DE4032096A1 - Emulsifier-free emulsion polymers for pharmaceuticapreparations - Google Patents

Abstract

An emulsion polymer which has been treated with an extractant in which the emulsion polymer is not soluble and thus freed from emulsifiers and surfactants and other auxilliaries soluble in the solvent, is new. The emulsion polymer which can serve as a carrier (or sustained release pharmaceuticals is based on methyl and/or ethyl esters of acrylic and/or methacrylic acid, or consists of poly-lactide, polystyrene, polyvinylacetate, polyvinyl-pyrrolidone, polybutadiene, polyacrylonitrile, etc..

Description

The present invention relates to emulsifiers liberated emulsion polymers, their preparation and their use in pharmaceutical preparations delayed drug release.

Certain emulsion polymers - such as B. - emulsion polymerized esters of acrylic acid or Methacrylic acid - are in the past few years indispensable tools in the production of Pharmaceuticals have become active ingredients a dosage form with delayed Drug release is sought [H. Determann and R. Lotz, Pharmaceutical Industry 32 (1970) 469].

Such forms of custody allow for a longer one Period of constant drug release and thus allow the number of daily to reduce the amount of medication being administered and thus simplifying the therapy scheme.

In the course of developing these depot forms are next to a variety of tablets and capsules u. a. also active substance-containing plasters with controlled Drug release has been described.

For the production of such depot forms are from the State of the art also numerous processes known.

For example, the manufacture can be done in this way take place that the emulsion polymer from Suspending agent freed the polymer isolated in this way the active ingredient in a suitable - organic - Solvent dissolves, then the solvent  evaporates and the solid active ingredient-containing polyacrylate one below the glass transition temperature of the polymer Ground temperature and the active ingredient Polyacrylate powder using either Tableting aids to tablets or other Way - for example by insertion in capsules - processed.

Also the production of plasters containing active ingredients is known from the prior art; it takes place in in an analogous manner (see European patent specification 20 905).

Suitable for the preparation of such preparations As already mentioned at the beginning, emulsion polymers are Esters of acrylic or methacrylic acid, such as. B. the commercially available products with the overarching Product name Eudragit from Röhm, Darmstadt.

Such emulsion polymers are in the way made that the water-insoluble monomer with Emulsified in water using emulsifiers or surfactants and using the usual initiators Polymerization is initiated or carried out. The in this type of polymerization In many cases, polymer dispersions are direct usable and available in the form of dispersions. Drug release systems based on such emulsion polymers were prepared however, have the disadvantage that the release rate of the active ingredient from the thermal treatment of the Active ingredient release system in the manufacturing process as well may depend on storage.

It is therefore the object of the present invention Drug release systems based on Emulsion polymers - especially based on Polyacrylic acid esters or polymethacrylic acid esters - to provide the one described above Not showing dependency and also after longer storage time and different Storage conditions are essentially identical Have release characteristics.

Surprisingly, it has now been found that the Dependence of the release rate on the thermal Pretreatment during the manufacturing process, the in the release behavior of drug delivery systems could be observed on the presence of the Emulsifier.

It is another object of the present invention emulsifier-free emulsion polymers and a process to make available for their manufacture.

According to the invention in the manufacture of Drug release systems used Emulsion polymers freed from the emulsifier and therefrom - with methods known per se - the corresponding emulsifier-free drug delivery systems.  

For removing the emulsifier or extractable excipients come in several processes Consider. In principle, the emulsion polymer is used an extractant treated in which the Polymer itself does not dissolve.

For the extraction method according to the invention preferably water used.

However, it depends on the type of polymers used - possible any other Use solvent or solvent mixture in which the polymer itself is not soluble.

On the one hand, there is the Possibility to remove the emulsifier from the commercially available Remove the emulsion by precipitating the polymer.

This can be done using conventional methods such. B. by Precipitation with a suitable solvent or Acid, by salting out, freezing out or extraction can be achieved.

Another option is to use the emulsifier or the auxiliary material (s) - after removing the Dispersant - to be removed from the polymer. To For example, the following methods are available:

Equilibrium extraction, Soxleth method, Column extraction or dialysis.

Alternatively, other separation methods - such as. B. the Suitable for centrifugation.  

The extraction of the dried acrylate (Eudragit NE 30 D ^R ) is preferred.

The dried acrylate is in a suitable Equipment crushed or ground and with water that is constantly renewed, extracted. The is preferred Emulsifier by freezing the corresponding one Emulsion polymers and subsequent thawing as well Washing with a suitable solvent - preferably water - removed.

