economical and that have the effect of accelerating penetration on more than one active substance.

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Ρ-9200262

We have now discovered, to our surprise, that certain lanolin derivatives have the property of increasing the penetration of certain pharmaceutical substances or active substances through the skin. These substances are normally used in the cosmetic industry for the manufacture of creams and lotions.

The task is solved according to the invention by lanolin derivatives alone or in a mixture with isopropyl alcohol esters with long-chain fatty acids and / or polyethylene glycol ethers of longer-chain fatty alcohols, which act as a penetration enhancer in formulations containing pharmaceutical substances or other pharmaceutical substances .

Preferred lanolin derivatives are selected from the group that. consists of acetylate lanolin, alcoholic lanolin-alcohol, alkoxylate lanolin, lanolinic acid, polyethoxylate lanolinic acid, lanolinic acid esters with alkali alcohols, such as isopropyl alcohololithol When polyethoxylate lanolin derivatives are used, the number of ethylene oxide molecules is between 2 and 50.

Linear or branched alcohols with Cj ^ to C ₄ , primarily primary or secondary, are suitable primarily as esters of lanolinic acid with short-chain aliphatic alcohols. Examples are methanol,

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Ρ-9200262 ethanol, n-propanol, n-butanol, isopropanol. Saturated or unsaturated fatty acids, such as lauric, palmitic and stearic acid, are also suitable as myristic, oleic and linoleic acids as long-chain fatty acid esters of lanolin alcohol.

If long-chain fatty acid isopropanol and / or longer-chain polyethylene glycol fatty acid esters are used in combination with lanolin derivatives, the aforementioned fatty acids are suitable as fatty acid constituents of the corresponding isopropanol esters. Alcohols corresponding to the aforementioned fatty acids, such as oleic, lauric, cetyl and stearyl alcohol, or their polyethylene ™ glycol ethers obtained from the said alcohols by reaction with differing molecular weights of ethylene oxide, are suitable as typical fatty alcohols longer chains. Known products are the condensation product of oleic alcohol of 2 to 50 moles of ethylene oxide, lauric alcohol of 2 to 40 moles, cetyl alcohol of 2 to 45 molars and stearyl alcohol of 2 to 100 moles of ethylene oxide.

Penetration is an accelerant consisting primarily of 1 to 100% by weight, in particular 1 to 60% by weight, of a lanolin derivative of 0 to 60% by weight, in particular 10 to 30% by weight, of an isopropyl alcohol ester; and from 0 to 99, preferably 30 to 90% by weight, of polyethylene glycol ether fatty

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Ρ-9200262 acids (sum of ingredients equal to 100).

if penetration enhancer is used in the therapeutic transdermal system (TTS), there is a penetration layer inaccessible to the active substances and at least one reservoir containing the active substance containing the penetration enhancer, a device for mounting the system on the skin, and if necessary, a removable trigger lining. The simplest example is the existence of a so-called monolayer formulation in which penetration is an accelerating substance (together with the active substance) expanded in a preferably self-adhesive matrix, provided with a trigger coating that is dehesive on the skin side and a cover layer away from the skin. In addition to a monolayer formulation of this type in which a penetration accelerator contained in a preferably self-adhesive matrix of solution or suspension, the pharmaceutical substance may also be finely ground with a penetration-enhancing substance, using the mixture on a base, preferably a piece of bonded fabric, or knitted or crocheted fabrics. The lining is then attached to the skin using a self-adhesive film.

In addition, multi-layer TTS can also be used. For example, in such a case, the pharmaceutical substance is applied to the substrate, either on its own or in part by penetration of the accelerating agent, which is applied to or in the first adhesive layer with respect to the skin, with either the total amount of the penetrating accelerator or

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Ρ-9200262 at least a portion extends in a layer separate from the reservoir, preferably in an adhesive layer of the cover coat. Penetration of the accelerant may thus be present in different layers in different concentrations or amounts.

It has been shown that the substances used as penetration enhancers according to the invention can be used both together with a pharmaceutical substance in a conventional matrix formulation with self-adhesive properties known to one skilled in the art, as well as in association with a pharmaceutical or active substance in jelly, cream or even in an ointment fixed in the therapeutic system and that they can be contacted directly with intact skin.

