DK175982B1 - Pharmaceutical compsns. for trans:dermal admin. - contg. bopindolol, methysergide, tizanidine, clemastine or ketotifen - Google Patents

Abstract

Pharmaceutical compsns. for transdermal systemic admin. of an active agent are claimed, where (a) the active agent is bopindolol (I) or methysergide (II), or (b) the active agent is (I) (II), tizanidine (III) clemastine (IV) or ketotifen (V) in a reservoir comprising a hydrophilic polymer.

Description

DK 175982 B1

The present invention relates to a pharmaceutical composition for transdermal systemic administration of pharmacologically active agents as set forth in claim 1, with advantageous embodiments set forth in claims 2-4. The invention also relates to a process for the preparation of such a composition as claimed in claim 5 and to the use of a polyacrylate as claimed in claim 6.

Many pharmaceutical compositions for prolonged transdermal administration of pharmacologically active agents have been proposed in the systemic circuit. These generally comprise essentially a solid reservoir or matrix made of a solid polymer or gel containing the pharmacologically active agent dispersed therein. On one side of the drug reservoir there is a coating which is impermeable to the drug and on the other hand there is a protective tear strip which is removed before use. The coating may be larger than the drug reservoir and may have near its edges an adhesive layer to retain the protective tear strip and, when removed, to adhere the device to the skin. Further or alternatively, a reservoir permeability adhesive layer may be applied to the reservoir to retain the protective tear strip and adhere the device to the skin. In some suggestions, the drug reservoir has a drug permeability! a regulatory membrane or device attached thereto through which the pharmacologically active agent passes, in order to regulate the rate of penetration of the active agent, __ e.g. to prevent dose drop ("dose dumping").

2o

When used after the stripping strip has been removed, the device adheres to the skin and the pharmacologically active agent passes from the drug reservoir to the skin. More complicated systems have been proposed to improve the penetration rate of the pharmacologically active agent through the skin. However, most systems do not provide a sufficient penetration rate for the pharmacologically active agent or they have other disadvantages. Prior to the priority date of this application, the transdermal pharmaceutical compositions for systemic administration of commercially available drugs were limited to pharmacologically active agents existing in liquid form, e.g., scopolamine or nitro-glycerine, and as in all cases easily penetrate the skin.

Thus, new ways are needed to address the issue of transdermal application of solid and liquid pharmacologically active agents using controlled release systems.

The invention can be used in conjunction with the pharmacologically active agent bopindolol, 4- (2-benzoyloxy-3-tert.butylaminopropoxy) -2-methylindole, a β-blocker known for oral administration, for example in the treatment of hypertension. and methysergide, (9,10-didehydro-N- [1- (hydroxy methyl) propyl] -1,6-di methylergoline-8-carboxamide), a known serotonin antagonist, eg for the prophylaxis of migraine.

The penetration of the skin by these active agents can be observed by standard tests in vitro or in vivo.

One in Wtro test is the well known diffusion test which can be performed in accordance with the principles described in GB 2098865 A and by T.J. Franz in J. Invest. With reference to 6H, 1975, pp. 194-195. Solutions 20 containing the active agent in unlabelled or radiolabelled form are applied to one side of isolated pieces of intact human skin or skin from hairless rats and having an area of about 2 cm2. The other side of the skin is in contact with physiological saline solution. The amount of active agent in the saline solution is measured by conventional means, for example, by HPLC or spectrophotometric techniques or by determining the radioactivity.

Using rat skin, a penetration flux of 0.1-10 µg / cm 2 / hour is typically observed from the active agents over 24 hours.

In general, an amount of bopindolol or methysergide of from ca. 1 to 6 mg, eg 5 mg in a dose for 1-3 days.

