SI8512016A8 - Process for production of plaster with active substance - Google Patents

Description

PROCEDURE FOR PRODUCING FLASTERS WITH ACTIVE MATERIAL

1. TECHNICAL FIELD

The present invention falls within the field of patch production for medical purposes. According to the International Patent Classification, it belongs to Group A 61 1 15/00.

2. TECHNICAL PROBLEM

A technical problem solved by the present invention is a method of manufacturing a medical patch for the controlled release of the active substance to the skin, consisting of a single coating layer, with a water-insoluble adhesive film coupled to it, consisting of a mass of rubber / adhesive resin in which they are soluble , that is, partially soluble active substances and a removable adhesive film that covers the film.

3. BACKGROUND OF THE INVENTION

According to the methods known to date for the production of active substance patches, in particular in the areas of beta-blockages, steroid hormones, calcium antagonists and cardiac drugs, substances that are soluble in water are dispersed in a water-insoluble matrix. The fiaster produced in this way results in a slow release of the active substances. The cumulative amounts of active substances per unit time, ai

2.

as a rule, both in homogeneous and in heterogeneous matrix systems, proportional to the square root of time, wherein, among other things, the release profile is also dependent on the geometry of the shape at hand. Thus, when switching from a ball system to a film shape or a surface system, the increase in the curve showing the release of the active substance per unit time, that is, the active substances are always released at a constant rate over a long period of time.

The so-called active-substance patches, in which the active substances are arranged in thin hydrophobic films, are conceptually simple, batch-based pharmaceutical products that are principally suitable for transdermal administration of the active substances.

In practice, however, according to the prior art, patches of this type with the active substance produced so far are not usable for the controlled transdermal delivery of the active substances over long periods of time. Thus, the thermodynamic activity of the active substances in the base of the patch and on the skin, together with the previously known proposed adjustments, is not sufficient to achieve the required rate of release of the active substances, and in particular the desired length of release of the active substance, at a still acceptable size of the patch.

If a larger amount of active substance is incorporated into such a patch than that corresponding to the sorption power of the film-forming patch components, then the active substance must be as small as possible to be amorphously distributed into the adhesive matrix, to allow rapid additional dissolution for as long as possible_ . maintained the length.applications of the saturation state of the adhesive adhesive and 3 thus kept the degree of decrease in the rate of release of the active substance from the patch as small as possible.

One possibility in respect of respectable methods for obtaining a film patch is that the coating process consists of sprays, that the film-forming material and the active substance are dissolved together in an organic solvent, that the solution is concentrated to a viscosity suitable for coating, and then solution of adhesive containing

3 ...

Coat the active substance on large strips and dry.

This process, however, causes readily volatile, liquid or crystalline active substances a stability problem for rubber-patch films of conventional adhesive formulations, conditioned by subsequent crystallization and evaporation processes, which lead to uncontrolled and non-reproducible release of the active substance and deterioration of adhesive properties.

Galenic development of an active substance patch of this kind is particularly difficult in practice, since it is necessary to optimize the patch formulations both in terms of adhesive properties and in terms of their permeability to the incorporated active substance, ie. of active substance.

4. DESCRIPTION OF THE SYSTEM

A process for the production of an active substance patch consisting of a single coating layer with a water-insoluble adhesive film of rubber / adhesive resin in which soluble or partially soluble active substances and one protective layer covering the adhesive film are coupled, and which is removable according to the invention consists in the fact that the components of the mass of the rubber / adhesive resin are dissolved in an organic solvent and are dispersed in this solution. the active substance together with the water-swellable polymer which is insoluble in the mass of the rubber / adhesive resin and in a solution of this mass ₍ in an amount of 3 to 3θ% by weight relative to the mass of the rubber / adhesive resin, this dispersion is :, in in this case, after evaporation of one part of the solvent, it is applied to the adhesively treated protective layer.