Despite repeated use, no skin irritation was detected.

The penetration enhancement effect is particularly useful with the active substance Verapamil 5 ~ (n- (3,4-dimethoxyphenethyl) N-methyl ~ amino) -23,4-dimethoxyphenyl) -2-isopropyl-valeronitrile and Gallopamil 5 ((3,4 -dimethoxy phenethyl) methylamino) -2-isopropl ~ 2- (3,4,5 ~ trimethoxyphenyl) valeronitrile. Penetration enhancement of isopropyl myristate from PCT / W087 / 00042 was described for Verapamile. The lanolin derivatives used according to the invention exhibit a much stronger penetration-enhancing effect for Verapamile, however, as can be seen in the following examples.

The invention will be explained in detail by the following examples:

6 · - / ·

Ρ-9200262

A. A single-layer formulation

The regulations described as a single-layer formulation refer to a self-adhesive matrix formulation with the following TTS construction (see Figure 1): the self-adhesive matrix 2 is laid on a protective layer 1 which is adhesive and covered with a cover 3.

Single Layer Formulation Example 1:

According to the present invention, a pharmaceutical product is produced with a single-layer construction of an adhesive matrix containing the active substances as follows:

Pressure-sensitive adhesive mass, which contains penetration of an accelerating ingredient and a pharmaceutical substance comprising:

0.170 kg of polyisobutylene (with an average molecular weight of 900,000 to 1,400,000)

0.202 kci solid aliphatic hydrocarbon resin (trade name: Hercures C, molecular weight around 1100)

0.152 kg polyterpene resin

0.072 kg ethylene oxide polymer HCKCl ^ -CH ^ -O) _n H n - 200 (PEG200)

0.072 kg colloidal silica

0.079 kg isopropyl myristate

0.181 kg Galloparnile

1,200 kg special spirit of 80-li'O boiling range as solvent

Ρ-9200262 is applied to both a protective layer that has been aluminized on one side and made adhesive on both sides to give an adhesive layer of 82 g / m ² after the solvent has evaporated.

After the adhesive layer has been covered with an impermeable cover layer made of polyester, the resulting laminate is separated into individual parts according to the therapeutic requirements.

Result of Example 1:

Content: 14.80 mg / 10 cm ² Gallopamil

By he rate of penetration (mouse skin): 9.61 mg Gallopamila / 10 ^cm2 / 24 h

Single Layer Formulation Example 2:

Production of Example 1:

Composition: 0.213 kg of polyisobutylene

0.253 kg of hydrocarbon resin 0.190 kg of polyterpene resin 0.045 kg of PEG 200

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Ρ-9200262

0.091 kg Aerosile 200 0.050 kg isopropylanolate 0.045 kg isopropyl myristate 0.113 kg Verapamile

1,400 kg of special spirit of boiling range 80-100

Adhesive layer after solvent has evaporated: 74 g / m ²

Result of Example 2:

Content: 8.4 mg Verapamil / 10 cm ²

The penetration rate (mouse skin): 5.71 mg Verapamil / 10 ^cm2 / 24 h

Single Layer Formulation Example 3:

Production by Example 1.

Composition: 0.213 kg of polyisobutylene

0.253 kg of hydrocarbon resin 0.190 kg of polyterpene resin

0.045 kg PEG 200

0.091 kg Aerosile 200

0.050 kg of isopropillanolate

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Ρ-9200262

0,045 kg polyoxyethylene (10) oleyl alcohol ether 0,113 kg Verapamil

1,300 kg of special spirit of boiling range 80-110

Adhesive layer after solvent evaporation: 85 g / m ²

Result of Example 3:

Contents: 9.62 mg Verapamil / 10 cm ²

The penetration rate (mouse skin): 6.14 mg Verapamil / 10 ^cm2 / 24 h

Single Layer Formulation Example 4:

t '

Production by Example 1.