The active agents may be administered in any liquid or solid transdermal pharmaceutical composition, e.g., as described in Remington's Pharmaceutical 1 175 3 DK 175982 B1

Sciences, 16th Edition, Mack; Sucker, Fuchs and Spieser, Phar-pharmaceutical Tecnology, 1st ed., Springer, and in GB 2098865 A or DE-OS 3212053. The composition is conveniently in the form of a viscous liquid, ointment or solid matrix. The active agent may be incorporated into a patch.

It has now been found that the aforementioned active agents, bopindolol and methysergide, as well as the pharmacologically active agents tizanidine, ketotifen and clemastine can be advantageously administered transdermally from a drug reservoir comprising a polyacrylate polymer containing cationic ester groups and dispersed with the pharmacologically active agent. .

Tizanidine, ketotifen and clemastine have previously been described for transdermal administration. GB 2098865 A discloses topical microemulsions containing these pharmacologically active agents. The microemulsions should be applied to the skin as a cream.

Tizanidine is a known myotonolytic agent, for example for the treatment of local muscle spasms such as rheumatic pain and spastic conditions.

The invention relates to the use of these active agents in a hydrophilic polymer for the preparation of a transdermal drug suitable for systemic administration of the active agent through intact skin.

25

The hydrophilic polymers absorb water and are permeable to water, for example moisture from the skin, although the polymers may be insoluble in water. The polymers can swell and release a large amount of pharmacologically active agent, leading to a high concentration gradient of pharmacologically active agent between the skin surface and the stratum corneum at a pH of from 4 to 7, preferably at skin pH, e.g. .5. If desired, they may be soluble in organic solvents. Examples of suitable polymers include polyacrylamide and copolymers thereof, polyvinylpyrrolidone (PVP), vinyl acetate-vinyl alcohol copolymers, polyvinyl alcohol (PVA) and derivatives thereof, ethyl cellulose and other cellulose and starch derivatives.

4 DK 175982 B1

The polymer preferably has an average molecular weight of about

50,000 - approx. 300,000 Daltons such as 100,000-200,000 Daltons, and are preferably film-forming.

Hydrophilic polyacrylates are preferred polymers. The acrylate may be substituted, for example, a methacrylate. They may be commercially available acrylate-methacrylate copolymers. Some or all of the acid groups may be esterified, for example with alkyl groups such as methyl or ethyl groups. Preferably, at least 2% of the alkyl groups may contain polymeric substituents, e.g., a hydroxy group.

It has been found that polyacrylates containing cationic functional groups are particularly preferred.

The invention relates to pharmaceutical compositions for transdermal systemic administration of pharmaceutically active agents through intact skin, wherein the active agent is in a reservoir containing a polyacrylate polymer containing cationic ester groups.

The invention also relates to the use of a polyacrylate containing cationic ester groups for the preparation of a drug suitable for transdermal systemic administration of a pharmacologically active agent through the intact skin of a patient.

Examples of cationic groups include dialkylaminoalkyl groups, e.g., dimethylaminoalkyl groups.

Particularly preferred cationic groups include quaternary ammonium groups, preferably a tri (alkyl) aminoalkyl group. Examples of such groups are trimethylaminoethyl ester groups.

The polyacrylate may contain some carboxylic acid groups in free form or salt anions, for example chloro anions, in order to balance the cationic groups.

The ratio of cationic groups to neutral groups is preferably from 1:10 to 1:50, for example from 1:20 to 1:40.

35 5 DK 175982 B1

Preferably, the polymers have an alkali number (defined in a manner analogous to the acid number) of from ca. 10 to approx. 200 mg KOH per g polymer, eg 10-30 mg KOH per ml. g polymer.

Examples of commercially available polymers of this type include: 1) Polymers of acrylate and methacrylate esters containing neutral methyl and ethyl ester groups and cationic trimethylaminoethyl ester groups. Chloride ions are present. Average molecular weight 150,000 Daltons. Viscosity (20 ° C) maximum 15 cP. Refractive index 1,380-1,385. Density 0.815-0.835 g / cm1. Ratio of cationic ester groups to neutral alkyl groups 1:20, giving an alkali λ of 28.1 mg KOH per liter. g of polymer (Eudragit® RL 100 available from Rohm, Darmstadt, West Germany) or 1:40, giving an alkali content of 15.2 mg KOH per day. g of polymer (Eudragit® RS 100, also available from Rohm).

