Medicated dressing

Method of making effective patches

The invention relates to a process for the preparation of rubber-based patch formulations for the transdermal, controlled and long- term administration of active ingredients, in particular beta-blockers, steroid hormones, calcium antagonists and cardioprotective drugs, as well as to development and manufacturing.

Formulations in which water-soluble active ingredients are dispersed in a water-insoluble matrix are known to result in a slower release of the active ingredient from the formulation. The amounts of active substance released cumulatively per unit time are generally proportional to the square root of time in both homogeneous and heterogeneous matrix systems, but the release profile also depends on e.g. the geometry of the output form. Thus, with the transition from spherical to membrane-like or flat-sided systems, the curve describing the release of the active substance per unit time becomes more uniform, i.e. the active substance is released over a longer period of time at a virtually constant rate.

The so-called active patches, in which the active ingredients are distributed in thin, hydrophobic adhesive films, are thus, in principle, simple, serial preparations which are suitable for the transdermal administration of the active ingredients.

In practice, however, prior art active patches have not hitherto been suitable for transdermal administration of the active ingredient over a long period of time. Thus, the thermodynamic activity of the active ingredient in the patch substrate and on the skin, including hitherto known excipients, is not sufficient to achieve the required rate of active ingredient release, and in particular the desired long-term release of the active ingredient.

If such an active substance is incorporated into such a patch in such a way that the sorption capacity of the membrane part of the patch is exceeded, the active substance must be as finely divided as possible, even amorphously distributed in the adhesive matrix, so that the the amount of reduction can be kept to a minimum. One possibility associated with the application method in the manufacture of patch films involves dissolving the film former and the active ingredient in a common organic solvent, evaporating the solution to a viscosity spreadability and then applying the active ingredient-containing adhesive solution to the sheets and drying. However, this method leads to stability problems for volatile, liquid or crystalline active ingredients, which are common in the rubber films of patches, due to post-crystallization and evaporation processes which cause uncontrolled and irreversible release of the active substance and loss of adhesion properties.

The galenic development of these types of active patches is very difficult in practice, moreover, because the manufacture of the patch has to be optimized both in terms of adhesion properties and permeation of the active substance or substances.

Accordingly, it is an object of the present invention to overcome the above-mentioned difficulties associated with active patches, in particular in the release and preparation of beta-blockers, steroid hormones, calcium antagonists and cardiac agents such as bupranolol, propranolol, estradiol, nitroglycerin or isosorbitol dinitrate. and to provide a method of making an effective patch, from which the active substance is released in a reproducible and as controlled manner as possible throughout the administration period in a high total amount of active substance.

The essential features of the invention are set out in the appended claims.

The active patch prepared by the method of the invention, which releases the above-mentioned active substances in a controlled manner on the skin in particular, consists, like previously known active patches, of an impermeable cover layer, an adhesive film of water-insoluble e.g. polyisobutylene, styrene-butadiene polymers, styrene-isoprene polymers, styrene-ethylene / butene polymers or cis-1,4-polyisoprene and a resin moiety, e.g. rosin and its derivatives, β-pinene-derived polyterpene resins or hydrocarbon resins in which the active ingredient or ingredients are soluble or soluble, in a partially insoluble and partially dissolved form, and a release liner covering the adhesive film. The patch prepared by the method of the invention contains, together with the active substance or substances, one or more water-swellable polymers in an amount of 3 to 30% by weight, based on the rubber / adhesive resin mass containing the active substance.

When, according to the invention, water-swellable polymers insoluble in the rubber / adhesive resin mass are incorporated as fillers, the release rate and in particular the total amount released is increased by up to 100% and more.

In contrast, it is known from the literature (see YW Chien JR Robinson's Substained And Controlled Release Drug Delivery Systems, Chapter 4, pp. 255-256, Marcel Dekker-Verlag 1978) that in patch technology common fillers such as silica and zinc oxide reduce silicone-based or diffusion coefficients of solids and gaseous substances in natural rubber-based polymeric matrix systems. In addition, when water-swellable polymers insoluble in the rubber / adhesive resin mass are added during manufacture, stable binding is achieved which exceeds the binding of the active ingredient parts and / or the viscosity of the adhesive solution used to make the active patch according to the invention and the adhesive film coherence and adhesion.

