Percutaneous therapeutic system with galantamine as biologically active ingredience

The invention relates to a transdermal therapeutic system (TTS) containing galanthamine (4a, 5, 9, 10, 11, 12-hexahydro-3-methoxy-11-methyl-6H-benzofuro (3a, 3,2-ef) (2) benzazepines -6-ol) as an active ingredient.

Due to its pharmacological properties, galantamine belongs to the group of reversible cholinesterase inhibitors and its action is similar to that of physostigmine and neostigmine. However, galantamine has a 3 to 6 times greater therapeutic range because it is not as toxic as physostigmine or neostigmine. This feature of galantamine is offset by its slightly weaker anti-cholinesterase action than physostigmine or neostigmine at analogous doses.

Galantamine is mainly used to treat narrow-angle glaucoma and as an antidote to curare administration. Galantamine is used experimentally to treat Alzheimer's disease.

The use of galantamine for the treatment of alcohol addiction is also known (Opitz, K, DE 40 10 079).

Treatment of Alzheimer's disease and alcohol dependence requires long-term action and forms of treatment that take into account the special circumstances of both diseases. Known treatments or long-term drip infusion are not applicable. However, the use of TTS is an alternative form of treatment.

EP 449 247 discloses transdermal therapeutic systems containing galanthamine, but due to their low skin penetration rate they are only suitable for the treatment of alcoholism.

The object of the present invention is to prepare galanthamine or a pharmaceutically acceptable salt thereof in the form of a transdermal therapeutic system which secrete galanthamine.

175 083 or a pharmaceutically acceptable salt thereof in a controlled manner over a period of at least 24 hours, and further ensures that galantamine does not degrade to any significant extent during storage of the finished transdermal therapeutic systems and, when the system is used, penetrates the human skin to the required extent.

The transdermal therapeutic system for administering galanthamine to the skin, with an outer layer impermeable to a biologically active substance, a self-adhesive reservoir layer and an optionally removable protective layer, is characterized according to the invention in that the reservoir layer contains 40-80% by weight of a polymeric material selected from the group of polyacrylates, 0.1-30 % by weight of softener, 0.1-30% by weight of galanthamine base or one of its pharmaceutically acceptable salts and 0.1-30% by weight of carboxylic acid as a penetration enhancer.

The polymeric material selected from the group of polyacrylates is preferably the polymerization product of acrylic acid or its esters or methacrylic acid or its esters, esters of acrylic acid being esters of this acid with straight-chain or branched alcohols of 4-10 carbon atoms or esters of this acid with alcohols. with 2-4 carbon atoms. On the other hand, esters of methacrylic acid are esters of this acid with amino alcohols.

The polymeric material preferably comprises self-crosslinking or non-crosslinking acrylate copolymers.

Hydrobromide and hydrochloride are especially used as pharmaceutically acceptable salts of galanthamine.

The back layer of the system, impermeable to the biologically active substance, can be made of both flexible and inelastic material. These materials can be obtained from polymeric foils or metal foils, such as, for example, aluminum foil, which are used alone or coated with a polymeric support. Textiles can also be used if the components of the containment layer, due to their physical properties, cannot penetrate through them. A preferred form of solution is the back layer, which is an adhesive material of an aluminum vapor film.

The reservoir layer of the system consists of a polymer matrix and a biologically active substance, the polymer matrix ensuring the cohesiveness of the system. It consists of a base polymer and, if appropriate, customary additives. The choice of the base polymer depends on the chemical and physical properties of galanthamine.

Polymers based on acrylates and / or methacrylates are used.

Preferred acrylate-based polymers are self-crosslinking acrylate copolymers composed of 2-ethylhexylacrylate, vinyl acetate and acrylic acid, optionally with non-crosslinking acrylate copolymers without a titanium chelate ester.

Polymers that are added to the base polymer are polymethacrylates and polyvinyl compounds.