This process of the invention produces ^ active substance patches, in particular in the areas of beta-blockade, steroid hormones, calcium antagonists, and for heart active agents such as bupranolol, propranolol, estradiol, nitroglycerin.

4.

or isosorbitinitrate.

The process according to the invention provides a patch with the active substance comprising an impermeable cover layer, with a water-insoluble adhesive film of a rubber / adhesive resin bonded on the basis of natural or synthetic rubbers such as e.g. polyisobutylene, styrene-butadiene polymers, styrene-isoprene polymers, styrene-ethylene / butylene polymers and cis1,4-polyisoprene as well as a single resin fraction, e.g. of rosin and its derivatives, poly-terpene resins from β-pinene, hydrocarbon resins, in which the active substances are soluble and are partly in permafrost and partly in soluble form, a protective layer covering the adhesive film.

It is surprising, according to the invention, to incorporate water-swellable polymers such as. of the fillers, which are insoluble in the mass of the rubber / adhesive resin, achieves an increase in the rate of release per unit time, and in particular of the amount released by a total of about 100 percent or more. In contrast, it is known from the literature (cf. YW, Chien in JR Robinson's Substained and Controlled Release Drug Delivery Systems ”, s, Chapter 4, pp. 255-256, Marcel Dekker-Verlag 1978) that plaster technology has been used fillers such as e.g. silicon dioxide and einkoxide in the polymer matrix system .. based on silicone or peirodic rubber, lead to a decrease in the diffusion coefficients of solids and gases. In addition, the production by the addition of water-swellable polymers results in the stable binding of excess active substances contained in the adhesive mass and / or the increase of the viscosity of the adhesive solution in the finished patch with the active substance according to the invention, thereby improving the coherence and adhesion properties of the adhesive film.

Examples of active substance patches obtained by the process of the invention gd $ Xi rubber / adhesive resin mass added water-swollen polymers are products such as galactomannans, cellulose products, tracracanth, polyglycosides, polyvinylpyrrolidones, finely powdered polyamides, water-soluble aminocaridamide

5.

vinyl polymers, agar-like algae products, mixed methylvinyl ether and maleic anhydride polymers, guar gum, types such as hydroxypropylguar gum or guar flour, gum arabic, dextrin and .dextran, microbiologically obtained polysaccharide gum such as B59 dissociate the type of keltrol or synthetically derived polysaccharide such as the Ficoll product, methylglucose derivatives, hydroxymethylpropylcellulose, polygalacturonic acid derivatives such as pectin or the amedated product pectinamide.

Galactomannans, microcrystalline celluloses and tragacanth, galactomannans and tragacanth for steroid hormone estradiol, microcrystalline celluloses for bupranolol and nitroglycerin, are particularly suitable in the case.

According to one particular embodiment of the present invention, the adhesive film is divided from a rubber / adhesive resin mass into a single-layer film containing the active substances and a reservoir containing water-swellable polymers 'from ^:' rubber / adhesive resin, and with a protective layer in this case, there is an adhesive layer containing the active substance consisting of a mass of rubber / adhesive resin, there is a separating layer between the reservoir layer and the adhesive layer, which is x active material dissolved for the mass of rubber / adhesive resin. completely permeable and, for water-swellable polymer, impermeable iv or only partially permeable. The split-release embodiment is advantageous when the adhesive film is distributed in the voar layer and in the adhesive layer.

As the following Examples 1 to 10 show, affecting, the water-swellable polymers of the invention are added to adhesive films based on the mass of rubber / adhesive resin significantly on the release properties of lipophilic active substances. A therapeutically advantageous release profile can be achieved by choosing to find added products from the group of water-swellable polymers, their concentration and a combination of these different products within the scope of the invention, without changing the pads to a new patch substrate.

6.

In the case of nitroglycerin and isosorbitdinitrate, since in simple adhesive tapes, in which the active substance is in. dissolved form, according to the literature, the danger of too fast, uncontrolled release of the active substance, as well as problems of stability, dosage and handling (compare, e.g., DE-OS 3 200 369). The therapeutically required amount can then be achieved only by applying a large surface patch, or when the adhesive medium does not bind the active substance sufficiently, so that the active substance is released in too short a time for long-term treatment.

