DD278492A1 - METHOD FOR PRODUCING AN ANTITHROMBOTIC ACTIVE PAVER - Google Patents

Abstract

The invention relates to a method for producing an antithrombotic active substance patch having sufficient penetrability and good, over a long time persistent drug dosing. The active ingredient patch according to the invention contains heparin and / or heparinoids as the active ingredient component. The active ingredient patches prepared according to the invention exhibit markedly prolonged thrombin times in bovine fibrinogen and corresponding therapeutic effects in thrombophlebitis and thromboses in corresponding in vitro experiments. The said antithrombotic active ingredient is in a filled rubber pressure-sensitive adhesive premix containing from 15% to 25% of plasticizers, which consists of at least 70% lanolin, in pure form or in the form of an adduct with zeolites and / or phyllosilicates introduced the pressure-sensitive adhesive mixture. The zeolites and / or sheet silicates have an active ingredient loading of 0.5% to 50%. The active substance-containing composition is prepared at temperatures of 20C and subsequently applied to a carrier material with a mass coverage of 150 gm 2 to 400 gm 2 in the direct or transfer coating process and dried at temperatures of 20C to 110C.

Description

Field of application of the invention

The invention relates to a method for producing an antithrombotic active substance patch for use in human medicine.

Characteristic of the known technical solutions

Pharmaceutical preparations for the percutaneous treatment of thromboses and embolisms are known, these are essentially preparations in the form of ointments.

A limiting factor for the use of preparations for percutaneous therapy is the low, due to molecular processes and low lipid solubility penetrability of heparin. In addition, as a disadvantage of any percutaneous application in the form of ointments or sprays the difficult Dcsierbarkeit.

Also known are applications of transdermal therapeutic systems in drugs with molecular sizes up to 10OOgmol ¹ in a variety of systems with different release controls and drugs.

Thus, e.g. Dosiermembranen in the specifications DE-OS 2135533, US-PS 3598122 and JS-PS 3797494 used. There are also supersaturated drug-solvent complexes known from DD-WP 217989 or were proposed in the DD-WP application 273884.4 for use.

Disadvantages of these technical solutions consist in the high cost of controlling the drug release especially in the dosing membranes as well as in problems of production-moderate production of multi-layer combinations.

Another solution is that the pressure-sensitive adhesive itself is used as metering membranes, such as e.g. in EP-PS 33615,

wherein in this case the vote of the penetration rate of the active ingredient by the adhesive is particularly difficult and thus readjust for each active substance. This high expenditures are required for the production of active ingredient patches and some agents have not yet been developed for use in an active ingredient patch due to their high molecular weight.

Object of the invention

The object of the invention is to provide a method with which it is possible to produce a thrombolytic active substance patch having sufficient penetrability and for prolonged periods of prolonged drug dosability for human medicine.

Explanation of the essence of the invention

The object of the invention is to develop a method for producing an antithrombotic active substance patch having sufficient penetration capability and good drug dosing using antithrombotic substances having average molecular weights in the range from 1000 to 6000 gmol.sup.-1.

The object is achieved in that heparins and or oc! ^r Heparinoids whose molecular weight is in the range of 10OOgmol ¹ to eOOOgmol ¹ at narrow molecular weight distribution, in pure form or in the form of zeolite and / or layered silicate adducts having a loading in the range of 0.5% to 50%, in a pressure-sensitive adhesive premix at temperatures between 20 ⁰ C and 5O ⁰ C is incorporated. The pressure-sensitive adhesive premix used consists of 20 to 40 parts of natural and / or synthetic rubber

20 to 40 parts of natural and / or synthetic resin

15 to 25 parts of plasticizer

1 to 20 dividers, fillers

1 to 2 partsii antioxidants and based on 100 parts of solid product from 150 to 500 parts of solvents.

The provided with the drug pressure-sensitive adhesive premix is applied to a substrate either by direct or in the transfer coating method with a mass coverage of 150gm ² to 400gm ² and dried at temperatures from 2O ⁰ C to 110 ° C. Further processing to the ready-made active ingredient patch is done in a generally conventional manner. As heparins or heparinoids preferably infusion qualities of animal tissue or pentosan polysulfates are used. Particularly suitable is the sodium salt of pentosan polysulfate. The heparino or heparinoids can be used both in pure form and in the form of zeolite and / or layered silicate adducts. A zeolite is understood as meaning synthetic zeolites of the types A, X, Y and mordenite, and those of the magadiite type under a layered silicate, both in pure and in bound form. Particularly suitable are zeolites of the type 13 X. The zeolites or sheet silicates are loaded with amounts of active ingredient in the range of 0.5% to 50%, preferably 10% to 40%. As the main plasticizer component according to the invention lanolin is used, with a proportion of the total plasticizer from 50% to 70%.

When using the transfer coating method, silicone paper is used as the subcarrier. Surprisingly, it has been found that relatively large active substance molecules are absorbed or bound by these zeolites or phyllosilicates, and even more surprising is the effect that these complexes are readily destructible again on application to the skin, so that release of the active ingredient occurs ,

The corresponding drug-matrix system according to the invention from special zeolites and / or layer silicates with suitable cavity design (channel system) and the skilled person known loading with the candidate heparin or heparinoid produced. In this case, loading levels of 0.5% to 50%, but preferably from 10% to 40% realized. The coating density, the composition of the pressure-sensitive adhesive mass and the type of zeolite used then essentially determine the rate of release of the active substance, inter alia, by the path of the water after absorption from the surface of the skin, the transport of the water to the active substance or to the complex of active ingredient matrix by destruction of the active substance-matrix complex and the resulting content of "free" heparin or heparinoid in the pressure-sensitive adhesive mass. At the same time, the plasticizers cause an increased migration of the active substance to the skin surface and through the skin to thiombosis-forming skin areas.

