DK175236B1 - Pharmaceutical compsns. for trans:dermal admin. - 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

in DK 175236 B1

The present invention relates to pharmaceutical compositions, in particular for systemic transdermal administration of pharmacologically active agents.

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 one. 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, 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 drug permeable adhesive layer may be provided on the reservoir to hold the protective tear strip and adhere the device to the skin. In some proposals, the drug reservoir has a drug permeable regulatory membrane or device bound through which the pharmacologically active agent passes, in order to regulate the rate of penetration of the active agent, 20 for example, to prevent dose dumping.

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 have other disadvantages. Prior to the priority date of this application, the transdermal pharmaceutical compositions for systemic administration of drugs that were commercially available on a large scale were limited to pharmacologically active agents that exist in liquid form, e.g., scopolamine or nitroglycerin, and which in any case readily penetrate through skin.

In DK 175236 B1 H Thus, new ways are needed to address the issue of transdermal application of solid and liquid pharmacologically active! H means using controlled delivery systems.

H 5 Surprisingly, it has now been found that the pharmacologically active agent bopindolol, 4- (2-benzoyloxy-3-tert.butylaminopropoxy) -2-methylindole, which is a β-blocker known for oral administration, e.g. H treatment of hypertension, has particularly interesting properties with regard to transdermal administration. This substance is hereinafter referred to as "the active agent of the invention".

Skin penetration of this active agent can be observed at I

H standard tests in vitro or in vivo. IN

In 15 One in vitro test is the well known diffusion test that can be performed in I

in accordance with the principles described in GB 2098865 A and I

In T.J. Franz in J. Invest. Dermatol 6H, 1975, pp. 194-195. Solutions I

In containing the active agent in unlabelled or radiolabelled. IN

In form, on one side of insulated pieces, intact human skin I is applied

I 20 I

In or skin from hairless rats and with an area of approx. 2 cm2. The second one

The side of the skin is in contact with physiological saline solution. Quantity I

In that of active agent in the saline solution is measured on conventional I

By way, for example, by HPLC or spectrophotometric techniques or by

In 25 determine the radioactivity. IN

In one aspect, the present invention relates to the use of bopindolol I

as an active agent in the manufacture of a medicament suitable for I

In systemic transdermal administration. A further aspect of the I

In the present invention, a pharmaceutical composition for transdermal I relates

In systemic administration of an active agent, which composition is ^ I

Characterized in that the active agent is bopindolol. IN

In general, a quantity I is indicated for application, for example, behind the ear

In 35 bopindolol of approx. 1 to 6 mg, eg 5 mg in a dose for 1-3 days. IN

The active agent of the invention may be administered in any one of the following

In any conventional liquid or in any solid transdermal I

In pharmaceutical formulation, for example, as described in Remington's Pharmaceutical I

40 I

Sciences, 16th Edition, Mack; Sucker, Fuchs and Spieser, Pharmaceu-I

3 DK 175236 B1 tische Technologie, 1st edition, Springer and in GB 2098865 A or DOS 3212053, to which reference is made. The composition is conveniently in the form of viscous liquid, ointment or solid matrix. The active agent may be incorporated into a patch.

5

It has been found that bopindolol can be advantageously administered transdermally from a drug reservoir comprising a hydrophilic polymer having the pharmacologically active agent dispersed therein.

A further aspect of the present invention relates to a pharmaceutical composition for transdermal systemic administration of a pharmacologically active agent, characterized in that it contains bopindolol in a reservoir comprising a hydrophilic polymer. A further aspect of the present invention relates to the use of bopindolol in a hydrophilic polymer to produce a transdermal drug suitable for systemic administration of the active agent through intact skin.

The hydrophilic polymers absorb water and are permeable to water, for example 20 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 25 skin pH, e.g. 5th If desired, they may be soluble in organic solvents. Examples of suitable polymers include polyacrylamide and its copolymers, polyvinylpyrrolidone (PVP), vinyl acetate / vinyl alcohol copolymers, polyvinyl alcohol (PVA) and derivatives thereof, ethyl cellulose and other cellulose and starch derivatives.

Preferably, the polymer has an average molecular weight of approx.