Conventional manufacturing processes, in which the components of the patch are dissolved or dispersed in an organic solvent to the technically required application viscosity, can thus result in unstable, cross-sectional systems in which more of the active substance is dissolved than is equivalent to the sorption power of the components that educate the film.

In this case, especially in the case of highly volatile substances, significant decreases in the content or in the drying process occur. the excess amount of active substance crystallizes from the adhesive film during storage. These problems are overcome by the invention according to the method by which such insoluble products are added to the patches with active substance, which, when evaporated, can bind the active substance. above the saturation solubility of fiKn-forming components. By coating the adhesive solution onto a fabric that is impermeable or only partially permeable to water-swellable polymers and / or polymers. adsorbates of the active substances on these products, it is easy to concentrate and separate the active components and / or products which swell in water in a rubber / self-adhesive mass, if necessary for reasons of adhesive technique and / or biopharmaceutical reasons.

7.

By using fabric impermeable to adhesive, it saves e.g. the application of an additional adhesive layer, which, depending on the concentration of the water-swellable product, is required for the application of an impermeable cover layer or for satisfactory adhesion to the skin.

It is surprising to be able to regulate the release of the active materials according to the invention from a rubber patch by the use of water-swellable polymers, as exemplified in Examples 1 and 2, for example, e.g. increase the release rate without altering the concentration of the active substance in the patch;

Example 1

The kitroglycerin-rubber patch according to the invention with microcrystalline cellulose in one layered dispersion zone is obtained in the following way:

Adhesive adhesive masses of cellulose-free nitroglycerin consisting of 1,011 polyisobutylene (average molecular weight of 900,000 to 1,400,000; product of Oppanol B 100),

0.916 g of solid aliphatic hydrocarbon resin (product

Piccotao CBHT),

0.916 g of hydrated rosin resin (Abitol product)

0.094 g of triglyceride (Miglyol 812 product) as a solvent of g n-hexane as a solvent is applied to a protective layer which is filled with aluminum on one side and abrasively treated on both sides, leaving a sticky film of ca.

4.6 mg / cm. The adhesive film thus obtained is coated with a dispersion layer containing nitroglycerin / cellulose

8.

with a surface mass of about 19.2 mg / cm '.

This layer is obtained in an analogous manner from

2.2671 g of polyisobutylene (average molecular weight from 900,000 to I4OO.00; product Oppanol B 100),

2,0409 g of solid aliphatic hydrocarbon resin (product Piccotac CBHI),

2,0409 g of hydrated rosin resin (Abitol product), 0,2071 g of triglyceride (Myglyol 812 product) as solvent

5,700 g 5% (G / G) nitroglieerin cellulose dispersion (manufac.

5% nitroglycerin / Avicel pH 105 - dispersion), g of n-hexane.

After coating the dispersion layer with an impermeable coating layer, the resulting patch film is divided into individual containers according to therapeutic requirements.

Example 2 (Comparative Example)

The preparation was carried out as in Example 1, however, with 5% nitroglycerin lactose dispersion instead of nitroglieerin cellulose dispersion.

Release of active substances p

cm large patch films made according to Examples 1 and 2 are immersed in an isotonic sodium chloride solution at 37 ° C and the nitroglycerin release determined after 2, 4,

6, 8 and 24 hours by liquid chromatography. The volume of the release medium is chosen to maintain the immersion conditions during the experiment. "

The results are shown in FIG. 1.

Example 3

An estradiol active substance patch with galactomannan (product Meyprogat 90) as a water-swellable polymer in the adhesive adhesive dispersion layer is obtained as follows:

The adhesive adhesive, which contains oestradiol, consisting of the components and races given in Table 1? of the solvent (see formulations A, B, C, D) is applied to a protective layer which is filled with aluminum on one side and treated with adhesive on both sides to obtain a sticky film after evaporation of the solvent. in Table 1 by the given surface mass.

