WO2001080859A1

WO2001080859A1 - Transdermal therapeutic systems for applying moxonidine

Info

Publication number: WO2001080859A1
Application number: PCT/EP2001/003937
Authority: WO
Inventors: Frank Theobald
Original assignee: Lts Lohmann Therapie-Systeme Ag
Priority date: 2000-04-19
Filing date: 2001-04-06
Publication date: 2001-11-01
Also published as: DE10019311A1

Abstract

The invention relates to a transdermal therapeutic system comprising the active substance moxonidine (4-chloro-N-(4,5-dihydro-1H-imidazole-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine) or another alpha receptor agonist comprising an imidazole structure. The inventive system is also comprised of a backing layer that is impermeable to the active substance, of an adhesive active substance reservoir, which is based on polymer and which contains the active substance, and of a protective layer that can be removed before application. The invention is characterized in that the active substance reservoir contains, as base polymers, polymers that are selected from the group of hydrophilic polymers comprising polyvinylpyrrolidones, polyvinyl alcohols, hydroxypropylmethylcellulose and other cellulose derivatives and polyethylene glycols, and/or in that the active substance reservoir contains a mixture consisting of at least one longer-chain n-alkane-carboxylic acid and of at least one longer-chain unsaturated carboxylic acid.

Description

Transdermal therapeutic systems for the application of moxonidine

The invention relates to transdermal therapeutic systems which contain the active ingredient moxonidine (4-chloro-N- (4,5-dihydro-lH-imidazol-2-yl) -6-methoxy-2-methyl-5-pyrimidinamine) or other alpha- Contain receptor agonists with imidazole structure and which are suitable for the transdermal administration of these active substances for the treatment of high blood pressure.

The active ingredient moxonidine is used therapeutically to treat hypertension (high blood pressure). Moxonidine is a centrally acting alpha receptor agonist. For the administration of moxonidine, oral dosage forms, e.g. B. film-coated tablets, introduced in the market. The invention also relates to other substances which act on the central alpha-2 receptor and which contain an imidazole structure, e.g. B. Clonidine.

To treat hypertension, it is sensible and desirable to ensure a reduction in blood pressure during the entire application period. Therefore, the blood plasma level of the active ingredient should be kept at a constant level if possible. When moxonidine is administered orally, undesirable plasma peak values (peak values) can occur, which are often the cause of side effects. In addition, after oral administration, a significant proportion of the active ingredient is already metabolized during the first passage through the liver ("first pass" effect).

Transdermal therapeutic systems (TTS) enable the administration of active pharmaceutical ingredients through the skin. This type of administration is advantageous in many ways compared to oral administration. For one thing In this way, the above-mentioned "first pass" effect is avoided, and on the other hand, these systems enable a continuous and constant supply, so that the blood plasma level of the active substance is kept at a largely constant level. This ensures that the patient is adequately supplied with the respective active ingredient for therapeutic purposes during the entire application period. At the same time, this prevents the occurrence of plasma peak values (peak values) and thus reduces the risk of side effects.

Since these advantages are also of great importance in the medicinal treatment of hypertension, it is desirable to provide transdermal therapeutic systems which are suitable for the transdermal administration of moxonidine for hypertension therapy.

Transdermal therapeutic systems generally have a structure consisting of an active substance-impermeable backing layer, an associated pressure-sensitive adhesive active substance reservoir and a protective layer which can be removed before application. For application, the protective layer is removed and the TTS is attached to the patient's skin with the adhesive side of the drug reservoir. During the application period, the active substance is released from the reservoir into the patient's skin.

Transdermal systems for the application of moxonidine have already been proposed in EP 0 169 364 and US 4,882,163. The systems described there are self-adhesive TTS based on optionally cross-linked polyacrylates or based on polyisobutylenes in combination with synthetic or partially synthetic resins. Formulations based on polyvinyl alcohol, polyurethane and polysiloxane compositions were also mentioned. As a permeation enhancer, which increases the absorption of the Promoting active substance through the skin, longer-chain n-alkane carboxylic acids with at least 12 carbon atoms have been mentioned.

However, it has been found that the release rates (flux rates) which can be achieved with the TTS according to the abovementioned prior art are too low and are therefore unsatisfactory. In order to build up a therapeutically effective plasma concentration and maintain it at the required level, it is necessary to achieve the highest possible flux rate.