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

35

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 4Q may be esterified, for example with alkyl groups such as methyl or

I DK 175236 B1 I

I 4 I

In ethyl groups. Preferably, at least 2% of the alkyl groups may contain I

polar substituents, e.g., a hydroxy group. IN

It has been found that polyacrylates containing cationic functional I

In 5 groups are especially preferred. IN

Transdermal pharmaceutical preparations for systemic administration of I

In pharmacologically active agents through intact skin, where the active agent I

In Ί0, ‘is a reservoir comprising a polyacrylate containing cationic I

In functional groups, are new and form part of the form

In the present invention. IN

The present invention also relates to the use of bopindolol in an I

In 15 polyacrylate containing cationic groups to prepare an I

In drug suitable for transdermal systemic administration of the I

In pharmacologically active agent through intact skin of a patient. IN

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

In dimethylaminoalkyl groups. IN

Particularly preferred cationic groups include quaternary ammonium I

In groups, preferably a tri (alkyl) aminoalkyl group. Examples of I

In such groups, trimethylaminoethyl ester groups are. IN

The polyacrylate may contain some carboxylic acid groups in free form or I

In salt anions, for example chlorine anions, in order to balance the cationic I

In 30 niche groups. IN

The ratio of cationic groups to neutral groups is preferable

In the range from 1:10 to 1:50, for example, from 1:20 to 1:40. I 1

Examples of commercially available polymers of this type include - I

I ter: I

35 I

Preferably, the polymers have an alkalite (defined in a manner analogous

In with the acid number) of from approx. 10 to approx. 200 mg KOH per g of polymer, e.g.

In 10-30 mg KOH per ml. g polymer. IN

0) 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 5 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 number 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 of 15.2 mg KOH per ml. g polymer (Eudragit® RS 100, also available 10 from Rohm).

2) Polymer of methacrylate esters containing cationic trimethylaminoethyl ester groups and other neutral C 1-6 alkyl ester groups. Chloride ions are present. Average molecular weight 150,000. Viscosity 15 (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 Rohm).

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

25 Examples of additives include: 1) Polyoxyethylene phosphate carbon ethers. For example, the alcohol may be a C-Q-ie ”alcohol. For example, the HLB value may be from 10 to 18. A preferred example is polyoxyethylene (10) oleyl ether. A suitable ether may have a viscosity (25 ° C) of approx. 100 cP, a solidification point of approx. 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. For example, the fatty acid may be a 35 C₂₂2j fatty acid. The HLB value may be, for example, from 10 to 18. A preferred example is polyoxyethylene (20) sorbitan monooleate, for example Tween® 80 available from Atlas Chemie, West Germany.

I DK 175236 B1 I

I I

3) Polyoxyethylene (5-40) stearic acid esters, eg Myrj® available from I

In Atlas Chemie, West Germany. IN

I 4) Polyoxyethylene glycol fatty alcohol ethers, eg polyethylene glycol (6-25) - I

In cetyl ether, glycerine polyethylene ricinoleate, glycerine polyethylene glycol nitrogen

5 arat (labeled Cremophor® available from BASF, West Germany). IN

I 5) Polyoxyethylene glycols having a molecular weight of 200 to 600 Daltons, eg 300 I

I or 400 Daltons. IN

I) Esters of poly (2-7) ethylene glycol glycerol ether having at least one hydride

In oxy group and an aliphatic (Cg 22 ^ car ^ oxy'sVre 'f * polyethylene gly-

In 10 col- (7) -glyceryl cocoate, eg Cetiol® HE, from Henkel, West Germany. IN

I) Adipic acid lower alkyl esters, e.g. di-n-butyl adipate and diisopropyl

In adipat. IN

I 8) Glycerin polyethylene glycol ricinoleate, eg the product of 35 moles of ethylene-I

In oxide and castor oil, eg labeled Chremophor® EL available from BASF, I

In 15 West Germany. IN

I 9) Triacetin-Π, 2,3). IN

The amount and nature of the additive required will depend on a number of I

In factors such as the tenside HLB value and the required flexibility of I

In the unit. Surprisingly, the amount of additive does not affect I

To a significant extent, the ability of the polyacrylate to form films. In general I

I, the weight ratio of surfactant to hydrophilic polymer is from ca. 1:10 to 1

In 5: 1, for example, from 1:10 to 1: 3. 'I 1

The amount and nature of skin permeation present

In the means and / or additives will depend on a number of factors. Generally, I

Similarly, the weight ratio of skin permeation enhancer I

The drug reservoir may contain skin permeation I

In agents, e.g., 1-dodecylazacycloheptan-2-one (azone) and N, N-diethyl-m-toluene

I 25 amide (DEET). IN

7 DK 175236 B1 and hydrophilic polymer are 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 technique. 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 10 1:10. The resin may contain modifiers, extenders, for example with a softening point of approx. 50-100 ° C. Such extenders may have 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 15 may be present in an amount of from 5 to 40% by weight of the resin.