2) Polymer of methacrylate esters containing cationic trimethylaminoethyl ester groups and other neutral C 18 alkyl ester groups. Chloride ions are present. Average molecular weight 150,000. Viscosity (20 ° C) 10 cP. Refractive index 1.38. Density 0.815. Alkalit of 180 mg KOH per g of polymer (Eudragit® E 100, also available from 25 Rohm).

The drug reservoir may contain the plasticizing and / or plasticizing agents, preferably skin-compatible surfactants, for example to give the unit flexibility, and / or to partially or completely dissolve the pharmacologically active agent in the reservoir.

Examples of additives include: 35 6 DK 175982 B1 1) Polyoxyethylene fatty alcohol ethers. The alcohol may, for example, be a C12-2ig alcohol. For example, the HLB value may be from 10 to 18. A preferred example is polyoxyethylene (10) oleyl ether. A suitable ether can have a viscosity (25 ° C) of approx. 100 cP, a solidification point of approx.

5 16 ° C, an HLB value of 12.4 and an acid number of maximum 1.0 (Brij® 97 available from Atlas Chemie, West Germany).

2) Polyoxyethylene sorbitan fatty acid esters. The fatty acid may be, for example, a C 12 -ig "fatty acid. For example, the HLB value may be from 10 to 18. A preferred example is polyoxyethylene (20) sorbitan monooleate, for example Tween® 80 available from Atlas Chemie, West Germany.

3) Polyoxyethylene (5-40) stearic acid esters, eg Myrj® available from Atlas Chemie, West Germany.

4) Polyoxyethylene glycol fatty alcohol ethers, eg polyethylene glycol (6-25) cetyl ether, glycerol polyethylene ricinoleate, glycerol polyethylene glycol stearate (labeled Cremophor® available from BASF, West Germany).

5) Polyoxyethylene glycols having a molecular weight of 200 to 600 Daltons, e.g., 300 or 400 Daltons.

6) Esters of poly (2-7) ethylene glycol glycerol ether having at least one hydroxy group and an aliphatic (C6.22) carboxylic acid, e.g., polyethylene glycol (7) glyceryl cocoate, e.g., Cetiol® HE, from Henkel, West Germany.

7) Adipic acid lower alkyl esters, eg di-n-butyl adipate and diisopropyl adipate.

8) Glycerol polyethylene glycol ricinoleate, for example the product of 35 moles of ethylene oxide and castor oil, eg labeled Chremophor® EL available from BASF, West Germany.

9) Triacetin- (1,2,3).

The amount and nature of the necessary additive will depend on a number of factors, such as the HLB value of the surfactant and the necessary flexibility of the unit. Surprisingly, the amount of additive does not significantly affect the ability of the polyacrylate to form films. Generally, the weight ratio of surfactant to hydrophilic polymer is from 1:10 to 5: 1, e.g., 1:10 to 1: 3.

The drug reservoir may contain skin permeation agents, e.g., 1-dodecylazacycloheptan-2-one (azone) and N, N-diethyl-m-toluamide (DEET).

The amount and nature of skin penetration promoters and / or additives present will depend on a number of factors. Generally, the weight ratio of skin permeation promoting agent to hydrophilic polymer will be from approx. 1: 1 to 1:10. The amount of surfactant and / or skin permeation agent is preferably from about

3 to approx. 50% by weight, preferably 20-40% by weight of the pharmaceutical composition.