The water-swellable polymers to be added to the rubber / adhesive resin mass of the active patch according to the invention are galactomannan, microcrystalline cellulose and tragacanth. Particularly preferred are galactomannan and tragacanth for the estradiol steroid hormone and microcrystalline cellulose for bupranolol and nitroglycerin.

According to a preferred embodiment of the invention, the adhesive film formed from the rubber / adhesive resin mass consists of a single-layer rubber / adhesive resin stock layer containing the active substance and water-swellable polymer, and a protective layer of rubber / adhesive resin adhesive , which completely passes through the rubber / adhesive resin mass and the active substance dissolved therein, but does not pass at all or only partially through the water-swellable polymer. An embodiment comprising a separating layer is preferred when the adhesive film is divided into a storage layer and an adhesive layer.

As can be seen from Examples 1 to 10 below, water-swellable polymers in rubber / resin-based adhesive films have a significant effect on the release properties of lipophilic active ingredients. The desired therapeutic release profile of a particular active ingredient can advantageously be achieved by selecting the product used according to the invention from among the water-swellable polymers, the concentration and combination of the product within the limits of the invention without the need to change to a new patch base.

In the case of nitroglycerin and isosorbitol dinitrate, there is a risk of too rapid, uncontrolled release and stability, dosing and handling difficulties in simple adhesive tapes in which the active substance is in dissolved form (see, e.g., DE-A-3 200 369). Therapeutically required amounts can then only be achieved with large patches and the adhesive base is not able to bind the active substance sufficiently, which is why the active substance is released too quickly for long-term treatment.

Conventional manufacturing methods in which the components of a patch are dissolved or dispersed in an organic solvent to a mixture with a technically required spreadable viscosity can thus result in unstable, supersaturated systems such that the active ingredient initially dissolves more than the sorption capacity of the film-forming components. In this case, especially in the case of volatile substances, significant reductions in concentration already occur during the drying process or an excess of the active substance crystallizes out of the adhesive film during storage. These problems can be avoided in the active patches according to the invention by using insoluble products which are able to bind the active substance during evaporation. At the same time, an even distribution of the active substance in the adhesive matrix is ​​achieved and it is possible to mix in amounts of the active substance which exceed the saturation point of the film-forming components. In addition, when the adhesive solution is applied to a fabric which is impermeable or only partially permeable to water-swellable polymers or active ingredients adsorbed on these products, concentration or a gradual decrease in the concentration of active ingredients and / or water-swellable products in a rubber and self-adhesive this is necessary for gluing technical and / or biopharmaceutical reasons.

When adhesive-permeable fabrics are used, it is not necessary, for example, to apply an additional layer of adhesive, which is necessary depending on the concentration of swellable products under the influence of water, to adhere the impermeable cover layer or to achieve sufficient adhesion to the skin.

The possibility of controlling the release of the active substance from the rubber patches by using water-swellable polymers according to the invention is surprising. As can be seen from Examples 1 and 2, the release rate can be increased in this way without changing the concentration of active substance in the patch.

Example 1

Nitroglycerin rubber patches containing microcrystalline cellulose in the form of a layered dispersion zone are prepared as follows:

Sticky adhesive, free of nitroglycerin and cellulose, containing the following ingredients:

1.018 g of polyisobutene (average molecular weight

900 000 - 1 400 000; Oppanol B 100,

0.916 g of solid aliphatic hydrocarbon resin Piccotac

CBHT,

0.916 g of hydrogenated rosin resin Abitol,

0.094 g of triglyceride Miglyol 812 as solvent, g of n-hexane as solvent is applied to a protective layer coated on one side with aluminum using vacuum metallization and loosely provided on both sides so that after evaporation of the solvent an adhesive film of about 4.6 mg / cm is obtained. A dispersion layer containing nitroglycerin and cellulose is applied to the adhesive film thus obtained to an amount of 19.2 mg / cm.