It was therefore the object of the present invention to provide transdermal therapeutic systems which enable transdermal administration of the active ingredient moxonidine at high flux rates, so that the applicability in the therapeutic treatment of hypertension is improved.

Surprisingly, this object is achieved according to the invention in that, in the case of TTSs containing moxonidine with the features of the preamble of claim 1, either (A) the active substance reservoir contains, as base polymers, those polymers which are selected from the group of hydrophilic polymers which include polyvinylpyrrolidones, polyvinyl alcohols and hydroxy - Propylmethylcellulose and other cellulose derivatives and polyethylene glycols, or that (B) in the TTS mentioned in the preamble, the active substance reservoir contains a mixture of at least one long-chain n-alkane carboxylic acid and at least one long-chain unsaturated carboxylic acid, where "longer-chain" means that the number the C atoms is at least 12. The two measures (A) and (B) mentioned each result in an increase in the active substance flux; however, they can also be used in combination. As can be seen from FIG. 1 and FIG. 2, the TTS according to the invention have compared to the known ones Comparative examples prepared recipes significantly improved flux rates.

In particular, it has been found that formulations of TTS according to the invention which contain hydrophilic polymers, e.g. B. polyvinylpyrrolidones (PVP) or hydroxypropylmethyl cellulose, as base polymers of the active substance matrix, have significantly higher flux rates compared to the formulations known from the prior art.

In the TTS according to the invention, another active ingredient from the group of substances having an action on the central alpha-2 receptor and containing an imidazole structure can also be used as the active ingredient; in particular, the active ingredient clonidine (2- (2, 6-dichloroanilino) -4,5-dihydroimidazole) comes into consideration.

The active substance reservoir, which contains the active substance moxonidine in dissolved or dispersed form, is essentially based on polymers that form an active substance matrix; these polymers are also referred to as base polymers. The proportion of the base polymers is at least 40% by weight, preferably at least 55% by weight, based on the total active substance reservoir. The active substance reservoir has pressure-sensitive adhesive properties which are caused by the base polymers used or by additionally added tackifying substances. Furthermore, it is also possible to provide the active substance reservoir on the skin side with a pressure-sensitive adhesive layer. In the simplest embodiment, the active substance reservoir of the TTS according to the invention is a single-layer polymer matrix. In deviation from this, the TTS can have a layered structure of the active substance reservoir with at least two polymer matrix layers. In addition to the drug reservoir discussed above, the structure of the TTS according to the invention comprises a drug-impermeable backing layer and a detachable protective film which is also drug-impermeable. A large number of skin-compatible plastic films, such as, for example, are suitable as the material for the backing layer. B. films made of polyvinyl chloride, ethylene vinyl acetate, vinyl acetate, polyethylene, polypropylene or cellulose derivatives. Particularly suitable as a material for the backing layer are polyesters, which are particularly strong. Furthermore, it may be useful in individual cases to provide the backing layer consisting of film material with an additional support, e.g. B. by vapor deposition with metals or other diffusion-blocking additives such as silicon dioxide, aluminum oxide or similar substances known to the person skilled in the art.

In principle, the same materials can be used for the removable protective layer as for the backing layer, provided that this layer is subjected to a suitable surface treatment, e.g. B. fluorosiliconization, is subjected so that it is removable from the pressure sensitive adhesive layer covered by it and can be removed before application of the TTS. In addition, other materials can be used as removable protective layers, such as. B. polytetrafluoroethylene treated paper, cellophane, polyvinyl chloride or the like.

According to the invention, irrespective of the use of hydrophilic base polymers for the active substance matrix, the flux rates can also be increased in that the active substance-containing reservoir contains a mixture or combination of at least one long-chain n-alkane carboxylic acid and at least one long-chain unsaturated carboxylic acid (see Fig. 2). The longer chain n-alkane carboxylic acid is preferably selected from the group comprising lauric acid (dodecanoic acid), myristic acid, palmitic acid and stearic acid; but other long-chain saturated carboxylic acids are also suitable. Mixtures of various long-chain saturated carboxylic acids can also be used.

A combination of lauric acid (dodecanoic acid) with an unsaturated long-chain fatty acid, eg. B. oleic acid. The longer-chain unsaturated carboxylic acid (s) is / are preferably selected from the group comprising palitoleic acid, oleic acid, linoleic acid, linolenic acid and arachidonic acid. The number of carbon atoms in the long-chain n-alkane carboxylic acid or long-chain unsaturated carboxylic acid is at least 12 and preferably at most 30.

