Method of efficient substance's released quantity increase

The present invention relates to formulations of rubber-based patches for the controlled transcutaneous administration of active substances, in particular beta-blockers, steroid hormones, calcium antagonists and drugs acting on the skin for a prolonged period of time, with improved release properties as well as showing advantages in the development and manufacture of patch films.

Formulations in which the water-soluble active ingredients are dispersed in a water-insoluble matrix result in a delayed release of the active ingredient from the formulation. The amounts of active substance released cumulatively per unit of time are generally both homogeneous and heterogeneous matrix systems proportional to the square root of time, the form of release being dependent inter alia on the geometry of the container to be delivered. Thus, when switching from a spherical system to a film-shaped system or a sheet-like system, a curve is reproduced reproducing the release rate of the active ingredient over a period of time that is increasingly flattened, i.e. the active ingredient or active ingredients are released after. increasing time period in practically constant quantities.

The so-called medicated plasters, in which the active substances are distributed in thin hydrophobic adhesive films, are therefore conceptually simple, serial-formulated pharmaceutical preparations for the active substance which are essentially suitable for transcutaneous application of the active substances.

However, active substance patches of this type known in the prior art cannot be used in practice for a controllable transcutaneous delivery of the active substance over a longer period. Thus, the thermodynamic activity of the active substance in the patch base, including the skin, is not sufficient for the auxiliary actuation hitherto known to achieve the required amount of active substance release and in particular the necessary release of the active substance over the desired period of time at the patch size. still acceptable.

If more than the corresponding amount of active ingredient is incorporated into such a patch. then the active ingredient must be distributed as finely as possible to amorphous in the adhesive matrix in order to maintain the saturation state of the pressure-sensitive adhesive as rapidly as possible during the application and thereby maintain the degree of release rate of the effective substances from the patch as small as possible. One possibility related to the conventional coating method for the production of patch films is that the film former is dissolved together with the active ingredient in an organic solvent, the solution is concentrated to a viscosity at which it can be coated and the active ingredient adhesive solution is then spread. on large-area belts and dried. However, in the case of readily volatile, liquid or crystalline active substances in adhesive formulations customary in rubber patch films, this method leads to problems of stabilization, due to additional crystallization and evaporation processes, which lead to uncontrolled and unrepeatable release of the active substance and deterioration of adhesive properties.

The galenic development of active substance patches of this kind has been very difficult in practice, in addition to the need to optimize the formulation of the patches both with regard to their adhesive properties of the patches, with respect to the permeability of the active ingredient or active ingredients.

The object of the present invention is to overcome the aforementioned drawbacks of the prior art active substance-containing patches, in particular in the field of beta-blockers, steroid hormones, calcium antagonists and substances affecting the heart activity such as bupranolol, propranolol, estradiol, nitroglycerin or isosorbitdinitrate. a substance, especially its release amount, an increase in viscosity, the ability to soak up water and improve the adhesion of transdermal therapeutic systems.

CS 270 207 B2

The method of increasing the amount of active substance released, increasing the viscosity, water-absorbency and improving the adhesion of transdermal therapeutic systems by the addition of an adjuvant consists in using a water-swellable polysaccharide insoluble in binder or a mixture of such polysaccharides in an amount of 3. up to 30% by weight of the binder.

The active substance-containing patch for the controlled release, in particular of the aforementioned substances on the skin, consists of an insoluble coating layer associated with the water-insoluble adhesive film consisting of a mixture of rubber and adhesive resin mass based on natural or synthetic rubbers such as polyisobutylene, styrene-butadiene polymers, styrene-isoprene polymers, styrene-ethylene / butylene polymers, and cis-1,4-polyisoprene, as well as the proportions of resins, for example, rosin and derivatives thereof, polyterpene resins and O-pinene, hydrocarbon resins in which the active substance (s) are (are) present or present in partially dissolved and partially undissolved form and from the protective layer, covering the adhesive film, which can be detached again. The active substance-containing patch contains one or more water-swellable polymers in an amount of 3 to 30% by weight, based on the active ingredient-containing rubber-adhesive resin mixture.