The layer is prepared in a similar way from the following ingredients:

2.2671 g of polyisobutene (average molecular weight 900,000 1,400,000; Oppanol B 100,

2.0409 g of solid aliphatic hydrocarbon resin Piccotac CBHT,

2.0409 g of hydrogenated rosin resin Abitol,

0.2071 g of triglyceride Miglyol 812 as solvent,

5.700 g of 5% (w / w) nitroglycerin cellulose powder (5% Nitroglycerin / Avicel pH 105 powder) g n-hexane

The dispersion layer is covered with an impermeable cover layer and the resulting patch is cut into pieces suitable for therapeutic purposes.

Example 2 (comparative example)

The preparation is carried out according to Example 1, but instead of nitroglycerin-cellulose powder, 5% nitroglycerin-lactose powder is used.

Release of active substance:

cm patch films prepared according to Examples and 2 are immersed in 37 ° C isotonic sodium chloride solution and the amount of nitroglycerin released in 2, 4, 6, 8 and 24 hours is measured by liquid chromatography. The volume of the release medium is chosen so as to avoid enrichment conditions (Sink-Bedingungen) during the experiment.

The results obtained are shown in Figure 1.

Example 3

An estradiol-containing patch containing galactomannan (Meyprogat 90) as a water-swellable polymer in the adhesive dispersion layer was prepared as follows:

The estradiol-containing adhesive mass consisting of the ingredients and solvent ingredients listed in Table 1 (see compositions A, B, C and D) is applied on one side to a protective coating coated with aluminum by vacuum metallization and removable on both sides, so that after evaporation of the solvent per unit area are in accordance with Table 1.

The adhesive layer containing estradiol and galactomannan is coated with an impermeable cover layer and then the patches are cut into pieces suitable for therapeutic purposes.

Table 1: Formulations for the preparation of estradiol-containing galactomannan patches

Ingredient Amount (g / 1000 cm)

formulation

<td></td><td>A</td><td>B</td><td>C</td><td>D</td>

<td>178-estradiol, micronized (particle size &lt;9 / Um)</td><td> 0,42</td><td> 0,3</td><td> 0,27</td><td> 0,5</td>

<td>Galactomannan (Meyprogat 90)</td><td> 1,5</td><td> 0,9</td><td> 0,9</td><td> 0,5</td>

<td>Polyisobutylene (Oppanol B 100)</td><td> 3,0</td><td> -</td><td> -</td><td> -</td>

<td>Hydrated rosin (Abitol)</td><td> 3,0</td><td> -</td><td> 1,5</td><td> -</td>

<td>Solid hydrogenated hydrocarbon resin (Piccotac CBHT)</td><td> 3,0</td><td> -</td><td> -</td><td> -</td>

<td>Tri-block polystyrene-polyisoprene-polystyrene copolymer (Cariflex TR 1107)</td><td></td><td> 1,7</td><td> 1,7</td><td> 1,7</td>

<td>Solid aromatic hydrocarbon resin (Piccovar L 60)</td><td> —</td><td> 2,2</td><td> 2,2</td><td> 2,2</td>

<td>Polyterpene resin (Dercolyte S 10)</td><td> -</td><td> 1,5</td><td> -</td><td> 1,5</td>

<td>1,2-propanediol</td><td> 0,5</td><td> 0,15</td><td> 0,15</td><td> 0,2</td>

<td>Triglycerides (Miglyol 812)</td><td> 0,5</td><td> -</td><td> -</td><td> -</td>

<td>Special gasoline 80-100 as solvent</td><td> 64</td><td> 19</td><td> 19</td><td> 19</td>

<td>2 Amount per unit area in mg / cm</td><td> 11,9</td><td> 6,75</td><td> 6,72</td><td> 6,60</td>

For comparison purposes, estradiol patches corresponding to formulations AC are prepared without galactomannan. Table 2 shows the weights per unit area of ​​these filler-free adhesive films. The deviation from the quantitative compositions of estradiol patches according to Table 1 is partly due to technological reasons and partly due to toxic pharmaceutical reasons; filler-free adhesive films were developed according to the galenic scale so that the greatest possible release of the active substance was achieved.