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

The active agent for use in any of the aforementioned 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 salt forms include the hydrogen malonate, hydrogen maleate, hydrogen fumarate, hydrochloride, tartrate, etc. Preferably, a solid active agent has an average particle diameter of from about 30%. 30 to approx. 50 ym.

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.

I DK 175236 B1 I

I 8 I

The pharmaceutical compositions of the invention are useful for systemic I

In the administration of pharmacologically active agents through intact skin, I

In as indicated by standard tests in vitro and in vivo. IN

For example, in the release of active agent from the pharmaceutical compositions, I

I 5 is followed by the amount of active agent released by shaking I

In the pharmaceutical composition in 0.9% NaCl solution at 37 ° C at an I

At a stirring speed of approx. 120 rpm for example, is determined per minute

You by ultraviolet spectroscope !. IN

I The penetration of the active agent through isolated rat and I

In 10 human skins can be followed by the well-known diffusion test performed in I

In accordance with the principles described, for example, in GB I

In 2098865 A and in T.J. Franz, J.Invest.Dermatol. 54, 1975, pp. 191-195. IN

In the pharmaceutical compositions of the invention are applied to the outer I

In side of isolated pieces of rat or human skin with an area of I

For approx. 2 cm2. The rat skin is hairless. The other side is washed continuously

In with physiological saline solution. The amount of active agent in salt I

In the water is determined by conventional means, for example HPLC. Then you can

In the permeation flux over 24 hours, and, if desired, I

In the flux at the stationary state. The permeation flux rate I

I 20 is of the order of 1-10 vg / cm2 / hour. IN

I I

Alternatively, the active agent penetration can be followed in vivo by I

In applying the pharmaceutical composition to intact skin, eg on the breast, I

In the back, arm or behind the ear, on a subject and measure

In the amount of active agent in the blood. IN

The pharmaceutical compositions of the invention may be used for the same I

In indications known for oral or intravenous administration. IN

In the amount of pharmaceutically active agent to be administered, you will

You depend individually on the drug release of the pharmaceutical preparations

In stirring properties, the rate of drug penetration observed at I

In 30 tests in vitro and in vivo, the potency of the active agent, the size of I

In the skin contact area, the part of the body to which the device adheres, I

I and the desired duration of action. The amount of active agent and the I

In the area of pharmaceutical preparations etc. can be determined by usual I

9 DK 175236 B1 bioavailability tests comparing the blood levels of active agents after administration of the active agent in a pharmaceutical composition of the invention to intact skin and blood levels of an active agent observed after oral 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 a drug in the matrix through the skin within a 3-day period.

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

25 to about 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 of bopindolol are a dose of 1-10 mg in a 10 cm 2 area to be administered once over 3 consecutive 30 consecutive days each week for the treatment of hypertension.

The pharmaceutical compositions of the invention may be prepared in a conventional manner 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 widely. 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.

I DK 175236 B1 I 10

If the drug reservoir is not self-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 H 5 and has a thickness of approx. 1 to approx. 200 µm, preferably I 10-TOO µm. If the adhesive layer is thin enough, it will

In the mean means pass through it. Alternatively, the adhesive layer I

You are applied to the edges of an outer cover of the drug reservoir, and

In the outer cover can be adhered to the intact skin, whereby the drug I

In -jo portion of the reservoir is kept in close contact with the intact skin. IN

The drug reservoir may be prepared in a conventional manner, for example, in an I

adhesive patch or a patch. If it is a polymer matrix, it can

are prepared by dispersing or dissolving the pharmacologically active I

In a solution of the polymer and other additives in a volatile I

In organic solvent, eg ethanol, methylene chloride or acetone. IN

A film is formed by spreading the dispersion or solution over I

In the outer protective cover. The wet film may have a thickness of I

For approx. 0.05-0.5 mm, for example from 0.1 to approx. 0.3 mm. The film is allowed to dry, I

