DD217989A1 - Method for producing a pharmaceutical preparation - Google Patents

Abstract

The invention relates to a method for producing a pharmaceutical preparation suitable for long-term therapy in the form of a solvent-containing film. The aim is an easy to produce film with well reproducible controlled release of the drug. According to the invention, an oversaturated drug solution is permanently immobilized in the film and control of drug lavage is achieved by the proportion and / or dielectric constant of the solvent and / or the thermodynamic activity of the drug and / or the combination of multiple layers of the film. The preparation takes place in such a way that the drug solution immobilized in the film contains a multiple of the amount of drug normally soluble in the solvent and that recrystallization of the drug is excluded.

Description

Verfaliren for the preparation of a pharmaceutical preparation

Anwenau area of the invention

The present invention relates to a process for producing a pharmaceutical preparation suitable for long-term therapy in the form of a film which can be used for numerous types of administration and various applications with locally and / or systemically active drugs.

Characteristic of the known technical solu conditions

Various multilayer composite systems have already become known, which are used in the form of a film or use a film to control the drug delivery. For example, U.S. Patent Nos. 3,598,122, 3,598,123, 3,742,951, 3,797,494, 3,996,934, 3,995,632, 4,060,084, 3,731,683, and 4,031,894 describe such sandwich and laminar systems, respectively. Piles are difficult to produce because of their complicated structure and their production requires a high investment and manufacturing cost. Moreover, the drug contained in the multi-layered reservoir systems is utilized to a limited extent, corresponding to low bioavailability.

On the other hand, it has proved to be advantageous to produce pharmaceutical preparations in the form of a film in which the medicaments are incorporated. Corresponding preparations are known from DE-OS 2 432 925, 2 218 200, 2 207 635. These consist of substances such as hydroxyalkyl cellulose, polyamic acid, etc., which are soluble in water

In addition, pharmaceutical preparations are known from ΏΏ ~ AP 150 849, DB-AS 2449865, which consist of suitable substances and thus in principle yield films suitable for long-term therapy. DD-AP 150 849 and others also disclose the use of a copolymer of alkyl esters of acrylic and / or methacrylic acid as film formers. "All of these technical solutions provide film preparations which are undefined in terms of solvent content and activity and, consequently, control of drug diffusibility In the film and the drug release from the film or not sufficiently enable. "For example, proposed in the DD-AP 150, the release rate of the drug by loading a polyacrylate film with solvent and by type and amount of added water-forming auxiliary substances to regulate" This procedure a subsequent Loading can not be realized without additional and high investment and manufacturing costs. In addition, it is difficult to ensure reproducible conditions for such a subsequent loading of the films and thus a constant bioavailability of the incorporated active ingredient »

A method by which the drug can crystallize from a solution (e.g., DD-AP 150 849) provides films containing the drug in low thenaodynamic activity that are of low utilization and therefore uneconomical.

Ziel_jdgr invention

The aim of the invention is to avoid these disadvantages and to provide a suitable for long-term therapy pharmaceutical preparation in the form of a film, which can be produced easily and inexpensively, a well reproducible, controlled release of drugs as independent as possible from external influences and up to ensures high turnover and allows a variation of the release speed according to different applications.

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The invention has for its object to develop a method by which film-forming base materials (film former) and the drugs to be applied can be processed together with a physiologically acceptable solvent to an easy-to-use, suitable for long-term therapy pharmaceutical preparation in the form of a solvent-containing film.

According to the invention, a pharmaceutical preparation in the form of a solvent-containing film is produced, which is characterized in that the film consists of a known film former (eg Eudragit ^R , Röhm Pharma GmbH, Darmstadt, FRG or Scopacryl, VEB Chemische Werke Buna, Schkopau, DDR) and contains the drug in the form of a supersaturated solution. A 1.1 to 2, the rock supersaturated solution of the drug is preferably aimed at in the film, which is _v achieved in that an undersaturated solution of a drug solution or suspension of the film former and the mixture is dried to the film. The diffusion path increasing with time is usually considered by having a solid drug depot and a saturated solution in the film matrix or by having a corresponding concentration gradient by increasing the drug concentration in the film with increasing distance from the release surface. According to the invention may be disregarded by the presence of a supersaturated drug solution in the film of increasing with time diffusion path or be compensated by the fact that a sandwich (multi-layer) preparation of films of the invention is applied.

A preparation of the pharmaceutical preparation according to the invention can be carried out by dispersing in an aqueous suspension of a suitable film former (Eudragit E 30]), Plex 4791 D, Scopacryl D 34Q) an aqueous solution of a drug. The mixture is, if these functions are not yet through the film former suspension or

Drug solution can be met, with added excipients, which cause 'in the finished film, a supersaturated drug solution is permanently immobilized and the dielectric constant of the solution and the thermodynamic activity of the arsenic reach the desired values. Subsequently, the mixture is dried in a suitable manner and then formed at IiIm.

As auxiliaries are alcohols, especially ethanol ₅ Poly "* öle5 particular glycerol, polyacids, especially polyacrylic acid in a mixture with other polymers (z> Bo Scopacryl D 339, Carbopol 941) and amines ₉ amino acids and ammonium compounds which are"

The following examples illustrate the invention in no way restrictive manner

Isosorbide dinitrate-containing preparation isosorbide dinitrate (ISDlI), dissolved advantageously in isoeorbid dimethyl ether or another suitable solvent ₉ , optionally with the addition of ethanol, polyol and / or a polyacid (Scopacryl D 339) ¹ ^ ⁰ - further auxiliaries with a film former suspension (Scopacryl D 340) mixed * The viscous mixture is poured or spread on a horizontal smooth surface (eg * polyethylene film 100 μm thick, Teflon, etc.) and dried at max. 40 ⁰ C in air (24 h at 20 22 ⁰ C, up to 4 h at 40 ⁰ C) or in vacuo (up to 4 h at torr) dried "The resulting ISDN film is removed from the pad and in split desired pieces.