After coating the estradiol / galactomannan-obtained adhesive-adhesive layer with an impermeable coating layer, the patch films are divided into individual pieces as appropriate. requirements.

Table 1: Production formula of estradiol patch containing galactomannan

Components 17 f * estradiol micron. (particle size <9 pm A 0.42 Quantity (g / 1,000 cm ^) B. 0.3 recipes C 0.27 D 0.5 Galactomannan (product of Meyprogat 90) 1.5 0.9 0.9 0.5 Polyisobutylene {product Oppanol B 100}. 3.0 - - - Hydrated rosin & um (Abitol product) 3.0 - 1.5 - Solid Hydrated Hydrocarbon Resin (Piccotac CBHT Product) 3.0 - - - Tr «block: polystyrene-polyisoprene-polystyiol copolymer (product Cariflex TR 1107) 1.7 1.7 1.7

10.

Solid aromatic hydrocarbon A B C D resin (product Piccovar L 60) - 2.2 2.2 2.2 Polyterpene resin (product Dercolyte S 10) - 1.5 - 1.5 1,2 propanediol. 0.5 0.15 0.15 0.2 Triglyceride (Miglyol 812 product) 0.5 - - - Special gasoline 80 - 100 as solvent 64 19 19 ¹⁹ 2 Surface mass mg / cm 11.9 6.75 6.72 6,60

For comparison, an estradiol patch was produced according to recipes A through G, but without the addition of galactomannan. Table 2 gives the proportions of the components and the surface between these non-filler adhesive films. The deviations in the quantitative composition according to the Table 1 presented estradiol patches are due partly to technological and partly to pharmaceutical reasons; non-filler adhesive films have been developed in galenic volume, in order to obtain as much release of the active substance as possible in the evening.

Table 2 Gastric estradiol: galactomannan-free patches

Component

Est-Estradiol micron. (Particle size Z 9 _; um)

Polyisobutylene (product Oppanol B 100)

Hydrated rosin (product Abitol)

Solid Hydrogenated Hydrocarbon Resin (Piccotac CBHT Product)

Amount (g / 1,000 cnF Recipe

A 'B' C '

0.39 0.51 0.51

1.95

2.34 - 1.19

2,34

Triblock polystyrene-polyisoprene-polystyrene copolymer (product Carifler TR 1107)

Solid aromatic hydrocarbon resin (product Piccovar L 60)

A '

B 'C'

1.32 1.32

1.98 1.98

Polyterpene resin (product Dercolyte S 10 - 1,19

1,2-Propanediol

Triglyceride (Miglyol 812 product.

Surface mass mg / cm

0.39 0.10 0.10

0.39 .7.8 5.1 5.1

In vitro release of active substances:

Determination is performed as in ^ opiaanoDU example 1 2 or. 2 using 10 cm large patch pieces and at 34 ° G. The cumulative release rates of the patches according to the invention A to D and those without galactomannan, and otherwise qualitatively the same composition of the comparative patches A'do C 'are given in parallel in Table 3.

As can be seen, the addition of galactomannan as a water-swellable polymer to · single-layer estradiol-patch films has the effect of increasing the cumulative estradiol (= £ 2) - release rate.

Table β: E2 "oslob ^a čljanj ^e (jig / 10 cm ² ), n 5 = 2 Weather (h) Recipes A A ' B B ' C C ' 2 47,4 17.5 42,7 35,3 70.1 36,6 4 79.1 33,7 6 108,2 ./. 8 ./. 55,4 24 252,1 123,4 323,3 182,1 395,4 229,9

12.

Release of active substances in vivo:

Two test strips were applied on the side of the chest

a) 1 Plaster a '10 cm produced according to Example 3, recipe B o

b) 2 Plaster a '10 cm produced according to Example 3, recipe D.