According to a preferred embodiment, the active substance reservoir of the moxonidine-containing TTS according to the invention contains a mixture of at least one long-chain n-

Alkane carboxylic acid and at least one long-chain unsaturated carboxylic acid, where "longer chain" means that the number of C atoms is at least 12. In this case, the active substance reservoir is built up using hydrophilic polymers, preferably polyvinyl alcohols, and / or polymers from the group comprising polyacrylates, polyisobutylenes, polystyrenes, polydimethylsiloxanes as base polymers.

If the base polymers selected for the production of the active substance reservoir result in an active substance reservoir which has inadequate viscosity properties, suitable polymers can be added to increase the viscosity, e.g. B. polyacrylates, polyvinyl pyrrolidones or cellulose derivatives. One or more plasticizers can also be added. be set to ensure sufficient elasticity and processability; suitable franking agent substances are known to the person skilled in the art.

In addition, it can be advantageous and have a favorable effect on the active substance release if the active substance reservoir contains at least one mono- or polyhydric alcohol, the concentration of the alcohol or alcohols being 0.5 to 20% by weight, preferably 2.5 to 10% by weight .-%, based on the total mass of the drug reservoir. Glyerol is used as a particularly preferred polyhydric alcohol.

As mentioned above, the TTS according to the invention are distinguished by a significantly increased flux rate. Based on the active ingredient moxonidine, this is at least 1.5 μg / cm ² h, preferably even at least 7 to 10 μg / cm ² h. The active substance content in the active substance reservoir of the TTS according to the invention is in the range from 1% by weight to 50% by weight, preferably in the range from 5% by weight to 40% by weight.

To further improve the release of active ingredient through the skin, one or more permeation accelerators (enhancers) can also be added to the active ingredient-containing reservoir. Such substances are generally known to the person skilled in the art. Suitable permeation accelerators (enhancers) are, for example, substances which are selected from the group comprising polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, esters of fatty acids with methanol, ethanol or isopropanol, and esters of fatty alcohols with acetic acid or lactic acid. Combinations of two or more enhancers can also be used to optimize the active ingredient flow.

In order to improve the stability of the TTS according to the invention, antioxidants or at least at least one such substance may be added; substances suitable for this are known to the person skilled in the art. Antioxidants selected from the group comprising butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, tocopherol, ascorbic acid and ascorbyl palmitate are preferably used. The addition of synergists, for example citric acid, is also advantageous.

In a further preferred embodiment of the TTS containing moxonidine according to the invention it is provided that the active substance reservoir additionally has a fleece or a fabric which is impregnated with the active substance moxonidine. During production, the procedure can be such that the active ingredient moxonidine is dissolved in one or more penetration accelerators or in a suitable solvent and then metered onto the fleece or fabric.

The TTS according to the invention can advantageously be used for the treatment of high blood pressure. Depending on the active substance content and the flux rate achieved, the application time is d. H. the wearing time of a single TTS, approx. 6 h to 7 days. During this time transdermal administration maintains a therapeutically effective blood level.

In order to adapt the flux rates to the respective requirements, and in particular in order to be able to achieve a constant active ingredient delivery profile over longer application periods, special embodiments of the TTS according to the invention are provided which have a polymer layer on the application side (ie on the side facing the skin). This polymer layer can be composed of polyisobutylene, polyacrylate, polydimethylsiloxanes, polystyrenes, polyisoprene, natural resins or partially or fully synthetic resins. be built, and combinations of such polymers can be used. This polymer layer enables control of the flux rate or a controlled delay in the release of active ingredient.

The invention and its advantages are explained in more detail by the following examples and comparative examples:

Examples

Comparative example

TTS containing moxonidine, produced according to a recipe based on EP 0 169 364 and US 4,882,163.