Composition: 0.223 kg of polyisobutylene

0.265 kg of hydrocarbon resin 0.199 kg of polyterpene resin 0.047 kg of PEG 200

0.095 kg isopropillanolate 0.119 kg Gallopamile

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Ρ-9200262

Adhesive layer after solvent evaporation: 75 g / m ²

Result of Example 4:

Content: 8.89 mg Gallopamile / 10 cm ²

The penetration rate t

(mouse skin): 5.71 mg Gallopamila / 10 ^cm2 / 24 h

In order to produce further self-adhesive matrix formulations, the substances listed in the table are mixed in the form of solutions and suspensions (solvent or dispersing agent: petroleum spirit) applied to a protective layer which was made detergent by means of a solvent-free coating. warmed up and lined with mantle cover. The dry mass of the self-adhesive matrix (FG) j® is given in g / m2 in tabular form (T stands for parts by mass). The protective layer and the covering layer are the same as in Examples 1 to 4.

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- 15 Single Layer Formulation

i-f- C L · · 1 2 5 4 FG ^X g / m ² 95 74 82 79 Poliso- butelen 25,5 T 22,5 T 22,5 T 22,5 T Hydrocarbon resin 28,0 T 26,5 T ' 26,5 T 26,5 T Polyterpene resins 21,0 T 20,0 T 20,0 T 20,0 T PEG 200 5,0 T 4,8 T 4,8 T 4,8 T Colloidal silicate 10,0 T 9,5 t t ·· 9,5 T 9,5 T Penetration accelerator - lanolins alcohol 5,0 T lanolins alcohol 5,0 T 5,0 T acetylated lanolins alcohol Penetration accelerator - - - - Pharmaceutical substance A 12.5 T A 11.9 T A 11.9 T A 11.9 T Content mg / 10 cm ^ 11,88 8.76 9.74 9.58

'FG: weight per unit area • 2 ^: . L juij jrra, <i.chl! & 70-53S TcLx 32? Iovž \ a ;. , 37 YUn3>. .

- 1 no. 5 6 7 8 FG ^X g / m ² 72 90 91 85 Foliiso- butelen 22,5 T 22,5 T 22,5 T 22,5 T Hydrocarbon resin 26,5 T 26,5 T 26,5 T 26,5 T Foliterpene resin 20,0 T 20,0 T 20,0 T 20,0 T PEG 200 4,8 T 4,8 T 4,8 T 4,8 T Colloidal silicate 9,5 T 9,5 T 9,5 T 9,5 T Penetration accelerator isoproylanolate 5.0 T PPG-5lanolin alcohol pfer S, OT hydroxylated alcohol 5,0 T lanolin linoleate 5) 0 T Penetration accelerator - - - Pharmaceutical substance A 11.9 T B 11,9 T A 11.9 T A 11.9 T Content p mg / 10 cm 8.55 10.69 9.62 10,45

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No. 9 10 ^{......... 1} l 11 12 fg ^x 2 g / m 72 166 87 79 Poliiso- butelen 22,3 t 22,3 T 22,3 T 21,2 T Hydrocarbon resin 26,5 T 26,5 T Abitol 26.5 T 25,5 T loliterpene resins 19,9 T 19,9 T 19,9 T 18,9 T PEG 200 4.7 T 4.7 T 4,5 T 4,5 T Kolodni silicate 9,5 T 9,5 T 9,5 T 9,0 T Penetration accelerator Isopropyl- lanolate 5,2 T Isopropillanalate '5,2 T Isopropylenolate 5.2 T Isopropillanolate 5.9T Penetration accelerator - - - Pharmaceutical substance A 11.9 T A 11,9 t B 11,9 T A 11.3 T Content o mg / 10 cm 8.53 19,67 10,31 8.90

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- 18 Table A, Single Layer Formulation, continued

No. 1 2 5 4 5 6 7 The rate release p 24 h mg / 10 cnr 1,72 2.24 5,00 2.75 4.89 5.91 5.59 Mouse skin% 14.5 25.5 50.8 29.1 57,2 55.5 55,2

No _fc 8 ——... — .....- 1 9 10 11 12 Relaxation rate 24 h p mg / 10 cnr 5.05 f 4,18 2.76 5.81 5.70 Mouse skin% 48.5 49,0 14,0 57,0 41,6

A: verapamile base

B; gallopamile base polyisobutene hydrocarbon resin polyterpene resin PEG 200 colloidal SiOg 200 ϋθ'Έτ: · '.ΐ' <

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Β. Tank Formulation (Fine Grinding)

The instruction discussed in B.) refers in each case to the fine grinding of pharmaceutical substances by penetration of the accelerating agents indicated in the tables. In order to produce TTS, these mixtures are used on the substrate or carrier at the concentrations indicated in the table.