The manufacture of the drug delivery systems is - how already mentioned - known from the prior art and u. a. in German Offenlegungsschrift 33 14 003 as well as in European Patent 00 86 997 which is hereby incorporated by reference.

In addition to those mentioned at the beginning, the carrier material is Polymers are also suitable for those polymers which are based on the emulsion polymerization process leave, such as B. PVC, polylactide, polystyrene, Polyvinyl acetate, polybutadiene, polyacrylonitrile, Polyvinyl pyrriolidone, polyvinyl ester, polyvinyl ether and their copolymers. Polymers are preferred on the Basis of esters of acrylic and / or Methacrylic acid.

Emulsion-polymerized are particularly preferred Copolymers of methyl and / or ethyl esters Acrylic and methacrylic acid.  

As pharmaceutical active compounds are suitable in addition to clonidine, inter alia, ranitidine, cimetidine, atenolol, enalapril, captopril, nifedipine, naproxen, diclofenac, diclofenac sodium, piroxicam, Cefaclor, diltiazem, ketotifen, ketotifen hydrogen fumarate, salbutamol, propranolol, amoxicillin, triamterene, norethisterone , Mestranol, Cefotoxamine, Cefotoxamine Sodium, Ceftriaxone, Ceftriaxone Disodium, Cefalexin, Dipyridamol, Alprazolam, Cefoxitin, Ciclosporin, Metoprolol Tartrate, Aciclovir, Sulindac, Clavulanic Acid, Methyldopa, Nicardylinidoline, Tamardifinidolinolone, Tamardifinidoline, Tamardifinidoline, Tamardifinidolinolone, Tamardifinidoline, Tamardifinidoline, Tamardifinidoline, Tamardifinidolinolone, Tamardipinidinidone, Tamardifinidoline, Tamardifinidinolone, Tamardifinidinolone, Tamardifinidinolone, Tamardifinidoline, Tamardifinidinoline, Tamardifinidinolone, Tamardipinoline, Tamardipinoline, Tamardipinoline, Tamardipinoline, Tamardipinoline, Tamardifinone, Glyphinidinoline, Tifin , Doxorubicin, amiloride, amilorid-HCl, hydrochlorothiazide, dihydroergocornin, dihydroergocorninmethane sulfonate, erythromycin, erythromycin stearate, triazolam, latamoxef, cromoglicinic acid, ceftazidim, clenbuterol, dynotinolate doliminatex, tolinone ditone, bromine hexinate dolomate Caffeine and acetylsalicylic acid re - or vitamins - such as B. Vitamin A, A ₁ , A ₂ , B ₁ , B ₂ , B ₄ , B ₆ , B ₁₂ , C (ascorbic acid), ascorbyl palmitate and other pharmacologically acceptable derivatives of ascorbic acid, D, D ₁ , D ₂ , D ₃ , D ₄ , E, H, K, K ₁ , K ₂ , P and Q - or active ingredients - such as. B. Avoparcin, Flavopholipol, Monensin, Monensin Sodium, Salinomycin, Carbadox, Nitrovin and Olaquindox, as well as active ingredients as listed in the 1990 Red List (Editio Cantor Verlag für Medizin und Naturwissenschaften GmbH and Co. KG, Aulendorf / Württemb.) are hereby referred to in terms of content.

The emulsion polymer is used for production usually with the active ingredient in a suitable - organic - solvent dissolved, the solvent evaporated and the solid, active ingredient-containing polyacrylate processed according to the intended use.

Explanation and discussion of the drawings:

Figs. 1 to 7 indicate the influence of the thermal pretreatment and the storage time on the emulsifier-release rates - polyacrylate (Eudragit) produced - active substance release systems again. The active substance is clonidine in all cases. In contrast, FIGS. 8 and 9 show that the thermal treatment and storage time have a negligible influence on emulsifier-free active ingredient release systems.

Explanations to Figures 1 to 13 in detail:

Figs. 1 to 5 and 8 and 10 indicate the release characteristics of various preparations of active compound consisting of 1.00 wt .-% and 99.00 wt .-% clonidine acrylate again. FIGS. 6, 7 and 9 show the release characteristics of active agent release systems corresponding polyvinylpyrrolidonhaltiger again.

An untreated or an Eudragit NE 30 D ^R brand polyacrylate from Röhm, Darmstadt, was used as the acrylate in accordance with the respective information. The grain size of the respective preparation is in a range of 315-400 µm. The amount of active ingredient contained amounts to 130 µg (= 100%).

To Fig. 1

Ch. 20 / U does not stand for one dried at 20 ° C annealed sample.