By incorporating water-swellable polymers as fillers which are insoluble in the rubber / adhesive resin mass, the amount of active substance released per time unit and in particular the total amount released is increased by 100% or more. On the other hand, it is known from the literature - cf. YWChien in JRRobinson ”Substained and Controlled Release Drug Oelivery Systems, Chap. 4, p. 255 - 256, Marcel Dekker - 1978 - that fillers customary in patch technology are, for example, silica and zinc oxide in silicone or natural rubber polymer matrix systems, leading to a reduction in the diffusion coefficients of solid and gaseous substances. In addition, the production of water-swellable polymers provides stable bonding of the bulk of the active ingredient present in the adhesive and / or an increase in the viscosity of the adhesive solution used in the manufacture of active substance-containing patches as well as improved coherence and adhesion of the adhesive film.

Examples of water-swellable polymers added to the rubber / adhesive resin mass of active substance-containing patches are products such as galactoma, cellulose products, tragacanth, polyglycosides, polyvinylpyrrolidones, finely divided polyamides, water-soluble polyacrylamide, carboxyvinylpolymers, agar-like algae products , blended polymers of methyl vinyl ether and maleic anhydride, guar gum, types such as hydroxypropyl guar gum or guar meal, gummi arabicum (gum arabic), dextrin and and dextran, microbiologically derived polysaccharide gum such as polysaccharide 8 1459 or water-soluble types of colols, or synthetically obtained polysaccharides as ficoll, methylglucose derivatives, hydroxymethylpropylcellulose, polygalacturic acid amide derivatives or pectinecturide amide as pectin or urine.

Galactose, microcrystalline cellulose and tragacanth are preferred. Especially preferred are galactomann and tragacant for the steroid hormone estradide, microcrystalline cellulose for cupranol and nitroglycerin.

The rubber / adhesive resin adhesive film may be divided into a monolayer rubber / adhesive resin storage layer containing the active ingredient and water swellable polymers and adhesive substrate layers arranged therein as a protective layer and optionally containing the active ingredient and between the storage layer and there is a separating layer on the substrate layer of the adhesive, which is permeable to a mass consisting of rubber and an adhesive resin and the active substance dissolved therein and impermeable or only partially permeable to the polymer swelling in the beams. The separating layer embodiment is advantageous when the adhesive film is divided between the storage layer and the adhesive sorbent layer.

CS 270 207 B2

As the following Examples 1 to 10 show, the water-swellable polymers used according to the invention in the adhesive films based on the mass consisting of rubber and adhesive resin have a decisive influence on the release properties of the lipophilic active substances. The therapeutically desired form of release can be obtained for a given active ingredient preferably by selecting a product selected from the group of water-swellable polymers, a concentration of the product and a combination of these products within the range of the invention without changing the base of the patch.

Precisely in the case of nitroglycerin and isosorbitdinitrate, simple adhesive strips in which the active substance is present in dissolved form, according to the literature, present the risk of rapid, uncontrolled release as well as stability, dosing and handling / compare problems. DE-0S.3 200 369 /. The therapeutically required amount can then only be achieved by the use of large patches or the adhesive backing is not able to bind the active substance sufficiently, so that the release of the active substance in too short a time leads to long-term treatment. *

Conventional manufacturing processes in which the components of the patch dissolve or disperse in organic solvents until a technically necessary viscosity for coating can be achieved can lead to the formation of unstable supersaturated systems by dissolving more active substance than the sorptive capacity of the film-forming components. In this case, in particular, the easily volatile substances already undergo a considerable reduction in the content or, in the case of storage, in the adhesive film, the content of the active substance, if any, is too high during drying. These problems can be avoided by using patches containing the active substances according to the invention by using insoluble substances which are capable of binding the active substance during evaporation. At the same time, a fine distribution of the active ingredient in the adhesive matrix is ​​achieved and it is possible to produce amounts of active ingredient exceeding the saturation of the film-forming components. In addition, by coating the tissue adhesive which is impermeable or only partially permeable to the water-swellable polymers or adsorbates of the active substance on these products, it is necessary, if it is necessary for technical reasons relating to gluing and / or biopharmaceutical reasons, simply by concentrating and graduating the concentration of the active ingredients and / or water swellable products in the mass consisting of rubber and a self-adhesive mass.