If desired, the drug reservoir may contain a hydrophobic elastomer, e.g., a synthetic resin. Such resins are common in the plastics art. Suitable resins include non-swellable acrylate resins. These, if desired, can be sticky. For example, the weight ratio of hydrophilic polymer to resin may be from 1: 0.5 to 1:10. The resin may contain modifiers, extenders, e.g., with a softening point of approx. 50-100 ° C. Such extenders may have 25 adhesive or softening properties. Examples of such extenders include resin acids, glyceryl and phthalate esters of resin acids, hydrogenated abietyl alcohol and its phthalate esters. For example, the extender may be present in an amount of from 5 to 40% by weight of the resin.

30

Any pharmacologically active agent capable of penetrating the skin may be dispersed in the polyacrylate polymer. The indication for which the active agent is used is not critical. It is preferred that the daily transdermal dose for 35 such agents is less than 20 mg per day. per day, eg less than 10 ml per day. day.

8 DK 175982 B1

The active agent for use in any of the above pharmaceutical compositions may be in free form, e.g. free base form, or in pharmaceutically acceptable salt form, e.g. pharmaceutically acceptable acid addition salt form.

Such acid addition salts forms include the hydrogen malonate, hydrogen malinate, hydrogen fumarate, hydrochloride, tartrate, etc. A solid active agent preferably has an average particle diameter of from 30 to 50 microns.

10

The active agent may be partially suspended and / or partially dissolved in the reservoir. It can be dispersed so finely that, to the naked eye, it results in an evenly homogeneous film.

The pharmaceutical compositions of the invention are useful for the systemic administration of pharmacologically active agents through intact skin, as indicated by standard tests in vitro and in vivo.

For example, the release of active agent from the pharmaceutical compositions may be followed by the amount of active agent released by shaking the pharmaceutical composition in 0.9% NaCl solution at 37 ° C at a stirring rate of about 20 ° C. 120 rpm for example, is determined by ultraviolet spectroscope !.

The penetration of the active agent through isolated rat and human skin can be followed by the well-known diffusion test performed in accordance with the principles described, for example, in GB 2098865 A and in T.J. Franz, J.invest.Dermatol. £ 4, 1975, pp. 191-195.

The pharmaceutical compositions of the invention are applied to the outer side of isolated pieces of rat or human skin having an area of about 2 cm *. The rat skin is hairless. The other side is washed continuously · with physiological saline solution. The amount of active agent in the saline is determined in a conventional manner, e.g., HPLC. Then, the permeation flux can be determined over 24 hours and, if desired, the flux at the stationary state. The penetration flux rate is of the order of 1-10 µg / cmVtime.

DK 175982 B1 i | 9 i i

Alternatively, the active agent penetration can be followed in vivo by applying the pharmaceutical composition to intact skin, e.g., on the breast, | the back, arm or behind the ear, on a subject and measuring the amount of active agent in the blood.

5

The pharmaceutical compositions of the invention can be used for the same indications known for oral or intravenous administration. The amount of pharmaceutically active agent to be administered will depend individually on the drug release properties of the pharmaceutical preparations, the drug penetration rate observed by tests in vitro and in vivo, the potency of the active agent, [in the size of the skin contact area, the part of the body to which j »

the unit is glued and the desired duration of action. The amount of I

in active agent and the area of the pharmaceutical composition etc. can be determined by usual bioavailability tests comparing the blood levels of the active agent after administration of the active agent in a pharmaceutical composition according to the invention on intact skin and active blood levels observed after oral administration. or intravenous administration of a therapeutically effective dose of the pharmacologically active agent.

If the daily dose of a drug for oral administration is given, the choice of a suitable amount of drug to be incorporated into a transdermal composition of the invention will depend on the pharmacokinetic properties of the active agent, including the first-pass effect; the amount of drug that can be absorbed through the skin from the relevant matrix for a given application area and within a given time period; and the time during which the preparation is to be applied.

Thus, a drug with a high first-pass effect may require a relatively low amount in the transdermal preparation compared to the oral daily dose, since the first-pass effect will be avoided. On the other hand, in general, a maximum of only approx.

50% of the drug in the matrix through the skin within a 3-day period.