Table 2: Composition of galactomannan-free estradiol patch

<td rowspan="3">Constituent</td><td colspan="3">2 Amount (g / 1000 cm)</td>

<td colspan="3">formulation</td>

<td>A7</td><td>BJ_</td><td> 21</td>

<td>178-estradiol, micronized (particle size &lt;9 μm)</td><td> 0,39</td><td> 0,51</td><td> 0,51</td>

<td>Polyisobutylene (Oppanol B 100)</td><td> 1,95</td><td> —</td><td> —</td>

<td>Hydrautu rosin (Abitol)</td><td> 2,34</td><td> -</td><td> 1,19</td>

<td>Solid hydrogenated hydrocarbon resin (Piccotac CBHT)</td><td> 2,34</td><td> —</td><td> —</td>

<td>The three-block-polystyrene-polyisopreenipolystyreenikopolymeeri (Cariflex TR 1107)</td><td></td><td> 1,32</td><td> 1,32</td>

<td>Solid aromatic hydrocarbon resin (Piccovar L 60)</td><td> -</td><td> 1,98</td><td> 1,98</td>

<td>Polyterpene resin (Dercolyte S 10)</td><td> -</td><td> 1,19</td><td> -</td>

<td>1,2-propanediol</td><td> 0,39</td><td> 0,10</td><td> 0,10</td>

<td>Triglycerides (Miglyol 812)</td><td> 0,39</td><td> -</td><td> -</td>

<td>of Amount per unit area in mg / cm</td><td> 7,8</td><td> 5,1</td><td> 5,1</td>

In vitro release of the active substance:

The assay is performed as described for Examples 1 and 2 at 34 ° C using 10 cm² patch pieces of.

The cumulative release rates of the patches AD and galactomannan-free patches A'-C 'of the invention according to the invention, which are otherwise qualitatively similar in composition, are shown in Table 3.

From the results, it can be seen that the addition of galactomannan as a water-swellable polymer to the estradiol patch films formed from a single layer increases the estradiol release rate (= E₂-release).

Table 3: E₂release (, / Ug / 10 cm), n = 2

<td>Time (h)</td><td></td><td></td><td colspan="2">Formulations</td><td></td><td></td>

<td></td><td>A</td><td>A '</td><td>B</td><td>B '</td><td>C</td><td>C '</td>

<td></td><td> —</td><td></td><td> —</td><td> ——</td><td> —</td><td> ’ </td>

<td> 2</td><td> 47,4</td><td> 17,5</td><td> 42,7</td><td> 35,3</td><td> 70,1</td><td> 36,6</td>

<td> 4</td><td> 79,1</td><td> 33,7</td><td> ./·</td><td> ·/·</td><td> ./.</td><td> ./.</td>

<td> 6</td><td> 108,2</td><td> ./.</td><td> ·/.</td><td> ·/.</td><td> ·/.</td><td> ./·</td>

<td> 8</td><td> ·/.</td><td> 55,4</td><td> ./.</td><td> ./.</td><td> ./.</td><td> ./.</td>

<td> 24</td><td> 252,1</td><td> 123,4</td><td> 323,3</td><td> 182,1</td><td> 395,4</td><td> 229,9</td>

<td>affect</td><td>substance</td><td colspan="2">release in</td><td>vivo:</td><td></td><td></td>

the subject was placed on the side

a) 1 patch, size 10 cm, prepared according to Example 3 with Formulation B

b) 2 patches, each 10 cm in size, prepared according to Example 3, formulation D.

After 1 hour, the patches were removed and the residual estradiol content of each patch was determined chromatographically. The release rates thus estimated were as follows when one patch a 10 cm was used as the basis for calculation:

a) 203 / Ug

b) 208 / Ug

c) 92.5 / Ug

d) 100 / Ug

- subject

- subject

- subject

- subject

1 / formulation B

1 / formulation D 2 / formulation B 2 / formulation D

Bioavailability

In the personal experiments described above, blood samples were taken at 48, 38, 24, and 14 hours and immediately before application of the patch, and plasma estradiol levels were determined radioimmunologically. After gluing the patches, blood samples were taken at 10, 24, 34, 48, 58 and 72 hours. The mean increases in plasma oestradiol levels were as follows when one patch of 10 cm was used as a basis for counting:

<td>a)</td><td> 6,45</td><td>pg / ml</td><td>- subject</td><td>1 / formulation</td><td>B</td>

<td>b)</td><td> 6,65</td><td>pg / ml</td><td>- subject</td><td>1 / formulation</td><td>D</td>

<td>c)</td><td> 3,90</td><td>pg / ml</td><td>- subject</td><td>2 / formulation</td><td>B</td>

<td>d)</td><td> 1,47</td><td>pg / ml</td><td>- subject</td><td>2 / formulation</td><td>D</td>

According to this, estradiol (E₂) patches produce plasma E₂~ an increase in concentration in humans, with Formulation B of Example 3 giving a lower E compared to Formulation D.₂~ but higher galactomannan concentrations resulted in a relatively higher mean E₂~ increase in blood levels.