The use of adhesive-permeable fabric materials saves, for example, the application of an additional adhesive layer, which is necessary, depending on the concentration of the water-swellable products, for the application of the impermeable cover layer or for sufficient adherence to the skin.

The ability of the invention to control the release of the active ingredient from rubber rf plastics using water-swellable polymers is surprising. For example, as shown in Examples 1 and 2, the rate of release can be increased without changing the concentration of the active ingredient in the patch. ·

Example 1 ·

The nitroglycerin rubber patch of the present invention with microcrystalline cellulose in the layered dispersion region is produced as follows:

Nitroglycerin - cellulose - free adhesive consisting of

1.018 g of polyisobutylene / with an average molecular weight of 900,000 to 1,400,000; product Oppanol В L00 /,

0.916 g solid resin of aliphatic hydrocarbons (Piccotac СВНТ),

0.916 g hydrogenated / hardened / rosin / product Abitol /

0.094 g of triglyceride (product Myglyol 812) as solvent / g of hexane as solvent is applied to a protective layer on one side of which a layer of aluminum is vaporized and on both sides

CS 270 207 B2 non-sticky so that an adhesive film of about 4.6 mg / 2 cm is obtained after evaporation of the solvent. A dispersion layer comprising nitroglycerin and cellulose with a basis weight of about 19.2 mg / cm is laminated onto the binder adhesive film thus produced.

This layer is produced analogously:

2.2671 g polyisobutylene / average molecular weight 900.000 to 1.400.000;

product Oppanol В 100 /,

2,0409 g solid aliphatic hydrocarbon resin (Piccotac СВНТ),

2,049 g rosin (product Abitol),

0.2071 g triglyceride (product Myglyol 812) as solvent /,

5.700 g of 5% (G) G-nitroglycerin triturated on cellulose (5% nitroglycerin triturated on Avicel pH 105), hexane.

After covering the dispersion layer with an impermeable covering layer, the obtained patch film is divided into individual pieces in accordance with the therapeutic requirements.

Example 2 (comparative example) _t

The preparation is carried out as in Example 1, but with the spreading of 5% nitroglycerin on the lectose instead of spreading the nitroglycerin on the cellulose.

Release of active substance:

cm² the large patch films produced according to Examples 1 and 2 are soaked in an isotonic sodium chloride solution at 37 °. C and the released amount of nitroglycerin is determined by liquid chromatography after 2, 4, 6, 8 and 24 hours. The volume of the release medium is selected such that the conditions of decrease are maintained throughout the duration of the experiment.

The result is shown in Fig. 1.

Example 3

The plaster containing estradiol as the active substance, with a galactomann (Meyprogat 90) as a water-swellable polymer in the dispersion adhesive layer is prepared as follows:

The binder containing estradiol, consisting of the constituents and the proportion of solvent listed in Table 1 (see Formulations A, 8, C, O), is applied to a protective layer steamed on one side with aluminum and on both sides formed as non-sticky, to obtain, after evaporation of the solvent, an adhesive film having a basis weight as shown in Table 1.

After covering the binding adhesive layer containing estradiol / galactomann with an insoluble coating layer, the patch films are separated into individual pieces in accordance with the therapeutic requirements.

Table 1: Product formulation of an estradiol patch containing galactomann. 2

Folder. quantity / g / 1000 cm / recipe

<td></td><td>AND</td><td>В</td><td>C</td><td>D</td>

<td>17 O-estradiol micron.</td><td> ’ 0,42</td><td> 0.3</td><td> 0,27</td><td> 0,5</td>

<td>/ particle size &lt;9um /</td><td></td><td></td><td></td><td></td>

<td>galaktomana.</td><td> 1.5</td><td> 0,9</td><td> 0,9</td><td> 0,5</td>

<td>/ product Meyprogat 90 /</td><td></td><td></td><td></td><td></td>

<td>pólyisobutylene</td><td> 3,0</td><td> -</td><td> -</td><td> -</td>

/ product Oppanol 8 100 /

CS 270 207 02

<td></td><td>AND</td><td>В</td><td>C</td><td>D</td>

<td>hardened rosin / Product Abitol / solid hydrogenated resin</td><td> 3.0</td><td></td><td> 1,5</td><td></td>