35

The pharmaceutical compositions of the invention generally have, for example, an effective contact area of the drug reservoir on the skin of from about.

i i j 10 DK 175982 B1 1 to approx. 50 cm 2, preferably approx. 2-20 cm 2 and is intended to be applied for 1-7 days, preferably 1-3 days.

Examples of representative doses are: 5 1) Tizanidine A dose of 20 mg in a surface of approx. 10 cm2 to be administered once every 3 days for systemic treatment of rheumatic pain and muscle cramps.

10 2) Bopindolol A dose of 1-10 mg in a 10 cm2 area to be administered once over 3 consecutive days of each week for the treatment of hypertension.

3) Clemastine A dose of approx. 1-20 mg in a surface of approx. 10 cm 2, to be administered once every 3 days, for the treatment of allergies, eg hay fever.

4) Ketotifen A dose of approx. 1-20 mg in a surface of approx. 10 cm2, 20 to be administered once every 3 days for asthma prophylaxis.

5) Methysergide A dose of approx. 1-10 mg in a 10 cm2 surface area to be administered once every 3 days for 25 prophylaxis of migraine and interval treatment of migraine.

The pharmaceutical compositions of the invention can be prepared by conventional means by dispersing or dissolving an appropriate pharmacologically active agent in a hydrophilic drug reservoir.

The weight ratio of pharmacologically active agent to hydrophilic polymer may vary within wide limits. For example, the weight ratio may be sufficient to provide a saturation of the pharmacologically active agent in the drug reservoir. In general, the weight ratio is from approx. 1:10 to approx. 1: 1.

11 DK 175982 B1

For example, in the case of tizanidine, the amount may be, for example, from 10 to 40% by weight, such as 15-30 or 20-25% by weight.

If the drug reservoir is not itself adhesive, a pressure sensitive adhesive may be used to adhere the drug reservoir to intact skin. Any conventional adhesive may be used, for example a polyacrylate. The layer can be applied to the drug reservoir and have a thickness of from approx. 1 to approx. 200 µm, preferably 10-100 µm. If the adhesive layer is thin enough, the pharmacological agent will pass through it. Alternatively, the adhesive layer may be applied to the edges of an outer cover of the drug reservoir, and the outer cover may be adhered to the intact skin, thereby keeping the drug portion in close contact with the intact skin.

The drug reservoir may be prepared in a conventional manner, for example, in an adhesive patch or patch. If it is a polymer matrix, it can be prepared by dispersing or dissolving the pharmacologically active agent in a solution of the polymer and other additives in a volatile organic solvent, e.g., ethanol, methylene chloride or acetone.

20 A film is formed by spreading the dispersion or solution over the outer protective covering. The wet film can have a thickness of approx. 0.05-0.5 mm, for example from 0.1 to approx. 0.3 mm. The film is allowed to dry, for example at room temperature or slightly elevated temperature below 50 ° C. The drug reservoir may be built up in series of layers, providing an optional adhesive layer in the last layer.

The pharmaceutical compositions of the invention can be prepared in a conventional way for skin permeating pharmaceutical compositions. FIG. 1 of the drawing schematically shows a cross-section through the layers 30 of a representative pharmaceutical composition according to the invention. FIG. 2 of the drawing schematically shows a cross-section through another embodiment, for example in the form of a bandage or a patch. In Figures 1 and 2 there are several layers a * d, and in the case of Figs. 2 there is a further layer e.

The layer a is a medical cover made of, for example, polyester / aluminum laminate foil. Layer b is a barrier film, for example aluminum foil. If desired, this can be omitted. Layer c may be made from 1-10 µg of a drug reservoir. The drug reservoir is a homogeneous dispersion of active agent particles or an active agent solution in a polymer matrix. Layer d can be an adhesive layer. In one embodiment (not shown), layer d may extend between the outer edges of layer a and layer e. Alternatively, layer e may be omitted completely. Layers a 5 may extend around layers b-d of FIG. 2. Layer e is a protective tear layer adhered to the adhesive layer as well as to the edges of the cover layer a.