Example 4

A patch according to the invention with bupranolol as active ingredient and microcrystalline cellulose (Avicel pH 105) as a water-swellable polymer in an adhesive dispersion layer is prepared as follows:

The bupranolol-containing rubber / adhesive resin mass consisting of the ingredients listed in Table 4 (Formulation A) is applied in two successive steps to a protective layer coated on one side with aluminum by vacuum metallization and loosely equipped on both sides so that after evaporation of the solvent

14.7 mg / cm.

The dispersion layer containing bupranolol and cellulose is covered with an impermeable cover layer and then the patch is cut into pieces suitable for therapeutic purposes.

Example 5 (comparative example)

The preparation is carried out according to Example 4, but microcrystalline cellulose is not used as the water-swellable polymer. The amount of patch film is 13.5 mg / cm. The composition of the adhesive mass and the amount of solvent when applied are shown in Table 4.

Table 4:

Composition of the bupranolol patch when microcrystalline cellulose is used as water swellable

<td></td><td>as a polymer and when not in use (Examples 4 and 5)</td>

<td>Constituent</td><td>Amount (g / 1000 cm ^)</td>

formulation

<td colspan="2">A polymer included Bupranolol, micronized 1,2 (particle size &lt;50 μm)</td><td>B without polymer 1.2</td>

<td>Microcrystalline cellulose</td><td> 1,2</td><td> -</td>

<td>Polyisobutylene (Oppanol B 100)</td><td> 3,71</td><td> 3,71</td>

<td>Solid aromatic hydrocarbon resin (Piccovar L 60)</td><td> 6,69</td><td> 6,69</td>

<td>1,2-propanediol</td><td> 0,5</td><td> 0,5</td>

<td>Kovaparaffiini</td><td> 1,4</td><td> 1,4</td>

Special gasoline 80-110

Release of active substance:

The assay is performed as in Example 1 for nitroglycerin patches. Table 5 shows the cumulative release rates for the bupranolol patch of Example 4 of the invention and the non-cellulosic patch of Example 5.

The results show that the addition of cellulose as a water-swellable polymer to single-layer bupranolol patch films increases the cumulative release rates of the active substance ·

<td rowspan="2">Table 5: Time</td><td colspan="2">2 Release of bupranolol (mg / 25 cm):</td>

<td>Example 4</td><td>Example 5</td>

<td> 2</td><td> 6,46</td><td> 4,04</td>

<td> 4</td><td> 10,04</td><td> 5,77</td>

<td> 8</td><td> 15,37</td><td> 8,21</td>

<td> 24</td><td> 26,95</td><td> 14,20</td>

Example 6

Rubber-based estradiol patches with differently water-swellable polymers were prepared as follows:

The estradiol-containing adhesive, consisting of the ingredients and solvents shown in Table 6 (see formulations A, B, C), is applied to a protective layer coated on one side with vacuum metallised aluminum and loosely fitted on both sides so that after evaporation of the solvent 6 weights per unit area.

The adhesive layer containing estradiol and a swelling agent is covered with an impermeable cover layer and the resulting patch is cut into pieces suitable for therapeutic purposes.