Composition of the drug reservoir: (comparison recipe)

Moxonidine 10% by weight polyacrylate 75% by weight

Lauric acid 15 wt

Ethyl acetate is added to the polyacrylate; then lauric acid and moxonidine are added and a solids content of about 45% by weight (30-60% by weight) is established with ethyl acetate. The formulation is coated with a basis weight of approximately 100 g / m ² (50-300 g / m ² ) on a siliconized PET (polyethylene terephthalate) film or on another suitable film. To remove the organic solvents, the film is dried at room temperature and then in a drying cabinet. Then a flexible cover film (e.g. PET film, 15-23 µm) is laminated on and a TTS of a defined size is punched out using suitable tools. Example recipe I

TTS containing moxonidine according to the invention with the following composition of the active substance reservoir:

Moxonidine 9.6 wt

Polyvinylpyrrolidone 64.8 wt .-% lauric acid 4.8 wt

Glycerol 16.8% by weight ethanol 4.0% by weight

In this recipe, the glycerol is first in a suitable solvent, for. B. ethanol. Lauric acid, polyvinylpyrrolidone and moxonidine are then added. With a suitable solvent, e.g. For example, ethanol, a solids content of 35% by weight is set, the solids content also being in the range of 20-50% by weight. The formulation is spread with a basis weight of approx. 100 g / m ² (optionally also 50-300 g / m ² ) on a siliconized PET film or another suitable film. To remove the organic solvents, the film is dried at room temperature and then in a drying cabinet. Then a flexible cover film (e.g. PET film, 15-23 µm) is laminated on and a TTS of a defined size is punched out using suitable tools. Example recipe II

Moxonidine 35 parts by weight hydroxypropyl methyl cellulose 60 parts by weight

Lauric acid 5 parts by weight

In this recipe, the lauric acid is first in a suitable solvent, for. B. ethanol, dissolved or suspended. Then hydroxypropylmethyl cellulose and moxonidine are added. With a suitable solvent, e.g. For example, ethanol, a solids content of 28 parts by weight is set (solids contents in the range of 10-50 parts by weight are also possible). The formulation is spread with a basis weight of approximately 100 g / m ² (or 50-300 g / m ² ) on a siliconized PET film or another suitable film. To remove the organic solvents, the film is dried at room temperature and then in a drying cabinet.

A flexible cover film (e.g. PET film, 15-23 μm) is then laminated on and a TTS of a defined size is punched out using suitable tools.

The flux of the active substance was determined using the TTS prepared according to the comparison formulation or according to example formulations I and II. The flux values were obtained by experiments on Franz cells using human skin. Human full skin (breast) was used for this. The application area was 1.148 cm ² . Served as an acceptor medium Phosphate buffer solution with a pH of 5.5. The investigation was carried out at a temperature of 32 ° C.

The results of these active substance flux measurements using the various formulations mentioned above are shown in FIGS. 1 and 2.

Regarding the results, it should be noted that the flux rates achieved with the use of whole human skin can in principle only be compared to a limited extent with test results obtained with skin samples from other animal organisms. In general, higher flux values are achieved with hides from other origins (e.g. guinea pigs, cow udders) than when using full human skin.

1 shows a graphical representation of the flux rates which were achieved with the various TTS formulations mentioned above, namely with TTS according to the example formulations I and II or with TTS according to the comparison formulation. It can be clearly seen that the TTS according to the invention according to example formulations I and II have an increased flux rate over a release period of at least 72 h compared to the comparative example.

2 shows a graphical representation of active substance

Flux rates, which were obtained with the experimental arrangement described above using TTS according to the invention, the recipes for the drug reservoir containing a combination of oleic acid and lauric acid. Three different formulations were tested, which differ in the quantity ratio of oleic acid to lauric acid. Particularly high flux rates were achieved with TTS according to the invention in which the quantitative ratio of oleic acid: lauric acid was 1.5: 1. In addition, the flux rates shown in FIG. 2 are significantly higher than the flux rates achievable with the comparison formulation (FIG. 1).

Example for the production of a TTS with an inlaid fleece

The procedure for producing moxonidine-containing TTS with an inlaid fleece is as follows: The adhesive coat is applied in two steps. Part of the adhesive is applied to a release liner (as a carrier film) and covered with siliconized paper. Then a fleece of the required size is punched and placed on the adhesive line from which the siliconized paper has been removed. The enhancer solution containing the active ingredient, which also contains a mixture of saturated and unsaturated carboxylic acids (oleic acid, lauric acid) in this case, is pipetted onto the fleece disk or dripped on and evenly distributed.

The second part of the adhesive is applied to a siliconized paper and covered with a thin cover film (e.g. PET 19 μm). After removing the paper, this adhesive-coated cover film is laminated to the previously produced carrier film (with the fleece on top).