When used, any protective layer is torn off and the unit 10 is adhered to intact skin.

In the following examples, all temperatures are uncorrected. All quantities are in parts unless otherwise indicated.

15 Details of the components are given in "Lexicon for Pharmazie, Kosmetik und angrenzende Gebiete" by H.P. Fiedler, 2nd edition, Cantor Aulendorf, West Germany or from the relevant manufacturers.

In the following examples, the names given have the meaning given below: PAM Amine Polymer RL: Cationic polyacrylate / methacrylate polymer as defined above under the designation EUDRAGIT® RL 100.

25 PAM Amine polymer RS: Cationic polyacrylate / methacrylate polymer as defined above under the designation EUDRAGIT® RS 100.

30 PAM Amine polymer E: Cationic polymethacrylate polymer as defined above under the designation EUDRAGIT® E 100.

35 13 DK 175982 B1

Polyoxyethylene (10) -oleyl ether: BRIJ® 97 as defined above. Glycerol polyethylene glycol (35) -ricinoJeat = Cremophor® EL as defined above.

Polyoxyethylene (20) sorbitan monooleate = Tween® 80 as defined above.

Polyethylene (7) -glycol glyceryl cocoate = Cetiol® HE as defined above.

Synthetic acrylate resin is a self-crosslinking acrylate of the brand 10 Durotack 280-2416 available from Delft National Chemie,

Zutphen, The Netherlands and available as a light yellow solution containing 57% ethyl acetate, 32% ethanol, 9% hexane, 2% methanol: solids content 41%, viscosity (Brookfield) = 2100-6000 mPas, plasticity (Williams) ± 3 mm, density 0.94, flash point 15 0.94.

EXAMPLE A

Preparation of pharmaceutical composition containing a hydrophilic polymer

composition

Pharmacologically active agent 20%

Hydrophilic polymer 40% surfactant 40% Dissolve 1.2 g of hydrophilic polymer in 3 g of acetone or ethanol or another suitable volatile organic solvent with stirring for 1-2 hours. 0.6 g of pharmacologically active agent and 1.2 g of surfactant softener are added. The mixture is stirred vigorously for 5-20 minutes using a high speed stirrer to give a viscous mass.

The pulp is spread as a film on top of an aluminized polyester film (thickness 23 cm) using conventional apparatus, for example a 354 Erichsen film apparatus model 411/150. The pulp is spread over the film at a rate of 18 mm / second to form a film having a thickness of 0.2 mm in wet state.

14 DK 175982 B1

The film is allowed to dry at room temperature over 4-6 hours. The resulting hydrophilic polymer drug matrix weighs 8.5 mg per and contains 1.7 mg of active agent per ml. cm 2.

An additional film of an acrylate adhesive (Rohm Pharma 7708/47) is then applied on top of the drug polymer matrix J in the form of a thin layer (thickness 0.1 mm) in an analogous manner.

The aluminum foil is then cut into pieces with an area of 10 cm2.

10

Unless otherwise stated, the drug matrix is constructed from one film layer. It can, if desired, be built up as more than one layer.

Active agent release is measured in vitro by standard skin diffusion tests through freshly isolated hairless rat skin. The rat skin piece is placed in a Franz diffusion chamber, cf. T.J. Franz, J. Invest. Dermatoi 64, (1975), pp. 191-195. The receptor phase is continuously pumped and samples taken every hour are measured for active agent content using HPLC. The test lasts 24 hours and 20 the penetration flux is measured over 24 hours (hereinafter referred to as "flux") and, if desired, a flux at equilibrium state after a decay time of 3-10 hours.