Table 6: Composition of estradiol patch films when they contain differently water-swellable polymers ___________________________________________

Ingredient Quantity (g / 3000 cm)

formulation

<td></td><td>A</td><td>B</td><td>C</td>

<td>17β-estradiol, micronized</td><td> 1,5</td><td> 1,5</td><td> 1,5</td>

<td>(particle size &lt;9 μm)</td><td></td><td></td><td></td>

<td>Galactomannan (Meyprogat 90)</td><td> 1,5</td><td> -</td><td> -</td>

<td>tragacanth</td><td> -</td><td> 1,5</td><td> -</td>

<td>Microcrystalline cellulose</td><td> -</td><td> -</td><td> 1,5</td>

<td>(Avicel pH 105)</td><td></td><td></td><td></td>

<td>The three-block-polystyrene-polyiscpreeni-</td><td> 5,1</td><td> 5,1</td><td> 5,1</td>

<td>polystyrene copolymer (Cariflex TR 1107)</td><td></td><td></td><td></td>

<td>Solid hydrogenated hydrocarbon resin</td><td> 6,6</td><td> 6,6</td><td> 6,6</td>

<td>Piccotac CBHT)</td><td></td><td></td><td></td>

<td>Polyterpene resin (Dercolyte S 10)</td><td> 4,5</td><td> 4,5</td><td> 4,5</td>

<td>1,2-propanediol</td><td> 0,6</td><td> 0,6</td><td> 0,6</td>

<td>Special gasoline 80-100</td><td> 27</td><td> 27</td><td> 27</td>

<td>2 Amount per unit area in mg / cm</td><td> 6,6</td><td> 6,6</td><td> 6,6</td>

<td colspan="2">Table 7 shows the polymer products</td><td>water supply</td><td>Yes s-</td>

as a percentage of the weight of the sample at room temperature.

Table 7:

<td rowspan="2">Test agent</td><td colspan="3">Water intake Time</td>

<td>48 h</td><td>96 h</td><td>168 h</td>

<td>galactomannan (Meyprogat 90)</td><td> 69,72</td><td> 97,86</td><td> 112,14</td>

<td>tragacanth</td><td> 68,08</td><td> 84,51</td><td> 96,7</td>

<td>Microcrystalline cellulose</td><td> 14,7</td><td> 16,7</td><td> 21,5</td>

(Avicel pH 105)

Release of the active substance

Figure 2 shows the behavior of estradiol patches 6A to 6C as a function of time. The assay is performed according to Example 1 using 5 cm² patches at 34 ° C. The curves clearly show the dependence of the release of the active substance on the water-swellable polymer used.

A comparison with Table 7 shows that the release of the active substance increases as the water uptake capacity of the polymer used increases.

Example 7

Propanolol patches containing microcrystalline cellulose as a water-swellable polymer product were prepared as follows:

Propanolol-containing adhesive mass having the following composition

Propanolol, micronized 1.2 g

Microcrystalline cellulose (Avicel pH 105) 1.2 g

Tri-block polystyrene-poly (ethylene-3.71 g butene) -polystyrene copolymer (Kraton G 1657)

Solid aromatic hydrocarbon resin 5.0g (Piccovar L 60)

Liquid hydrocarbon mixture (Ondina oil G 33) 1.7 g

1,2-propanediol 0.34 g

Special gasoline 80-100 30g is applied in two successive sub-steps to a protective layer coated on one side with vacuum metallized aluminum and loosely fitted on both sides so that after evaporation of the solvent a layer weighing about 13.1 mg / cm is obtained. The adhesive layer is covered with an impermeable cover layer and the resulting patch is cut into pieces suitable for therapeutic purposes.

Release of the active substance;

The assay is performed according to Example 1 at 34 ° C. The cumulative release rates of the propranolol patch of the invention of Example 7 were 5.64; 11.31; 20.0 and 26.79 mg / 25 cm 2, 4, 8 and 24 hours (means of the two determinations).

Example 8

A patch containing verapamil as the active substance and galactomannan (Meyprogat 90) as a water-swellable polymer in the layered dispersion zone is prepared as follows:

Galactomannan-free adhesive adhesive having the following composition

1.08 g of polyisobutylene (average molecular weight

900 000 - 1 400 00) (Oppanol B 100)

1.35 g of solid aromatic hydrocarbon resin (Piccovar L 60)

0.96 g polyterpene resin (Dercolyte S 10)

0.24 g polyethylene glycol (average molecular weight 300) (Lutrol 300)