<td>from hydrocarbons / product Piccotac СВН1 /</td><td> 3,0</td><td></td><td></td><td></td>

<td>Polystyrene-polyisoprene polystyrene tri-block copolymer / Product Cariflex TR 1107 / Aromatic solid resin</td><td></td><td> 1.7</td><td> 1,7</td><td> 1.7</td>

<td>of hydrocarbons / product Piccovar L 60 /</td><td> —</td><td> 2,2</td><td> 2,2</td><td> 2,2</td>

<td>Polyester terpene resin / Oercolyte 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>triglyceride / product Miglyol 812 /</td><td> 0,5</td><td> —</td><td> -</td><td> -</td>

<td>special petrol as solvent</td><td> 64</td><td> 19</td><td> 19</td><td> 19</td>

<td>basis weight</td><td> 11,9</td><td> 6,75</td><td> 6,72</td><td> 6,60</td>

<td>For comparison, they were made in</td><td colspan="2">according to recipes A to</td><td>C analogously</td><td>assembled by estra</td>

diol patches, but without the addition of galactomans. Table 2 shows the components and basis weights of these adhesive films without fillers. The deviation in the quantitative composition from the estradiol patches listed in Table 1 is partly technologically and partly pharmaceutically: filler-free adhesive films have been produced on a galenic scale in order to achieve the greatest possible release of the active ingredient.

<td colspan="4">Table 2: Composition of estradiol patches free of galactomates</td>

<td rowspan="2">Component</td><td rowspan="2">quantity / g AND'</td><td colspan="2">2 / 1.000 cm / recipe</td>

<td>B. '</td><td>C'</td>

<td>17 O-estradiol micron, / particle size &lt;9 µm /</td><td> 0,59</td><td> 0,51</td><td> 0,51</td>

<td>polyisobutylene / product Oppanol В 100 /</td><td> 1.95</td><td> -</td><td> -</td>

<td>hardened rosin</td><td> 2-,34</td><td> -</td><td> 1,19</td>

<td>/ Product Abitol /</td><td></td><td></td><td></td>

<td>Solid hydrogenated hydrocarbon resin / Product Piccotac СВНТ /</td><td> 2.34</td><td></td><td></td>

<td>tri-block polystyrene-polyisoprene polystyrene copolymer. / product Cariflex TR 1107 /</td><td></td><td> 1,32</td><td> 1,32</td>

<td>Solid aromatic hydrocarbon resin / product Piccovar L 60 /</td><td></td><td> 1,90</td><td> 1,98</td>

<td>Polyether terpene resin / Dercolyte S 10 / 1,2-propanediol</td><td></td><td> 1,19</td><td></td>

CS 270 207 82

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

<td>triglyceride</td><td> 0,39</td><td> -</td><td> -</td>

<td>/ product Miglyol 812 /</td><td></td><td></td><td></td>

<td>basis weight</td><td> 7,8</td><td> 5,1</td><td> 5,1</td>

In vitro release of active substance:

The determination is carried out in the same manner as described in Example 1 or 2 using 10 cm patches² and at a temperature of 34 ° C. The cumulative release rates from the patches A to 0 according to the invention and from the comparative patches A to C free of galactomates, but otherwise of the same composition, are opposed in Table 3.

As can be seen, the addition of galactomans as a water-swellable polymer in single-layered estradiol patches causes an increase in the cumulatively released amount of estradiol / = Е₂/.

Table 3: E₂ - release (µg / 10 cm), n = 2 times / h / recipe

<td></td><td>AND</td><td>AND'</td><td>В</td><td>в '</td><td>С</td><td>С '</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>

In vivo release: *

Two patients under investigation were given an A / 1 patch, 9 and 10 cm, made according to Example 3, recipe V hf 2 patches of 10 cm, made according to Example 3, recipe D on the lateral chest. After 72 hours, the patches were removed and removed. the remaining estradiol content was determined by chromatography. Thus, 2 evaluated amounts of released substance per 1 patch and 10 cm were:

a / 203 ug - 1 examined / recipeВ b / 208 ug - 1 examined / recipe0 с / 92.5 ug - 2 examined / recipeВ d / 110 ug - 2 examined / recipeD.