For example 20 at room temperature or slightly elevated temperature below 50 ° C. IN

I The drug reservoir may be built up in series of layers, a

In any adhesive layer, the last layer is provided. IN

The pharmaceutical compositions of the invention may be prepared on an I

In 25 for skin penetrating pharmaceutical preparations conventional manner. IN

In FIG. 1 of the drawing schematically shows a cross section through the layers of an I

In representative pharmaceutical composition according to the invention. FIG. 2 on I

the drawing schematically shows a cross section of another embodiment, eg I

In the form of a bandage or patch. In Figures 1 and 2 there are I

In 30 several layers a-d, and in the case of FIG. 2 there is an additional layer e. The layer a I

You are a medical cover made of, for example, polyester / aluminum laminate foil

I lie. Layer b is a barrier film, for example aluminum foil. If desired, you can

In this one is omitted. Layer c may be made from 1-10 layers of a drug I

In part reservoir. The drug reservoir is a homogeneous dispersion of I

In 35 active agent particles or an active agent solution in an I

In polymer matrix. Layer d can be an adhesive layer. In one embodiment I

In layer DK (not shown) the layer d may extend between the outer edges of layers a and g layer e. Alternatively, layer e may be omitted completely. Layer a can stretch

look around layers b-d of FIG. 2. Create a protective tear

layers adhered to the adhesive layer as well as to the edges of the cover layer a. i * i 5

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

In the following examples, all temperatures are uncorrected. All quantities 10 are in parts by weight unless otherwise indicated.

Details of the components are given in "Lexicon fur 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 following meanings: PAM Amine polymer RL: Cationic polyacrylate / methacrylate polymer as defined above under the designation EUDRAGIT® RL 100.

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

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

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

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

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

i i

I DK 175236 B1 I

I 12 I

1 ° i

In Synthetic acrylate resin is a self-crosslinking acrylate of the brand I

In Durotack 280-2416, available from Delft National Chemie, I

In Zutphen, The Netherlands and is available as a light yellow solution which as a solution I

Contaminant contains 57% ethyl acetate, 32% ethanol, 9% hexane, 2% I

In methanol: solids content 41%, viscosity (Brookfield) = 2100-6000 I

In mPas, plasticity (Williams) ± 3 mm, density 0.94, flash point I

I 0.94. IN

EXAMPLE A I

I Preparation of pharmaceutical composition containing a hydrophilic poly-I

In more I

Composition I

In Pharmacologically active agent 20% I

In Hydrophilic polymer 40% I

In surfactant 40% I

In 20 U 9 hydrophilic polymer is dissolved in 3 g of acetone or ethanol or an I

In another conveniently volatile organic solvent under about I

Stir for 1-2 hours. 0.6 g of pharmacologically active agent and I are added

In 1.2 g of surfactant softener. The mixture is stirred vigorously for approx. 5-20 minutes

Use a high speed stirrer to give a viscous I

In 25 mass.

In the pulp, spread as a film on top of an aluminized polyester film I

I (thickness 23 µm) using conventional apparatus, e.g.

In Erichsen film apparatus model 411/150. The pulp is spread over the film I

At 30 at a speed of 18 mm / second ten! forming a film with an I

In the thickness of 0.2 mm in wet condition. IN

The film is allowed to dry at room temperature over 4-6 hours. The I

In the resulting hydrophilic polymer drug matrix weighs 8.5 mg per cm2 I

I 35 and contains 1.7 mg of active agent per day. cm 2. IN

13 DK 175236 B1

ISLAND

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

L 5 The aluminum foil is then cut into pieces with an area of approx. 10 cm2.

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

10

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. Dermatol 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 the permeation flux is measured over 24 hours (hereinafter referred to as "flux") and, if desired, a flux at equilibrium state 20 after a decay time of 3-10 hours.