Ch. 40 / U does not stand for a dried at 40 ° C annealed sample.

Ch. 20 / T stands for a sample that dried at 20 ° C and for 3 hours at 70 ° C had been annealed.

CH 40 / T stands for a sample that dried at 40 ° C and for 3 hours at 70 ° C had been annealed.

To Fig. 2

Ch 20 / U stands for an untempered sample, which after the Drying at 20 ° C had been measured.

Ch 20/0 stands for a sample that dried at 20 ° C and over a period of 15 hours at 70 ° C annealed and then measured.

Ch 20 / 0.5 / 20 stands for a sample at 20 ° C dried and added over a period of 15 hours 70 ° C annealed and - after a storage time of one half a month at 20 ° C - had been measured.

Ch 20/1/20 stands for a sample at 20 ° C dried and added over a period of 15 hours 70 ° C annealed and - after a storage time of one a month at 20 ° C - had been measured.  

Ch 20/2/20 stands for a sample that is at 20 ° C dried and added over a period of 15 hours 70 ° C and after a storage time of two Months at 20 ° C - had been measured.

Ch 20 / 4,5 / 20 stands for a sample at 20 ° C dried and added over a period of 15 hours 70 ° C and - after a storage time of four and a half months at 20 ° C - had been measured.

Ch 20/6/20 stands for a sample at 20 ° C dried and added over a period of 15 hours 70 ° C and after a storage time of six Months at 20 ° C - had been measured.

To Fig. 3

Ch 20 / U stands for an untempered sample, which after the Drying at 20 ° C had been measured.

Ch 20/0 stands for a sample that dried at 20 ° C and over a period of 15 hours at 70 ° C annealed and then measured.

Ch 20/7/40 stands for a sample at 20 ° C dried and added over a period of 15 hours 70 ° C and after a storage time of 7 Days at 40 ° C - had been measured.

Ch 20/14/40 stands for a sample at 20 ° C dried and added over a period of 15 hours 70 ° C and after a storage time of 14 Days at 40 ° C - had been measured.  

Ch 20/30/40 stands for a sample at 20 ° C dried and added over a period of 15 hours 70 ° C and after a storage period of 30 Days at 40 ° C - had been measured.

Ch 20/60/40 stands for a sample at 20 ° C dried and added over a period of 15 hours 70 ° C and after a storage time of 60 Days at 40 ° C - had been measured.

Ch 20/180/40 stands for a sample at 20 ° C dried and added over a period of 15 hours 70 ° C annealed and - after a storage time of 180 Days at 40 ° C - had been measured.

To Fig. 4

Ch 40 / U stands for an untempered sample, which after the Drying at 40 ° C had been measured.

Ch 40/0 stands for a sample that dried at 40 ° C and over a period of 15 hours at 70 ° C annealed and then measured.

Ch 40 / 0.5 / 20 stands for a sample at 40 ° C dried and added over a period of 15 hours 70 ° C annealed and - after a storage time of one half a month at 20 ° C - had been measured.

Ch 40/1/20 stands for a sample at 40 ° C dried and added over a period of 15 hours 70 ° C annealed and - after a storage time of one Month at 20 ° C - had been measured.  

Ch 40/2/20 stands for a sample that is at 40 ° C dried and added over a period of 15 hours 70 ° C and after a storage time of two Months at 20 ° C - had been measured.

Ch 40/6/20 stands for a sample at 40 ° C dried and added over a period of 15 hours 70 ° C and after a storage time of six Months at 20 ° C - had been measured.

To Fig. 5

Ch 40 / U stands for an untempered sample, which after the Drying at 40 ° C had been measured.

Ch 40/0 stands for a sample that dried at 40 ° C and over a period of 15 hours at 70 ° C annealed and then measured.

Ch 40 / 0.5 / 40 stands for a sample at 40 ° C dried and added over a period of 15 hours 70 ° C annealed and - after a storage time of one half a month at 40 ° C - had been measured.

Ch 40/1/40 stands for a sample at 40 ° C dried and added over a period of 15 hours 70 ° C annealed and - after a storage time of one Month at 40 ° C - had been measured.

Ch 40/2/40 stands for a sample at 40 ° C dried and added over a period of 15 hours 70 ° C and after a storage time of two Months at 40 ° C - had been measured.  

Ch 40/6/40 stands for a sample at 40 ° C dried and added over a period of 15 hours 70 ° C and after a storage time of six Months at 40 ° C - had been measured.

To Fig. 6

Ch 20 / U stands for a polyvinylpyrrolidone containing Untempered sample after drying at 20 ° C had been measured.