The methacrylates are preferably copolymers based on dimethylaminoethyl methacrylates and neutral methacrylic acid esters. The polyvinyl compounds, on the other hand, are especially polyvinylpyrrolidones and polyvinyl alcohols.

The choice of softener depends on the polymer. Higher alcohols, such as dodecanol, undecanol, octanol, oleyl alcohol and 2-octyldodecanol, esters of carboxylic acids, where these esters can also be formed with polyethoxylated alcohol, diethers of carboxylic acids, for example di-n-butyl adipate, are particularly suitable for use. and also triglycerides, especially medium chain octanoic / decanoic acid triglycerides from coconut oil. Further examples of suitable plasticizers are polyvalent alcohols such as glycerin and propanediol- (1,2) which may also be etherified with polyethylene glycol.

Permeation accelerators are all carboxylic acids that are physiologically tolerable. Acids such as octanoic acid, levulinic acid, undecenoic acid, oleic acid, octadecanoic acid and isomers thereof are particularly suitable for use.

175 083

The type of additives depends on the polymer used. Depending on their function, they can be divided into, for example, tackifiers, stabilizers, carriers and fillers. The generally known agents are used as physiologically tolerable substances.

The reservoir layer made of the above-mentioned components has such a self-adhesion as to ensure long-lasting contact with the skin.

The removable protective layer which comes into contact with the reservoir layer and is removed prior to application of the system is formed, for example, of the same substances that are used for the backsheet, provided that it is made removable, for example by a silicone treatment. Other removable protective layers are polytetrafluoroethylene, impregnated paper, cellophane or polyvinyl chloride. If the laminate used is divided into therapeutically compatible formats (patches) prior to application of the protective layer, then the formats of the protective layer subsequently applied may include a projecting end, which makes them easier to remove from the plaster.

The transdermal therapeutic system according to the invention is obtained by homogeneously (optionally in solution) mixed with the components of the self-adhesive reservoir layer and lubricated onto the bioactive substance-impermeable backing layer, after which the solvent or solvents are optionally removed. The adhesive layer is then provided with a suitable protective layer.

The reverse method is also possible, whereby the adhesive solution is first lubricated onto the protective layer. In this case, too, the solvent is removed and then covered with a backsheet.

Although the structure of galantamine is known to be very similar to opium-containing drugs, which only penetrate the skin to a small extent, it has surprisingly been found that the system of the invention provides transdermal absorption of galantamine so that it can be used in the treatment of Alzheimer's disease.

The following examples illustrate the invention:

EXAMPLE 1 10.0 g of octanoic acid and 10.0 g of isopropyl myristate are mixed with a stirrer. Then 10.0 g of galanthamine are added and the mixture is stirred until the solid is completely dissolved (approximately 30 minutes). While stirring, 130.0 g of a self-crosslinking acrylate copolymer consisting of 2-ethylhexyl acrylate, vinyl acetate and acrylic acid are added as a 45% solution in a mixed solvent (ethyl acetate: heptane: isopropanol: toluene: acetylacetone 37:26: 26: 4: 1) and the whole is homogenized. Then, an additional 10 g of a methacrylate copolymer based on dimethylaminomethacrylate and neutral methacrylic acid esters are poured in, while stirring, and stirring is continued at room temperature for 3 hours. The losses caused by slow evaporation are made up for.

150 g of 52.8% by weight of a tacky solution containing a biologically active substance are obtained, which are smeared with 350 µm cancer onto the aluminised and siliconized polyethylene film. After removing the solvent, by drying at 60 ° C for 30 minutes, the adhesive layer is covered with a 15 µm polyester film. With a suitable cutter, 16 cm surfaces are cut out² and removes the edges by grating.

The systems illustrated in Examples 2 through XI are prepared similarly to that in Example 1. The liquid components are always mixed first, and then galanthamine is sprinkled in. After it has dissolved, the sticky solution is added.

The table shows the components of the composition after drying and the release of the components of the system. The data presented in the table concern the controlled release of the system components into a physiological saline solution and through the excised animal skin of a rodent.