EXAMPLE 1

Tizanidine preparation

Prepared as described in Example A with a composition of 30

Tizanidine Hydrochloride 20% PAM Amine Polymer RL 40%

Polyoxyethylene-10-oleyl ether 40% B1

Active agent penetration rate in rat skin:

Penetration flux t ~ 0.0145 mg / cm2 / hour Total permeation - ~ 0.290 mg / cm2 approx. 21.46% ® Residue measured in plastics approx. 47% EXAMPLE 2 10 Tizanidine Preparation

Prepared analogously to that described in Example A with a composition of Tizanidine Hydrochloride 1.144 g PAM Amine Polymer RL 1.928 g

Polyoxyethylene-10-oleyl ether 1.928 g

The active agent is dissolved in 5 g of ethanol as solvent.

20

Spreading speed 6 mm / second

Wet film thickness 0.25 mm

Active agent concentration in film 2.6 mg / cm 2

No adhesive acrylate film is present.

25

Active agent penetration rate through rat skin:

Penetration flux = 8.5 µg / cm2 / hour Flux at equilibrium state = 16.2 µg / cm2 / hour.

30

In a clinical trial, a 2 cm 2 piece of the preparation was applied to the left forearm and after 12, 24 and 36 hours the residual tizanidine content in the piece was determined.

Flux rate = 5.1 µg / cmVh.

EXAMPLE 3 DK 175982 B1

Prepared as described in Example 2 using methylene chloride as solvent instead of ethanol. Composition: 5

Tizanidine Hydrochloride 1.144 g PAM Amine Polymer RL 1.928 g

Polyoxyethylene-10-oleyl ether 1.628 g Triacetre (1,2,3) 0.250 g 10

Penetration rate through rat skin:

Penetration flux ® 10.4 µg / cm2 / hour.

In a clinical trial, a 2 cm 2 piece was applied as in Example 2.

Penetration flux = 4.9 µg / cm 2 / hour.

EXAMPLE 4

Pharmaceutical tizanidine preparation 25 is prepared analogously to that described in Example 2.

Spread rate = 18 mm / second Wet film thickness: 0.2 mm Active agent concentration: 1.7 mg / cm2 An adhesive acrylate film layer is applied as in Example A.

Penetration rate through rat skin.

Penetration flux = 14.5 µg / cm2 / hour 35 Flux at equilibrium state = 30.8 µg / cm2 / hour.

EXAMPLE 5 17 DK 175982 B1

Pharmaceutical Thiazide Preparations 5 The surfactant of Example 2 is replaced by an equivalent amount of i) Polyethylene glycol 300 ii) Glycerol polyethylene glycol (35) -ricinoleate iii) Polyoxyethylene- (20) - $ orbitan monooleate 10 iv) Azone and / or PAM amine polymer RL are replaced PAM amine polymer RS or PM amine polymer E.

EXAMPLES 6-8 18 DK 175982 B1

Pharmaceutical Clemastine Preparations 5 The following preparations are prepared analogously to Example 2.

Example 6 7 8 -jQ Clemastine Hydrogen Fumarate 1 g 1.34 g 1 g PAM Amine Polymer RL 2 g PM Amine Polymer E - 2.41 g 2.66 g

Polyoxyethylene (10) oleyl ether 2 g 1.25 g

Polyethylene Glycol 300 - - 1.34 g 15

Solvent Acetone Acetone CH 2 OH

Solvent amount (g / - g dry film) 0.6 0.5 2.0

Wet film thickness (mm) 0.2 0.15 0.3

Spreading rate (mm / sec) 6 6 6

Acrylate adhesive film (thickness of wet film) 0.15 none none

Penetration of active agent through isolated rat skin Penetration flux (vg / cmVtime) 1.3 4.5 3.2

Flux at equilibrium state (pg / cmVh) 10 12 8.6 30 35 EXAMPLES 9-12 19 DK 175982 B1

Pharmaceutical Bopindolol Preparations 5 v The following preparations are prepared analogously to Example 2