Nitroglycerinhaltige preparation

Litroglycerin (HG), dissolved advantageously in ethanol or other suitable solvent, is optionally mixed with the addition of polyol and / or a polyacid and other Hilf8-substances as in Example 1 with a film former suspension (Scopacryl D 339) mixed and formed into a film »

The films of Example T and Example 2 are formulated so that the solvent (water) contents filled in Tables 1 and 2 are in a film loaded at 40% relative humidity. -

table

ISDH films according to Example 1

Designation Scopacryl Scopacryl D. 340 Water content DK value D 339 of the film

S 20 G % 79.9 1 50 99,60 0,090 79.7 2 - 00 ', 98.80 0,110 79.1 3 50 96,40 0.130 78.3 4 - 93.20 0,250 77.5 5 - 90.00 0,330 80.0 6 O, 99.80 0,022 79.5 7 xt 98.50 0,030 78.9 8th 2, 98,00 0,090 78.1 2, 97.50 0,101 Table 2

KG films after example 2

Designation Scopacryl D 339 Water content DK value

g of the movie %

12 ι

60.0 3.30 77.5 75.0 2.50 78.3 90.0 1.30 79.1 94.3 1.10 79.7 60.0 3 78 60.0 3 78 60.0, 3.5 77.5 60.0 4.0 78.5

For the characterization of the films, according to example 1 and 2 parameters are herängessogeiis, which are determined as follows?

In vitro study of isosorbide dinitrate liberation

A film is introduced as a donor into a Stricker diffusion cell and, at a fixed temperature and flow rate, is contacted with a defined volume of the acceptor (556. methanol, 2% IaCl in water). At certain intervals, 20% and 25%, respectively, are obtained. removed and replaced by fresh Akzeptormittels of Akzeptormittel in ά & η samples taken of the Akzeptormittels Isosorbiddinitratgehalt is by a photometric method determines "Taking into account the, dilution scheme of the check Münzel · Liberation Prof ile arise in Figure 1 and 2. FIG.

Phot © metric determination of isosorbide dinitrate

4.00 ml isosorbiddinitrathaltige Akzeptorprobe are mixed with 2 U 1,0il UaOH, 15 min in a water bath at 50 ⁰ C ER-

and cooled for 5 min in cold water. Thereafter, 1.0 ml of 4 l HCl, 1% al-procaine hydrochloride solution (0 _s 300 g / 100.00 ml of water) and I ₉ O n. N- (i-XTaphthyl) »ethylenediamine dihydrochloride _(0? 100 g / 10O ₉ 00 ml of water) was added" The absorbance at 550 in 1 cm layer thickness is against a blank under ¥ SE OF Spektrophotonaeters Spekol (VEB Carl Zeiss Jena) measured · The isosorbide dinitrate content results from a calibration curve ® ^N

In vitro study of Mtroglycerinliberation

The in vitro study of the Mtroglycerinliberation is carried out analogously to the investigation of Isosorbiddinitratliberation. 10% of the acceptor agent water is sampled and replaced with fresh acceptor agent. In the removed. Samples of the acceptor, the Ütroglyceringehält determined by a photometric method of Ermer i The found Liberationsprofile are shown in Figure 3 ₉ 4 and 5.

Photometric determination of nitrate glycerol

2.00 ml of nitroglycerin-containing acceptor sample are mixed in a 100 ml volumetric flask with 20.0 ml of water and 10.0 ml of 1 U UaOH and heated for 15 min in a water bath at 100 ⁰ C. The sample is cooled under running water, added with 9.0 ml of 1 N hydrochloric acid, 2.0 ml of reagent solution (0.10 g of o-C-naphthylamine, 1.00 g of sulfanilic acid and 9.0 g of tartaric acid in 100.00 ml of water) and filled up with water to 100.00 ml. 30 min after addition of the reagent solution, the absorbance at 530 nm and 1 cm layer thickness is measured against a blank sample using the spectrophotometer Spekol (VKB CarIv Zeiss Jena). The kitroglycerin content results from an iSich curve.

The results of the in vitro examination of films according to the invention set out in FIGS. 1 to 5 should in particular prove the good controllability of the quantities of drug diffusing out.

Claims (3)

1 _{β A} process for the preparation of a pharmaceutical preparation in the form of a solvent-containing film, suitable for long-term therapy, characterized in that a supersaturated drug solution in the film is permanently immobilized and a control of the drug liberated by the proportion and / or the dielectric constant of the solvent and / or the thermodynamic activity of the drug and / or the combination of several layers of the film takes place. 2. The method according to item 1, 'characterized in that the film between 0.01 and 50 wt., -%, Preferably between 0.02 and 0.5 GeWe% solvent having a dielectric constant between, 5 and 80, preferably between 70 and Bu and that optionally aid substances, such as alcohols, polyols ₉ polyacids, amines, amino acids, 'fertilize ammonium compounds, are included. 3 "process according to item 1 to 2, characterized in that the film is prepared so that the immobilized drug solution in the film a multiple, preferably 1.1 to 2 _? Contains 1 times the amount of drug that dissolves in Mormalbedingungea in the solvent and that recrystallization of the drug is excluded.