175 083

Release of galantamine from different TTS containing it.

<td>Example</td><td>Galantiasis</td><td>Polyacrylate</td><td>Polymethacrylate</td><td>I soften</td><td>Center accelerating prohnirys</td><td>Release [mg / (16²cm x 24 h)]</td><td>Penetration [mg / (16-cm x 24 h)]</td>

<td>AND</td><td> 10%</td><td>Acid PA 60%</td><td> 10%</td><td>Isopropyl myristin 10%</td><td>Octanoic acid 10%</td><td> 20,3</td><td> 10</td>

<td>II</td><td> 10%</td><td>Acid PA 55%</td><td> 15%</td><td>Isopropyl myristitis 10%</td><td>Octanoic acid 10%</td><td> 20,3</td><td> 1,0</td>

<td>III</td><td> 10%</td><td>Acid PA 55%</td><td> 10%</td><td>Isopropyl myristis 15%</td><td>Octanoic acid 10%</td><td> 20,4</td><td> 0,95</td>

<td>IV</td><td> 10%</td><td>Neutral PA 59%</td><td> 15%</td><td>Oleyl alcohol 5%</td><td>Octanoic acid 10% Dekseanthzol 1%</td><td> 20,6</td><td> 1,05</td>

<td>V</td><td> 10%</td><td>Neutral PA 59%</td><td> 15%</td><td>Isopropyl myristism 10%</td><td>Octanoic acid 10% Dexpazthnol 1%</td><td> 20,5</td><td> 1,05</td>

<td>VI</td><td> 10%</td><td>Neutral PA 59%</td><td> 15%</td><td>Oleyl alcohol 5%</td><td>Octanoic acid 10% Dhkspazthnol 1%</td><td> 18</td><td> 0,95</td>

<td>VII</td><td>like VI</td><td>like VI like VI</td><td>like VI</td><td>like VI</td><td>Oleic acid 10% Dekspaztenrl 1%</td><td> 18,5</td><td> 1,05</td>

<td>VIII</td><td>like VI</td><td>like VI like VI</td><td>like VI</td><td>like VI</td><td>Isroctidhkinic acid 10% Dexpazthzol 1%</td><td> 18</td><td> 1,05</td>

<td>IX</td><td>like VI</td><td>like VI like VI</td><td>like VI</td><td>like VI</td><td>Levulinic acid 10% Dexpynthzol 1%</td><td> 11</td><td> 0,3</td>

<td>X</td><td>like VI</td><td>like VI like VI</td><td>like VI</td><td>like VI</td><td>Undhkhzic acid 10% Dekseanthzol 1%</td><td> 18</td><td> 10</td>

<td>XI</td><td>like VI</td><td>Neutral PA 69%</td><td>like VI</td><td>like VI</td><td>Dhkseanthzol 1%</td><td> 18</td><td> 0,7</td>

Examples VI-VII and X-XI show that galantamine penetrates the skin of mice in sufficient quantity.

By adding octanoic, undecanoic, oleic and isooctadecanoic acids, the permeation rate can be increased by about 1.5 times.

In vitro release is determined in a shaking water bath at 37 ° C. The receiving environment is 100 cm³ physiological saline solution, which is completely replaced after 2, 4 and 8 hours. The concentration is determined after 2.4, 8 and 24 hours by HPLC (pressure liquid chromatography). Penetration into the skin of the mice is measured in a Franz diffusion cell.

Symbols in the table:

acid polyacrylate (PA) - acrylate copolymer composed of 2-ethylhexyl acrylate, vinyl acetate and acrylic acid, with an acid number of 40;

neutral PA - kk ^ j ^ olli ^ ^ and • aloylate composed of vinyl acetate acrylate and acrylic acid, acid number 1;

polymethacrylate - a basic copolymer based on dimethylamino methacrylate and neutral esters of methacrylic acid (KOH number 180).