The substrate may consist of:

Knitted fabrics

Soaked fabrics

Foam tires (with open pores).

A coat of knitted fabric, plywood or foam rubber that has been impregnated with a finely ground mixture is adhered to the skin by means of a self-adhesive layer.

Example 13:

t

130 mg of the mixture (finely ground), consisting of:

2.0 c 3 Verapamile 1,0 < g isopropillanolate 1,0 < .) polyoxyethylene (10) oleyl alcohol ether from * 'et:: u i 1,0 < ; isopropyl myristate

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Ρ-9200262 is applied to a patch consisting of a self-adhesive covering layer and a central piece of plywood.

Penetration of the pharmaceutical substance through the mouse skin after nanositvi: 15.26 mg Verapamil / 2.54 ^cm2 / 24 h.

Example 14:

g grinders (finely ground), consisting of:

2.0 g Verapamile

1.0 g of isopropillanolate is used for the patch consisting of a self-adhesive covering layer and a central piece of plywood. Penetration of the pharmaceutical substance through the mouse skin after nanositvi: 6.76 mg Verapamil / 2.54 cm ^2/24

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- 21 Tank formulation / finely ground /

- - - 1 no. 15 16 Medication / g / 2.5 2.0 Penetration accelerator / g / - isopropyl- lanolate 1.0 Penetration accelerator / g / PEG 200 4.0 PEG 200 4.0 Penetration accelerator / g / - 1.0 Miscellaneous colloidal silicate 0.9 - The amount of grinding _? G / 2.54 cm 9 * 260 Content medicines A 31,8 A 104,0 Relaxation on mouse skin 24 h p mg / 2.54 cnr 0.55 2.88 ΐ Release to non-mouse skin% 1.7 2.8

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C. Multilayer formulation

The multilayer formulation described below shows the following composition (see Fig. 2):

The adhesive layer (2) is applied to the adhesive-treated protective layer (1) on / or in which the reservoir (3) is mounted. The reservoir (3) comprises an adhesive sheath impregnated with both the pharmaceutical substance and the oleyl alcohol polyethylene glycol. The reservoir (3) is lined with a cover layer (5). To create such a system, we proceed as follows:

the adhesive-treated protective layer (4), coated with the adhesive (2), is provided with a jacket of connective fabric (3). This coat of the binder fabric is coated with the formulation of the active substance, then receives the support layer (5) covered with the adhesive.

Example 17:

Pro Zvodnja:

The release liner, which has been aluminized on one side and made adhesive on both sides, is covered with a mixture consisting of:

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72.1 g of polyacrylate adhesive solution

32.2 g of polyacrylate base 6.7 g of isopropyllanolate in such a way that 'after the solution has evaporated, the mass per unit area of 50 g / m ^{2 of the} adhesive layer (adhesive matrix 2).

A layer of binder cloth coated with a mixture consisting of equal parts of Verapamil and polyoxyethylene (10) of oleyl alcohol ether is applied to this adhesive layer.

Verapamil Concentration in Plywood after Coating:

65.3 mg / 13.85 cm ²

The coated bonded fabric and the covered protective layer are coated (laminated) with a pressure-sensitive support coat consisting of a polyacrylate matrix with a mass per unit area of 100 g / m ² and a polyester jacket in such a way that the coated bonding fabric is surrounded by two pressure sensitive matrices. The resulting laminate is cut in such a way that a 1 cm wide adhesive edge of the free active substance is left close to the bonding fabric.