25 1 35

I DK 175236 B1 I

I 14 I

I EXAMPLE; 1-4 I

In Pharmaceutical Bopindolol Preparations I

The following compositions are prepared analogously to Example A I

In Example 1 2 3 4 I

I 5 _: _ 'I

I Bopindolol Hydrogen Malonate 1.275 g 1.275 g - - I

In Bopindolol, free base - 1.0 g 1.0 g I

I PAM Amine Polymer RL 1.225 g 1.225 g - I

I PM Amine Polymer E - - 2.665 g 2.665 g I

Polyoxyethylene (10) oleyl ether - 0.25 g 1.335 g - I

In polyethylene (9) glycol I

In glyceryl coco ... 1.335 g I

In Azone 2.5 g 2.25 g I

I Solvent CF ^ C ^ CH ^ OH CH ^ OH I

Solvent amount (g / - I

In dry film) 1.0 1.0 4.0 4.0 I

Wet film thickness (mm) 0.25 0.25 0.3 0.3 I

In Spreading Rate I

I (mm / sec) 6 6 6 6 I

In 20 Acrylate Adhesive Film I

(Thickness of wet film) no no no no no I

Active agent penetration

In isolated rat skin I

In Penetration Flux I

I (tig / cm 2 / hr) 1.7 4.0 11.1 8.6 I

In Flux at equilibrium state

I (pg / cm 2 / hour) 5.7 12.5 59.0 33.0 I

15 DK 175236 B1

ISLAND

EXAMPLE C

Penetration of bopindolol from solutions t 5 Solutions of the following preparations are prepared and the permeation rate is observed.

Ingredients Cl C2 C3 10 Bopindolol Hydrogen Malonate - 1.0 g 1.0 g

Bopindolol (free base) 1.0 g

Ethanol (ml) 0.049 0.049 0.048

Acetone (ml) 0.049

Polyethylene glycol (7) -glyceryl cocoate 0.003 0.003 Water - - 0.048

Ozone - - 0.048

Penetration of active agent through rat skin (yg / cm2 / hour)

Flux 0.8 0.3 6.0 20

Flux at equilibrium state - - 5.8 25 1 35

Claims (15)

A pharmaceutical composition for transdermal systemic administration of an I I active substance, characterized in that the active substance is bopindotot. I I 5 I The composition of claim 1 in the form of a solid matrix. , I 3. Pharmaceutical composition for transdermal systemic administration of a. I I active substance, characterized in that the active substance is bopindolol and I I 10 the penetration rate of the skin is at least 0.3 pg / cm 2 / hour, measured I I on isolated rat skin. IN A pharmaceutical composition according to claim 3 having a permeation flux of 1 L at least 0.8 pg / cm 2 / hour. Pharmaceutical composition for transdermal systemic administration of a I I pharmacologically active substance, characterized in that it contains I I Bopindolol as an active substance in a reservoir containing a hydrophilic I I polymer in the form of a solid matrix. I I 20 I The composition of claim 5, wherein the polymer is a polyacrylate polymer. IN The composition of claim 5, wherein the polymer is a polyacrylate polymer having 11 I cathlonic functional groups. I I 25 I A composition according to any one of claims 5-7, wherein the polymer is an acrylate / - 1 L methacrylate polymer. IN A composition according to any one of claims 5-8, wherein the polymer contains trimethylaminoethyl ester groups. IN A composition according to any one of claims 5-9, in the form of an adhesive patch or patch of a) a cover layer, b) an active substance reservoir containing 1-10 layers, II of a homogeneous dispersion of active substance particles or a solution of II active substance in a polymer matrix and d) a layer of adhesive, reservoir c) being II disposed between layers a) and d). IN A composition according to any one of the preceding claims, containing a skin-compatible tibial surfactant. I I 40 I A composition according to any one of the preceding claims containing a hydrophobic I elastomer. In DK 175236 B1 Process for the preparation of a pharmaceutical composition for transdermal administration, characterized in that a) bopindolol is dispersed in a polyacrylate polymer containing cat. Ionic ester groups to form a drug reservoir, in b) bopindolol is dispersed in a hydrophilic polymer or c) bopindolol is dispersed in a suitable transdermal adjuvant and optionally an adhesive layer is applied. Use of bopindolol as an active agent in the manufacture of a medicament suitable for systemic transdermal administration, 15 Use according to claim 14, wherein the medicament is a composition defined in any one of claims 1-12. 20