Bioavailability:

In the above experiments, blood samples were collected 48, 38, 24, 14 hours as well as immediately prior to application of the patch and radioimmunoassay plasma estradiol concentrations were determined. After plastering, blood samples were taken after 10, 24, 34; 48, 58 and 72 hours. In the formulation, it went to the following increases in plasma estradiol concentrations (data are based on a 10 cm patch):

a / 6.45 pg / ml -? 1 examined / recipe8 * b / 6.65 pg / ml - 1 examined / recipe0 с / 3.90 pg / ml - 2 examined / recipe * 8 d / 1.47 pg / ml - 2 examined / recipe0.

Accordingly, application of the estradiol patch resulted in an increase in E₂ - plasma concentration in men, with recipe 8 with E₂ - an amount reduced compared to formula 0, but with an increased concentration of galactomans yielded a comparable average increase in E₂ - blood concentration.

CS 270 207 B2

Example 4

The active substance patch of bupranolol according to the invention with microcrystalline cellulose (product Avicel pH 105) as a water-swellable polymer in the dispersion binding adhesive layer is prepared as follows:.

A mass consisting of rubber and an adhesive resin containing bupranolol, consisting of the ingredients listed in Table 4 / Recipe? A / - is applied in two successive steps to a protective layer on one side with steamed aluminum and a non-sticky on both sides so that after removal of the solvent a fertile adhesive film 2 is obtained.

14.7 mg / cm. .

After covering the bupranolol / cellulose-containing dispersion layer with an insoluble coating layer, the patch films are divided into individual pieces in accordance with therapeutic requirements.

Example 5 / Comparative example / *

The preparation is carried out as in Example 4, but without the use of microcrystalline cellulose as a water-swellable polymer. The fertile weight of the patch film is 13.5 mg / cm 2. The composition and amount of solvent contained in the bonding adhesive during coating are shown in Table 4..

Table 4: Composition of bupranolol patch with and without microcrystalline cellulose as a water-swellable polymer (Examples 4 and 5)

<td>Component</td><td>quantity / g /</td><td>1.000 cm² /</td>

<td></td><td>AND</td><td>В</td>

<td></td><td>with polymer</td><td>without polymer</td>

<td>bupranolol micron. '</td><td> 1.2</td><td> 1,2</td>

<td>/ particle size &lt;50 µm /</td><td> *</td><td></td>

<td>microcrystalline cellulose</td><td> 1.2</td><td> -</td>

<td>pólyisóbutylen</td><td> 3.71</td><td> 3.71</td>

<td>/ product Oppanol 8 100 /</td><td></td><td></td>

<td>solid aromatic resin</td><td> 6.69</td><td> 6,69</td>

<td>of hydrocarbons</td><td></td><td></td>

<td>/ product Piccovar L 60 /</td><td></td><td></td>

<td>1,2-propanediol</td><td> 0.5</td><td> 0.5</td>

<td>hard paraffin</td><td> 1.4</td><td> 1.4</td>

<td>Special petrol 80-110</td><td> 55</td><td> 55</td>

Release of active substance *

The determination is carried out as described in Example 1 for nitroglycerin. The cumulatively released amounts of bupranolol from the inventive patch of Example 4 and the cellulose-free patch of Example 5 are opposed in Table 5.

As can be seen, the addition of cellulose as a water-swellable polymer in monolayer bupranol patch films causes an increase in the cumulative release amount of the active ingredient.

_w 2

Table 5: Bupranolol release (mg / 25 cm), n = 2 time Example 4 Example 5

6,46 4,04

CS 270 207 B2 time

Example 6 Example 4

10,04

15,37

26.95 example 5

5,77

8,21

14,20

Estradiol rubber-based plasters with water-swellable polymers of different strength were produced as follows:

The binder containing estradiol, consisting of the components listed in Table 6 and the proportions of solvent (see recipes А, В, С), is applied to the protective layer, steamed with aluminum on one side and non-sticky on both sides, to obtain adhesive after evaporation of the solvent. film basis weight given in Table 6.