Claims (16)

PATENT APPLICATIONS 1. Penetration of a psychedelic substance or other biologically active substance characterized by the use of lanolin derivatives by themselves or in a mixture with esters of isopropyl alcohols with long-chain fatty acids and / or polyethylene glycol ethers of longer-chain fatty alcohols. 2. A formulation for enhancing transdermal penetration of pharmaceutical substances or other biologically active substances, characterized by the penetration content of the accelerating portion of lanolin derivatives alone or in mixture with isopropyl alcohol esters with long-chain fatty acids and / or polyethylene glycol ethers of fat-accelerating fat-penetrating fatty-penetrating alcohols. substances. A formulation according to claim 2, characterized in that the lanolin derivatives are selected from the group consisting of acetylated lanolin, acetylated lanolin alcohol, alkoxylated lanolin, lanolinic acid, polyethoxylated lanolin alcohol, lanolinic acid esters with short-chain alipolylophthalic aliphatic aliphatic aliphatic aliphatic aliphatic Long-chain fatty acid esters of lanolinic acid. 'Celovške / 676-536 Tolsx 22-1C7 VIJ' p. Ρ-9200262 A formulation according to claim 2, characterized in that the isopropyl alcohol esters are selected from the group consisting of isopropylisostearate, isopropylurate, isopropylinoleate, isopropyl myristate, isopropyl palmitate and isopropylstearate. 5. A formulation according to claim 2, characterized in that the selected polyethylene glycol ethers of the long chain fatty alcohols are from the group consisting of oleyl alcohol reaction products with 2 to 50 moles of ethylene oxide, lauryl alcohol with 2 to 40 moles of ethylene oxide, cetyl alcohol with 2 to 45 moles of ethylene oxide and stearyl alcohol with 2 to 100 moles of ethylene oxide. Formulation according to one of Claims 1 to 5, characterized in that there is a penetration promoting agent of 1 to 100% by weight, preferably 1 to 60% by weight of the lanolin derivative, from 0 to 60% by weight, preferably 10 to 30% by weight of ester isopropyl alcohol, and from 0 to 90% by weight, preferably 30 to 90% by weight of the polyethylene glycol ether of the fatty alcohols of the longer chains, with the sum of the constituents always being 100. Device according to one of Claims 1 to 6, characterized in that 5 ~ (N ~ (3,4 ~ dimethoxyphenyl) ~ N-methyl-amino) ~ 2 ~ 3,4 dimethoxyphenyl) -2-isopropyl- va1 eronitri1 or 5- ((3,4dimethoxyphenethyl) methylamino) ~ 2 ~ isopropl ~ 2 (3,4,5-trimethoxyphenyl) valeronitrile as a pharmaceutical substance. Ρ-9200262 A formulation according to claim 7, characterized in that a penetration enhancer is placed in the transdermal therapeutic system for the management of the active substances through the skin, containing a base layer inaccessible to the active substances, and adjacent a reservoir containing the active substances in which contained penetration-enhancing part, preparation for attachment to the skin and re-separable trigger lining. A formulation according to claim 8, characterized in that the penetration portion is 0.5 to 99 weight percent of the total weight of the reservoir of the transdermal therapeutic system. A formulation according to claims 8 to 9, characterized in that it forms the active substance of 1 to 5 weight percent, preferably 10 to 30 weight percent percent of the total mass of the tank. A formulation according to one of claims 8 to 10, characterized in that a reservoir with at least one layer is formed. A formulation according to one of claims 8 to 11, characterized in that With ¹ , the penetration portion of the accelerating part is divided differently into different layers. A formulation according to any one of claims 8 to 11, characterized in that the composition is by percentage penetration of the accelerating part different in different layers. 0Nine? '| \ YJ-RJ? 2 LiLjijanKCc ^ vj '« Phone: 051 / 576-535 Telex 32-137 - 27 Ρ-9200262 A formulation according to one of claims 8 to 13, characterized in that the reservoir is self-adhesive. A formulation according to claim 14, characterized in that the voar reservoir comprises polyisobutylene or polyacrylate. 16. A process for the production of a formulation to increase the transdermal permeability of pharmaceutical substances or other biologically active substances, characterized in that an effective amount of penetration of the accelerating substance in solid form or in solution or dispersion is introduced into an inorganic or organic medium in a formulation containing at least one pharmaceutical substance or one biologically active substance.