Example 9 10 11 12 10 Bopindolol Hydrogen Malonate 1.275 g 1.275 g -

Bopindolol, free base - 1.0 g 1.0 g PAM Amine Polymer RL 1.225 g 1.225 g - PM Amine Polymer E - 2.665 g 2.665 g

Polyoxyethylene (10) oleyl ether - 0.25 g 1.335 g - Polyethylene (9) glycol glyceryl coco ... 1.335 g

Ozone 2.5 g 2.25 g -

Solvent CH2C12 CH2Cl2 CHgOH CHgOH

Solvent amount (g / - g dry film) 1.0 1.0 4.0 4.0

Wet film thickness (mm) 0.25 0.25 0.3 0.3

Spreading rate (mm / sec) 6 6 6 6 25 Acrylate adhesive film (thickness of wet film) none none none none

Penetration of active agent through isolated rat skin 2Q Penetration flux (pg / cmVtime) 1.7 4.0 11.1 8.6

Flux at equilibrium state (wg / cmVh) 5.7 12.5 59.0 33.0 EXAMPLES 13-16 20 DK 175982 B1

Pharmaceutical ketotifen preparations 5 The following preparations are prepared analogously to Example 2

Example 13 14 15 16

Ketotifen Hydrogen Fumarate 0.5 g 0.5 g ^ Ketotifen Free Base - 1.0 g 1.0 g PAM Amine Polymer RL - - 2.0 g 2.0 g PM Amine Polymer E 2.5 g 2.5 g -

Polyoxyethylene (20) sorbitan monooletate - - - 2.0 g

Polyethylene glycol 300 - 2.0 g -

Polyethylene glycol (7) glyceryl cocoate 2.0 g - 2.0 g

Solvent acetone acetone acetone acetone 20 Thickness of wet film (mm) 0.2 0.2 0.2 0.2

Spreading rate (mm / sec) 6 6 6 6

Acrylate adhesive film none none none none None None 25 Penetration of active agent through isolated rat skin 6.8 8.5 4.0 2.8

Penetration flux (yg / cmVtime)

Flux at equilibrium state 30 (µg / cmV) 10.0 15.0 18.0 12.0

EXAMPLE B

In a manner analogous to that described in Example A, a pharmaceutical composition is prepared without an adhesive acrylate layer. The drug matrix is based on an elastomer.

21 DK 175982 B1

Bl B2 Weight (g / m *) 80 79

Tizanidine Hydrochloride (mg / 10 cm *) 15.00 14.81

Tizanidine Free Base 17.16 16.95 5 Synthetic Acrylate Resin (parts by weight) 50 50 PAM Amine Polymer RL (parts by weight) 50 PM Amine Polymer E (parts by weight) 50

Polyethylene glycol 400 2% 2% 10 In vitro data, active agent release in mg / 10 cm * 2 hours 14.36 19.48 4 hours 15.78 22.22! 8 hours 17.33 24.03 24 hours 22.57 28.98

Claims (6)

Pharmaceutical composition for transdermal systemic administration of pharmacologically active agents, characterized in that the pharmacologically active agent is in a reservoir comprising a polyacrylate polymer containing cationic ester groups. Composition according to claim 1, characterized in that the polymer is an aryla t / methacrylate polymer. 10 Composition according to claim 1, characterized in that the polymer contains trimethylaminoethyl ester groups. A composition according to any one of claims 1-3, characterized in that it is in the form of an adhesive patch or patch comprising a) a cover layer, c) a drug reservoir comprising 1-10 layers of a homogeneous dispersion of particles of active agent or solution of active agent in a polymer matrix, and d) an adhesive layer, the reservoir c) being arranged between layers a) and d). 20 Process for preparing a pharmaceutical composition for transdermal administration, characterized in that a pharmaceutically active agent is dispersed in a polyacrylate polymer containing cationic ester groups to form a drug reservoir and optionally applied to an adhesive layer. Use of a polyalcrylate containing cationic ester groups for the preparation of a drug suitable for transdermal systemic administration of a pharmacologically active agent.