After covering the binding adhesive layer containing estradiol and the swellable material with a non-ointment covering layer, the patch films are divided into individual sections in accordance with therapeutic requirements.

Table 6: Composition of estradiol patches with different water swellable polymers

Ingredient quantity / g / 3.000 cm / recipe

G-estradiol micron, / particle size &lt;9 µm / galactomanna / product Meyprogat 90 / tragacanth microcrystalline cellulose · / product Avicel pH 105 / polybutyrene-polyisoprene polystyrene tri-block copolymer / product Cariflex TR 1107 / solid hydrogenated hydrocarbon resin / product Piccotac СВНТ / polyterter / Product Dercolyte S 10 /

1,2-propanediol special gasoline 80-100 basis weight mg / cm

<td>And.</td><td>В</td><td>C</td>

<td> 1,5</td><td> 1,5</td><td> 1,5</td>

<td> 1,5</td><td></td><td></td>

- 1,5

5,1 5,1 5,1

<td> 6,6·</td><td> 6,6</td><td> 6,6</td>

<td> 4,5</td><td> 4.5</td><td> 4,5</td>

<td> 0,6</td><td> 0,6</td><td> 0,6</td>

<td> 27</td><td> 27</td><td> 27</td>

<td> 6,6</td><td> . 6,6</td><td> 6,6</td>

Table 7 shows the time course of water absorption of polymeric products in a saturated atmosphere of water vapor in percent of weight at room temperature.

Table 7 galactomannan test substance / Meyprogat 90 / water uptake over h 96 h 168 h

69,72 97,86

112,14

CS 270 207 B2

<td>test substance</td><td>absorption</td><td>water during</td><td></td>

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

<td>t ragant;</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>

/ produkt Avicel pH 105 /

Release of the active substance

Giant. Fig. 2 shows the time course of estradiol release from the 6A to 6C patches. The assay was performed as described in Example 1 using 5 cm patch patches as well as at 34 ° C. shows clearly the dependence of the release of the active ingredient on the type of water-swellable polymer as filler.

Comparison with Table 7 shows that the release of the active ingredient increases along with the increasing water absorption capacity of the polymer product used. *

Example 7.

The propranolol patch with microcrystalline cellulose as a water-swellable polymer was produced as follows:

propranolol micron 1.2 g microcrystalline cellulose 1.2 g / product Avicel pH 105 / triple block copolymer polystyrene-3.71 g polyethylene butylene-polystyrene / product Kraton 0 1657). Solid aromatic resin · 5.0 g hydrocarbons *.

/ product Piccovar L 60 / * 'liquid hydrocarbon mixture .1,7 g / product Ondinaolej /

1,2-propanediol 0,34 g special petrol 00 - 10030 g is applied in two successive steps to a protective layer steamed with one side of aluminum and bilaterally formed non-sticky so that after removing the solvent a layer of about 13.1 mg / cm. After covering the binding adhesive layer with an impermeable covering layer, the patch film is divided into individual pieces in accordance with the therapeutic requirements. ,

Release of the active substance

The determination is carried out as in Example 1 at 34 ° C, the cumulative release amounts of propranolol from the inventive patch of Example 7 was 5.64; 11.31; 20.0;

and 26.79 mg / 25 cm at 2, 4, 8 and 24 hours respectively (mean of two determinations).

Example 8

A patch containing the active substance verapamil with galactomanno (product Meyprogat 90) as a water-swellable polymer in the layered dispersion region is prepared as follows:

Binding agent free of galactomans consisting of

1.08 g polyisobutylene / average molecular weight 900.000 to 1.400.000 / / Product Oppanol В 100 /

CS 270 207 B2

1.35 g aromatic hydrocarbon solid resin (Piccovar L 60)

0.9 &amp; g polyterpene resin / Dercolyte S 10 /

0.24 g polyethylene glycol (average molecular weight 300 / '/ Lutrol 300 product)