After 72 hours, the patches were removed and the residual estradiol content was determined chromatographically each time. The release rates thus estimated, relating to 1 patch a '10 cm from Mass, were:

a) 203 ^ ug - test lane 1 / recipe B

b) 208 jig - test lane 1 / recipe D

c) 92.5 / ig - test strip 3 / recipe B

d) 110 ^ ug - trial lane 2 / recipe D.

Bio-suitability

In the above tests, they were taken at 48, 38, 24, 14 hours as well as immediately before the application of the blood sample patch and the plasma estradiol concentration was determined radioimmunologically. After sticking the patch, blood samples are taken after 10,

24, 34, 48, 58 and 72 hours. In the middle, the following increases in plasma estradiol concentrations were obtained (data calculated on one patch of 10 cm):

a) 6.45 pg / ml - test strip 1 / recipe B

b) 6.65 pg / ml - test strip 1 / recipe D

c) 3.90 pg / ml - test strip 2 / recipe B

d) 1.47 pg / ml - trial .tracateSr / recipe D.

According to torn, administration of the estradiol (E ^) - patch led to a single increase in human plasma E ₂ concentration, while formulation B according to recipe D of example 3 gave a decrease in E ₂ - amount but increased galactomannan concentration in the test subject and was relatively higher. mean increase in E ₂ - blood concentrations.

13.

Example 4

The active ingredient bupranolol patch according to the invention with microcrystalline cellulose (Avicel pH lo5 product) as a water-swellable polymer in a sticky dispersion layer is obtained as follows:

The mass of rubber / adhesive resin containing bupranolol, 'consisting of the components in Table 4 (recipe A), is thus applied in two slurries one after the other to a protective layer which is filled with aluminum on one side and on both sides adhesively treated to produce, after removal of the solvent, a fusible film having a surface mass of 14.7 mg / cm.

After covering the bupranolol / cellulose-containing dispersion layer with an impermeable coating layer, the patch films are cut according to therapeutic requirements into individual pieces.

Example 5 (Comparative Example)

The preparation was carried out as in Example 4, however, without the use of microcrystalline cellulose as a water-swellable polymer. The surface mass, is 13.5 mg / cm. The composition and solvent volumes of the adhesive adhesive when coated are given in Table 4.

Table 4 · Composition of bupranolol patches with and without microcrystalline cellulose as a water-swellable polymer (Example 4 and 5) p

Component Quantity g / 1,000 cm)

Recepture

A B

Bupranolol-micron. (particle size 50 / uit) with polymer 1,2 polymer-free 1,2 Microcrystalline cellulose 1,2 - Polyisobutylene (product Oppanol B 100 3.71 3.71 v Solid aromatic hydrocarbon resin (product Piccovar L 60) · 6.69 6.69

14.

'. a 'B

1,2-Propandiol 0.5 0.5 Hard paraffin 1.4 1.4 Special gasoline 80-110 55 55

Release of the active substance

The determination was performed as exemplified in Example 1 for nitroglycerin patches. The cumulative release rates of the invention of the bupranolol patch according to example 4 and the cellulose-free patch according to example 5 are shown in parallel in Table 5

As can be seen, the addition of cellulose as a water-swellable polymer to · bupranolol flutter films built in a single layer acts to increase the cumulative release rates of the active substance.

Table 5 Bupranolone release (mg / 25 cm), n = 2

Weather Example 4 Example 5 2 6.46. 4.04 4 10.04 5.77 8 15,37 8.21 24 26,95 14,20.

Example 6

Rubber-based estradiol patch with polymers that are very water-swellable is obtained as follows:

The adhesive adhesive containing estradiol consisting of the components listed in Table 6 and the solvent content (see formulations A, B, C) is thus applied to the protective layer, which is on one side filled with aluminum and adhesively treated on both sides, afterwards solvent evaporation is obtained by a sticky film having a surface mass given in Table 6.