The preparation of active substance is carried out by 20 to 40 parts of natural and / or synthetic rubber in the solvent, preferably in gasoline, especially in low-aromatic boiling range benzene Kp 60 ° C to 12O ⁰ C, are pre-swollen and after a maturation period of 6h to 48h gradually with Components of the category

Fillers including the solid product heparin or heparinoids,

Plasticizer,

- resin

intimately mixed with each other in mixing devices.

As natural rubbers are preferably high-purity air-dried or smoked goods, as synthetic rubbers preferably block copolymers of butadiene and styrene or isoprene and styrene, or copolymers of styrene and butadiene in the form of hot or cold polymers used.

As fillers are metal oxides, such as. As TiO ₂ and ZnO, kaolins, chalk or diatomaceous earth, but also organic substances, such as flour used.

Plasticizers which are used are preferably lanolin, silicone oils or customary paraffinic plasticizers which serve for grading the adhesive force and for transport control.

The resins used are rosin or refined products of rosin which have been prepared by hydrogenation and / or esterification.

The invention will be explained in more detail with reference to exemplary embodiments:

embodiments example 1

The preparation of the antithrombotic active substance patch described below was carried out in a laboratory technicum.

In a laboratory kneading the following ingredients were processed to a homogeneous mass:

Recipe ingredient parts by weight natural rubber 28 KolophoiMumrnrz 32 lanolin 16 Effomoll E 3 silicone oil 1 wheat flour 15 Zeolite adduct with a degree of loading of 50% (zeolite of type 13X) 5 petrol 400

The zeolite adduct contains as active ingredient sodium pentosan polysulfate having a molecular weight <6000 gmol ', which is adsorbed to 50 wt .-% of a synthetic, thermally activated zeolite 13X type of VEB Chemiekombinat Bitterfeld. This wi ¹ d processing with wool wax to a premix and mixed at a temperature of 40 ° C in the mass.

In a transfer coating process, the mass is applied to silicone paper, dried at 5 ° C. and laminated to an aluminum composite film. This is followed by drying at 30 ⁰ C. The pressure sensitive adhesive overlay is 200grrT. ² In further process steps, packaging takes place up to the finished product.

The drug patch prepared in this manner was tested for release of active ingredient from the patch mass in vitro over a thrombin time limit.

For this purpose, defined pieces of plaster were incubated in a Tris buffer solution. Depending on the incubation period, the time taken for the production of bovine fibrinogen was measured from the respective experimental batch (checkmark method).

It could be demonstrated that in a test period of 24 hours, the drug was continuously delivered to the incubation medium.

Clinical studies have shown a significant therapeutic success in the diagnosis of thrombophlebitis and thrombosis compared to conventional treatment methods with externally applied antithrombotics.

Example 2

Instead of the 5 g of the zsolite adduct (using the zeolite of type 13X) with sodium pentosan polysulfate in Example 1, 2.5 g of pentosan polysulfate are used as the pure active ingredient and the amount of wheat flour as a filler is increased to 17.5 g.

The preparation of the mass and the results of the tests of the thrombin times and the clinical investigations were carried out analogously to Example 1.

Claims (8)

1. A process for the preparation of an anlithrombotic active substance patch with metering function of the pressure-sensitive adhesive, characterized in that heparins and υζνν. or heparinoids having molecular weights in the range of 10OOgmol ¹ to 6000gmol ¹ in a Haftklebstoffprämix consisting of rubber, natural and / or synthetic resin, plasticizers, antioxidants and a solvent content at temperatures between 2O ⁰ C and 50 ⁰ C incorporated and subsequently the resulting mass applied to a support material with a mass coverage of 150gm ² to 400gm ² and dried at temperatures of 20 ⁰ C to 110 ⁰ C and processed in a generally conventional manner to a drug patch. 2. The method according to claim 1, characterized in that a Haftklebstcffprämix is used, consisting of 20 to 40 parts natural and / or synthetic
20 to 40 parts of natural and / or synthetic resin
15 to 25 parts of plasticizer 1 to 20 parts of fillers 1 to 2 parts of antioxidants as well
based on 100 parts of solid product
150 to 500 parts of solvents
consists. 3. Process according to Claims 1 and 2, characterized in that preferably used as heparins or heparinoids infusion qualities of animal tissue or sodium pentosan polysulfates. 4. Process according to Claims 1 to 3, characterized in that the heparins or heparinoids are used as zeolite and / or as phyllosilicate adducts. 5. Process according to Claims 1 to 4, characterized in that with active ingredient amounts in the range of 0.5% to 50%, preferably 10% to 40% loaded zeolite and / or layered silicate adducts are used. 6. Process according to Claims 1 to 5, characterized in that zeolites of the type A, X, Y or mordenite are used. 7. Process according to Claims 1 to 5, characterized in that those of the magadiite type are used as sheet silicates. 8. Process according to Claims 1 to 5 and 6 or 7, characterized in that lanolin is used as the Hauptweichmacherkomponente with a proportion of 50% to 70% of the total amount of plasticizer.