Claims

claims

1. Transdermal therapeutic system with the active ingredient moxonidine (4-chloro-N- (4,5-dihydro-lH-imidazol-2-yl) -6-methoxy-2-methyl-5-pyrimidinamine) or another alpha-receptor -Agonists with an imidazole structure, with an active substance-impermeable backing layer, an associated, pressure-sensitive adhesive active substance reservoir containing the active substance and polymer-based, and a detachable protective layer prior to application, characterized in that the active substance reservoir as the base polymer contains those polymers which are selected from the group hydrophilic polymers which comprise polyvinylpyrrolidones, polyvinyl alcohols, hydroxypropylmethyl cellulose and other cellulose derivatives and polyethylene glycols, and / or that the active substance reservoir contains a mixture of at least one long-chain n-alkane carboxylic acid and at least one long-chain unsaturated carboxylic acid, where “longer chain” means that the number of carbon atoms is at least 12.

2. Transdermal therapeutic system according to claim 1, characterized in that it contains the active ingredient clonidine.

3. Transdermal therapeutic system according to claim 1 or 2, characterized in that the active substance reservoir contains a mixture of at least one long-chain n-alkane carboxylic acid and at least one long-chain unsaturated carboxylic acid, where "longer chain" means that the number of C atoms is at least 12, and that the active substance reservoir contains hydrophilic polymers, preferably polyvinyl alcohols, and / or polymers from the group comprising polyacrylates, polyisobutylenes, polystyrenes, polydimethylsiloxanes as base polymers.

4. Transdermal therapeutic system according to one of claims 1 to 3, characterized in that the longer-chain n-alkane carboxylic acid (s) is selected from the group comprising lauric acid (dodecanoic acid), myristic acid, palmitic acid and stearic acid, lauric acid being particularly preferred is preferred, and / or that the longer-chain unsaturated carboxylic acid (s) is or are selected from the group of long-chain unsaturated fatty acids, preferably from the group comprising palmitoleic acid, oleic acid, linoleic acid, linolenic acid and arachidonic acid.

5. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the active substance reservoir contains at least one mono- or polyhydric alcohol, preferably glycerol, the concentration of the alcohol or alcohols being 0.5 to 20% by weight. is preferably 2.5 to 10% by weight, based on the total mass of the active substance reservoir.

6. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that it has a flux rate, based on the active ingredient moxonidine and on full human skin, of at least 1.5 μg / cm ² h, preferably of at least 7 to 10 μg / cm ² h.

7. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the drug reservoir contains at least one permeation accelerator.

8. Transdermal therapeutic system according to one or the preceding claims, characterized in that the active substance reservoir contains at least one antioxidant, preferably selected from the group consisting of butylhydroxyto- toluene, butylated hydroxyanisole, propyl gallate, tocopherol, ascorbic acid and ascorbyl palmitate.

9. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the active substance reservoir has a fleece or tissue which contains the active substance.

10. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that it carries a polymer layer towards the application side which is composed of one or more polymers which are selected from the group consisting of polyisobutylene, polyacrylate, polydimethylsiloxanes, Polystyrenes, polyisoprene, natural resins and partially or fully synthetic resins, wherein this polymer layer serves to regulate the flux rate.

11. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the active substance reservoir contains one or more plasticizers.

12. Use of a transdermal therapeutic system containing the active ingredient moxonidine according to one or more of claims 1 to 11 for the transdermal administration of this active ingredient for the treatment of high blood pressure.

13. Use of a transdermal therapeutic system containing the active ingredient clonidine according to one or more of claims 1 to 11 for the transdermal administration of this active ingredient for the treatment of high blood pressure.

14. A method of manufacturing a transdermal system according to claim 9, comprising the steps of:

(a) applying a part of the adhesive to a release liner as a carrier film and covering this adhesive layer with siliconized paper;

(b) production of a fleece piece of the required area by means of contour punching;

(c) removing the paper from the adhesive layer produced in (a) and placing the piece of fleece on the adhesive layer;

(d) dosing the active substance-containing enhancer solution onto the nonwoven disk;

(d) Make a second coat of adhesive by applying the adhesive to siliconized paper and covering the

Adhesive with a cover sheet;

(e) Removing the paper from the adhesive layer from (d) and laminating this adhesive layer to the carrier film with the nonwoven laid on from steps (a) to (d).