0.3 g of a 1: 1 mixture of verapamil / silica (Aerosil 200) g of naphtha 80-110 as solvent is applied with a protective layer coated on one side with vacuum metallised aluminum and loosely fitted on both sides so that after evaporation of the solvent an adhesive film having a weight of about 1 3 mg / cm. A galactomannan16-containing dispersion layer weighing about 16.6 mg / cm is applied to the adhesive layer thus obtained. This layer is prepared in a similar way from the following ingredients:

<td> 10,8</td><td> 9</td><td>polyisobutene (average molecular weight 900,000 - 1,400,000) (Oppanol B 100)</td><td></td>

<td> 13,5</td><td>g</td><td>solid aromatic hydrocarbon resin (Piccovar</td><td>L 60)</td>

<td> 9,6</td><td>g</td><td>polyterpene resin (Dercolyte S 10)</td><td></td>

<td> 2,4</td><td>g</td><td>polyethylene glycol (average molecular weight 300; Lutrol 300)</td><td></td>

<td> 1,5</td><td>g</td><td>galactomannan (Meyprogat 90)</td><td></td>

<td> 12,0</td><td>g</td><td>verapamil / silica mixture 1: 1 (Aerosil 200)</td><td></td>

<td> 100,0</td><td>g</td><td>special gasoline 80-110</td><td></td>

<td colspan="2">and here</td><td>in the case of application to the impermeable</td><td>mirror</td>

coating layers. The resulting patch is cut into pieces suitable for therapeutic purposes.

Example 9 (comparative example)

The preparation is carried out according to Example 9, but galactomannan is not present as a water-swellable polymer.

In vivo release of the active substance:

A 5 cm patch prepared according to Example 8 or 9 was applied to the subject's forearm (below).

after 1 hour the patches were detached and the residual verapamil concentrations were determined chromatographically.

The amounts of verapamil released were as follows:

a) Example 8 (containing galactomannan): 0.31 mg / cm

b) Example 9 (without galactomannan): 0.15 mg / cm

These results indicate that the inclusion of a swellable polymer in an otherwise similar formulation results in a doubling of the in vivo release rate of verapamil.

Example 10

A patch containing bupranolol as active ingredient and microcrystalline cellulose (Avicel pH 105) as a water-swellable polymer in an adhesive dispersion layer is prepared as follows:

Bupranolol-containing rubber / adhesive resin mass with the following composition

Bupranolol 6.0 g Microcrystalline cellulose (Avicel pH 105) 6.0 g Polyisobutylene (Oppanol B 100) 18.55 g Solid aromatic hydrocarbon resin 33.45 g (Piccovar L 60)

Liquid hydrocarbon mixture (Ondinaöl G 33) 11.1 g 1,2-propanediol 1.7 g Naphtha 80-110 191.15 g is applied to a protective layer coated on one side with vacuum metallised aluminum and loosely fitted on both sides so that after removal of the solvent2 a layer weighing 15.4 cm is obtained. The covering is then performed with an impermeable cover layer and the resulting patch is cut into pieces suitable for therapeutic purposes.

In vitro release of the active substance:

The assay was performed according to Example 1 on 16 cm patch membranes at 34 ° C using phosphate buffer solution (pH = 5.5) as the release medium. The cumulative amounts of active substance released at 2, 4, 8, and 24 hours were 3.12, respectively; 4.30; 5.89 and 10.44 mg.

In vivo release of the active substance:

a 25 cm patch piece prepared according to Example 10 was glued to the side of the subject every 24 hours for 3 days. Each patch was removed after 24 hours and the residual bupranolol content was determined chromatographically. The averages of the amounts of active substance released individually were as follows: 13.49; 11.25; 13.70; 10.44;

14.76 and 12.81 mg / 25 cm / 24 h. The mean amount of bupranolol released per patch obtained between all subjects was 12.74 + 1.84 mg (n = 3 x 6).

This experiment showed good reproducibility in in vivo release and a relatively good agreement with the corresponding in vitro result of 16.31 mg / 25 cm 2/24 h (s 10.44 mg / 25 cm 2/24 h, see above). ).

Bioavailability:

In the subject experiments described above, 6, 12, 24, 36,

After 48, 60 and 72 hours, blood samples were determined and plasma bupranolol levels were determined. The results obtained are shown in Figure 3.

Due to the continuous release of the active substance, a steady state plasma concentration was reached within 3 days.