After covering the adhesive adhesive layer containing estradiolAmaterigu.who swells with a single impermeable cover layer, the patch filters are cut according to therapeutic requirements into individual pieces.

15.

Table 6: Water-swollen estradiol composition

Patch component with different polymers p> -Estradiol micron, (particle size zf 9 μm

Galactomannan (Mayprogat 90 product)

Tragrantic crystalline cellulose (product Avicel pH 105

Triblock polystyrene-polyisoprenepolystyrene copolymer (product Cariflez TR 1107)

Solid Hydrated Hydrocarbon Resin (Piccotac CBHT Product) ^r Oliterpene Resin (Dercolyte S 10 Product)

1,2-Propanediol

Special gasoline 80 - 100 p

Surface mass mg / cm amount (g / 3,000 cm ^) Recipe

A B C 1.5 1.5 1.5 1.5 - - a 1.5 - - - 1.5 5.1 5.1 5.1 6.6 6.6 6.6 4.5 4.5 4.5 0.6 0.6 0.6 27 27 27

6.6 6.6 6.6

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

16.

Table 7:

The substance that is> tested Water absorption inside 48 ^h 96 ^h I68 ^h Galactomannan (product of Meyprogat 90) 69.72 97.86 112.14 Tragant 68.08 84.51 96.7 Microcrystalline cellulose Avicel product pH 105) 14.7 16.7 21.5

Release of active substance t

FIG. 2 shows the time course of the estradiol patch 6A to 6 C. The determination is performed as described in Example 1 2 using 5 cm large patch films as at 34 ° C. The picture clearly shows the dependence of the release of the active substance on the type of water-swellable plomers added as fillers.

ⁱⁿ comparison with Table 7 it shows that with the increase in the water absorption capacity of the added polymer products, the release of the active substance increases.

Example 7

The propranolol patch with microcrystalline cellulose as a polymer / product is obtained as follows:

Adhesive adhesive containing propranolol consisting of

Propranolol micron 1.2 g microcrystalline cellulose (product Avicel pH 105) 1.2 g

Triblock polystyrene-polyethylenebutylene) -polystyrene copolymer (product Kraton G 1657 3.71 g

Solid aromatic hydrocarbon resins (product Piccovar L 60) 5,0 g

17.

1.7 g

O, 34g ³⁰ _g at

Liquid hydrocarbon mixtures (Ondinaol G 33 product)

1,2-Propandiol of Special Gasoline 80 - 100 is thus applied in. two degrees one for the second layer, which is unpaired with aluminum, and with both strands is a ^ hectically processed. that after removal of the solvent a layer of about 13.1 mg / cm ^ is obtained. after covering the adhesive adhesive layer with an impermeable coating layer, the s-e patch film is cut according to therapeutic requirements into individual pieces

Release of the active substance

The determination was made as described in Example 1 at 34 ° C, the cumulative release rates of the invention for the propranol patch of Example 7 were 5.64; 11.31; 20.0 and p

26.79 mg / 25 cm after 2, 4, 8 resp. 24 hours (mean from two determinations).

Example 8

A patch containing as active ingredient Verapamil with galactomannan (product Meyprogat 90) as a water-swellable polymer in a layer-like diffusion zone is obtained as follows:

A non-galactomannan-free adhesive mass consisting of

1.08 g of glyoisobutylene (average molecular weight from 900,000 to 1,400,000) (product Oppanol B 100)

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

0.96 g of polyterpene resin (product Dercolyte S 10)

18.