0.3 g of a 1: 1 mixture of Verapamil and silica / Aerosil 200 / g of special naphtha 80-110 as solvent is applied to a protective layer with one side steamed with aluminum and a two-sided non-sticky so that an adhesive film is obtained after evaporation of the solvent about 1.3 mg / cm. A dispersion layer containing a galactomann having a basis weight of about 16.6 mg / cm 2 is deposited onto the binder adhesive film thus produced. The production of this layer is carried out analogously from

10.8 g polyisobutylene (average molecular weight 900.000 to 1.400.000) / / product Oppanol 8 100 /

13.5 g of solid aromatic hydrocarbon resin / Piccovar L 60 /

9.6 g of polyterpene resin (Dercolyte S 10)

2.4 g of polyethylene glycol. .

(average molecular weight 300: Lutrol 300 product) /

1.5 g galactomans * / product Meyprogat 90 /

12.0 of a 1: 1 mixture of Verapamil and silica (product Aerosil 200)

100.0 g of special petrol 80-110, where the application is carried out on an impermeable cover layer. The obtained patch film is divided into individual pieces in accordance with the therapeutic requirements.

Example 9 (comparative example)

The preparation was carried out as in Example 8, but without the galactomans as a water-swellable polymer.

In vivo release of the active substance:

The subject was on the lower arm / inner side / 5 cm² After 24 hours, the plaster was removed and the content of Verapamil remaining therein was determined by chromatography. ·

The released amounts of Verapamil were * a (for Example 8) with galactomann /: 0.31 mg / cm b (for Example 9) without galactomans /: 0.15 mg / cm

This result shows that using a swelling polymer with an otherwise identical patch formulation could double the amount of Verapamil released in vivo.

CS 270 207 B2

1 Example 10

Patch containing as active substance Pupranolol with microcrystalline cellulose (Avicel pH 105) as a water-swellable polymer, in a binding adhesive dispersion layer,

<td colspan="2">sc produces as follows:</td>

<td>nupranolol</td><td>6,0 g</td>

<td>microcrystalline cellulose / produkt Avicel pH 105 /</td><td>6,0 g</td>

<td>polyisobutylene / product Oppanol 8 100 /</td><td>18,55 g</td>

<td>Solid aromatic hydrocarbon resin / product Piccovar L 60 /</td><td>33.45 g</td>

<td>liquid hydrocarbon mixture / product Ondinolej G 33 /</td><td>11,1 g</td>

<td>1,2-propanediol</td><td>1.7 g</td>

<td>special petrol 80 - 110</td><td>191.15 g</td>

The coating is applied on a protective layer unilaterally vaporized with aluminum and formed on both sides with a non-sticky coating so that, after removal of the solvent, an adhesive film having a basis weight of about 15.4 mg / cm is obtained. After covering with an impermeable covering layer, the patch films are divided into individual pieces in accordance with the therapeutic requirements.

In vitro release of active substance:

O

The determination was carried out as described in Example 1 on 16 cm large patch films in phosphate buffer solution (pH = 5.5) as the release medium and at 34 ° C. 12; 4.30; 5.89; or 10.44 mg, respectively.

In vivo release of the active substance:

For example, a 25 cm @ 2 patch according to Example 10 was adhered to the side of the chest for a period of 3 days for 24 hours each. The patch was removed after 24 hours and the remaining bupranolol content was determined by chromatography. The average values ​​of individually released amounts of active ingredient were 13.49; 11.25; 13.70; 10.44; 14.76, optionally 12.81 mg / 25 cm²/24 hours.

Interindividually, 12.74 - 1.64 mg (n = 3x6) of bupranolol was released per patch in the formulation. ₄

In this experiment, good in vivo reproducibility of release was shown and relatively good agreement with an in vitro result of 16.31 mg / 25 cm / 24 hours.

M = 10.44 mg / 25 cm²/ 24 hours, Sat /

Bioavailability.

In the investigated trial described above, blood samples were collected after 6, 12, 24, 36, 48, 60 and 72 hours application times and the concentration of bupranolol was determined by radioimmunoassay in plasma. The results are shown in Figure 3.

Consistent with the continuous release of the drug, a constant plasma level was formed over a period of 3 days / application.