0.24 g of Polyethylene glycol (average molecular weight of 300) (product Lutrol 300)

0.3 g Veraprami1 / silica 1: 1 mixture (Aerosil 200 product) g Special gasoline 80 -110 as solvent is applied to a protective layer which is filled with aluminum on one side and treated with adhesive on both sides to produce a solvent after evaporation of the solvent. adhesive film of about 1.3 mg / cm. The adhesive film obtained in this way lays a dispersion layer with a surface mass of 16.6 mg / cn? containing galactomannan. Obtaining this layer is done analogously from

10.8 rg of polyisobutylene (average molecular weight 900,000 to 1; · 400> 000) (product Oppanol B 100)

13.5 g of solid aromatic hydrocarbon resin (product Piccobar L 60)

9.6 g of polyterpene resin (product Dercolyte S 10)

2.4 g of polyethylene glycol (medium semiconductor mass of 300) (product Lutrol 300)

1.5 g galactomannan (product Meyprogat 90)

12,0 ..g Verapamil - - / silica 1: 1 (Aerosil 200 product)

L00,0 g of special gasoline 80 -110 where applied to an impermeable covering layer. The resulting fJ-M patch is cut according to therapeutic requirements into individual pieces.

Example 9 (Comparative Example)

The preparation is carried out according to Example 8, however, without galactomannan as a water-swellable polymer.

19.

Release of the active substance in vivo

The test strip is glued to the forearm (inner strap 5 cm in size according to example 8 or 9 of the patch produced.) After 24 hours, the patch is removed and the residual verapamil content is determined chromatographically each time.

The quantities of Verapamil released were 2

a) for Example 8 (with galactomannans): 0.31 mg / cm

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

This result shows that the addition of a swelling polymer with an otherwise identical patch formulation results in a doubling of the release rate of Verapamil.

Example 10

A patch containing Jupranolol as the active ingredient with microcrystalline cellulose (Avicel product pJ 105) as a swellable polymer and an adhesive adhesive dispersion layer is obtained as follows:

Mass of rubber / adhesive resin containing bupranolol a

consisting of; bupranolol 6,0 g microcrystalline cellulose (Avicel pH 105 product) 6,0 g polyisobutylene (product Oppanol B 100) 18,55 g Solid aromatic hydrocarbon carbon resins (product Piccovar L 60) 33,45 g Liquid hydrocarbon mixtures (product ondinaol G 33) 11,1 g 1,2-Propanediol 1.7 g Specialty Gasoline 80 - 110 191,15 g is thus applied to the protective layer which is from one with aluminum and adhesively treated on both sides

to be

20.

after removal of the solvent, a sticky film having a surface mass of about 15.4 mg / cm is obtained. After covering with one impermeable cover layer, the patch films are cut according to the therapeutic requirements into individual pieces.

Release of active substance in vitro

Determination is performed as described in Example 1 by 16 cm plaster films in: phosphate buffer solution (pH =

5.5) as the release medium and at 34 ° 0. The cumulative, released amounts of the active substance were 2, .4, and 3.12 after 24 hours ;; 4.30; 5,89 Rel. 10.44 mg.

Release of the active substance in vivo

Six bird straps are glued to the chest on the side o

for a period of 3 days, all 24 hours of size 25 οφ of the patch obtained according to Example 10. Each time after 24 hours, the patch was removed and the remaining bupranolol content was chromatographed. The mean values of individually-released amounts of the active substance were 13.49; 11.25; 13.70; 10.44; 14,76 Rel. 12.81 mg / 25 ^cm2 / 24 hours.

Inter individually released 12.74- 1.84 mg (n = 3 x 6) of bupranolol per patch in the agent.

In this experiment, there was good reproducibility 'in vivb release and a relatively good match with p

to corresponding in vitro results obtained from the 16.31 mg / 25 cm / 24 hours (= 10.44 mg / 25 ^cm2 / 24 hours).

Bioavailability:

In the experiments described above, after administration times of 6, 12, 24, 36, 48, 60 and 72 hours, blood samples were taken and Bupranolol plasma concentration was radioimmunoassay determined. The results are shown in Figure 3 ·

In accordance with the continuous release of the active substance, a constant plasma level is constructed over a 3-day application period.

Dos. 74376 - .P-2016/85 ... 03/12/1988

----- BEST SUBSCRIPTION SUBSCRIBER KNOWLEDGE MODE FOR INDUSTRIAL

USING THE APPLICANT FINDING

The kitroglycerin-rubber patch according to the invention with microcrystalline cellulose in one layered dispersion zone is obtained in the following way:

Adhesive cellulose-free adhesive mass of nitroglycerin consisting of, g _z

1,018 ^x 'polyisobutylene (average molecular weight from 900,000 to 1,400,000; product Oppanol B 100),

0.916 g of solid aliphatic hydrocarbon resin (product

Piccotac CBHT),

0.916 g of hydrated rosin resin (Abitol product)

0.094 g of triglyceride (Miglyol 812 product) as solvent of g n-hexane as solvent is applied to a protective layer which is filled with aluminum on one side and is adhesively treated on both sides, leaving a sticky film of ca.

4.6 mg / cm. For the adhesive film thus obtained, a dispersion layer containing nitroglycerin / cellulose is coated with a surface mass of about 19.2 mg / cm.

Obtaining this layer is done analogously from

2.2671 g of polyisobutylene (average molecular weight from 900,000 to 1,400.00; product Oppanol B 100),

2,0409 g of solid aliphatic hydrocarbon resin (Piccotac CBHI product), '2Ζ2,0409 g of hydrated rosin resin (Abitol product),

0.2071 g of triglyceride (product L'yglyol 812) as a creator

5.7OC g 5% (G / G) nitroglycerin cellulose dispersion (product 5% nitroglycerin / Avicel pH 105 - dispersion), g n-hexane.

After coating the dispersion layer with an impermeable coating layer, the resulting patch film is divided into individual layers. use according to therapeutic requirements.

Claims (7)

PATENT REQUIREMENTS 1. A method of producing a patch with active substance for the controlled release of the active substance through the skin, wherein the patch consists of three layers, an impermeable cover layer, a water-insoluble adhesive film with the active substance and a removable protective layer, which is a water insoluble adhesive film in which the active substances are soluble and partly in the insoluble and partly in the dissolved form, and which consists of rubber / adhesive resin based on natural or synthetic rubbers such as polyisobutylene, styrene-butadiene polymers, styrene-isoprene polymers, styreneethylene / butylene polymers and cis-1,4-polyisoprene, as well as a fraction of a resin such as rosin and its derivatives, poly-pyrene resins from ^ -pinene, hydrocarbon resins, are obtained by dissolving these components in organic solvents such as triglycerides, hydrocarbons, diols, and then the active substances such as beta-blockers, steroid hormones, calcium antaionists, and cardiac-acting substances such as bupranolol, propranolol, estradiol, and nitroglycerin, together with water-swellable polymeric soluble resins such as galactomannan, cellulose, polyethylene, polyethylene products .- tragacanth, synthetically obtained polysaccharides, in an amount of from 3 to 30% by weight. % by weight of rubber / adhesive resin and this dispersion is applied after evaporation of one part of the solvent to a protective layer which is filled with aluminum on one side and treated with adhesive, the solvent is evaporated and a impermeable coating layer is applied to the obtained adhesive film. 2. The method of claim 1, wherein the polymer is water-swellable and insoluble in the adhesive film is a single polysaccharide or a mixture of multiple polysaccharides. 3. The process of claim 1, wherein the polymer is water-swellable and insoluble in adhesive film, aalactomannan, microcrystalline cellulose or tragacanth. A process according to any one of claims 1 to 3, wherein the active substance is estradiol, and the water-swellable polymer which is insoluble in the adhesive film is ualactomannan. 5. The process according to claim 1, wherein the active substance is bupranolol and the water-swellable polymer, which is insoluble in adhesive film, is microcrystalline cellulose. The process according to any one of claims 1 to 3, wherein the active substance is nitroglycerin, and the water-swellable polymer, which is insoluble in adhesive film, is microcrystalline cellulose. The process according to any one of claims 1 to 3, wherein the active substance is propranolol and the water-swellable polymer is insoluble in the adhesive film microcrystalline cellulose.