Ch 40 / U stands for a polyvinylpyrrolidone containing Untempered sample after drying at 40 ° C had been measured.

Ch 20 / T stands for a polyvinylpyrrolidone Sample that after drying at 20 ° C over a Tempered for three hours at 70 ° C and had subsequently been measured.

Ch 40 / T stands for a polyvinylpyrrolidone Sample that after drying at 40 ° C over a Tempered for three hours at 70 ° C and had subsequently been measured.

To Fig. 7a

Ch 20 / U stands for a polyvinyl pyrrolidone Untempered sample after drying at 20 ° C had been measured.

Ch 20 / T stands for a polyvinylpyrrolidone Sample after drying at 20 ° C for 3 hours annealed at 70 ° C and then measured was.  

Ch 20/6/40 stands for a polyvinyl pyrrolidone Sample after drying at 20 ° C and three hours Annealing at 70 ° C and storage at 40 ° C for six months had been measured.

To Fig. 7b

Ch 40 / U stands for a polyvinyl pyrrolidone Untempered sample, which - after drying at 40 ° C - had been measured.

Ch 40 / T stands for a polyvinylpyrrolidone Sample after drying at 40 ° C for 3 hours annealed at 70 ° C and then measured was.

Ch 40/6/40 stands for a polyvinylpyrrolidone Sample after drying at 40 ° C and three hours Annealing at 70 ° C and storage at 40 ° C for six months had been measured.

To Fig. 8a

Ch 20 / U stands for an untempered sample, which after the Drying at 20 ° C had been measured.

Ch 40 / U stands for an untempered sample, which after the Drying at 40 ° C had been measured.

Ch 20 / T stands for a sample that after drying 20 ° C over a period of one hour at 70 ° C annealed and then measured.  

Ch 40 / T stands for a sample that after drying 40 ° C over a period of one hour at 70 ° C annealed and then measured.

To Fig. 8b

Ch 40 / U stands for an untempered Ch 40 / T / 3/40 sample stands for a sample that is on a sample for 3 hours Temperature of 70 ° C and after a three months of storage was measured. Ch 40 / U / 3/40 stands for an untempered sample, which after a three months storage at 40 ° C had been measured.

To Fig. 9a

Ch 20 / U stands for untempered polyvinylpyrrolidone-containing sample, which - after the Drying at 20 ° C - had been measured.

Ch 40 / U stands for an untempered one polyvinylpyrrolidone-containing sample, which - after the Drying at 40 ° C - had been measured.

Ch 20 / T stands for a polyvinylpyrrolidone Sample after drying at 20 ° C for one hour annealed at 70 ° C and then measured was.

Ch 40 / T stands for a polyvinylpyrrolidone Sample after drying at 40 ° C for one hour annealed at 70 ° C and then measured was.  

The measured values of the respective release rates were following sample treatment:

• 1) 2 hours in artificial gastric juice pH: 1.2;
• 2) 2 hours in artificial intestinal juice - pH: 6.5;
• 3) another 2 hours in artificial intestinal juice - pH: 6.5;
• 4) another 2 hours in artificial intestinal juice - pH: 6.5.

To Fig. 9b

Ch 40 / U stands for an untempered sample.

Ch 40 / T / 3/40 stands for a sample that lasts 3 hours had been heated to a temperature of 70 ° C and were measured after three months of storage.

Ch / 46 / U / 3/40 stands for an untempered sample that measured after storage for three months at 40 ° C had been.

To Fig. 10

Ch W stands for an untempered one - straight out of the aqueous dispersion - the sample produced in a Temperature of 20 ° C had been dried and was measured immediately.  

Ch W / 3/20 stands for an untempered - straight from the aqueous dispersion - the sample produced after the Manufacturing over a period of three months had been stored at a temperature of 20 ° C and was then measured.

Ch W / 3/40 stands for an untempered - straight from the aqueous dispersion - the sample produced after the Manufacturing over a period of 3 months at a Temperature of 40 ° C had been stored and was then measured.

1 shows the release rates of emulsifier-containing preparations which had not been annealed or had been annealed for 3 hours at 70.degree . C. (melting of the emulsifier) and had been dried at temperatures of 20.degree. C. or 40.degree . C. as a function of time . From Fig. 1 it is clear that the release rates of emulsifier-containing untempered matrices assume the highest values for a given period of time, the release rates of the preparation dried at 20 ° C being comparatively higher than that of the active ingredient preparation dried at 40 ° C.

In contrast, the release rates of the tempered samples indicate significantly smaller values.  

Fig. 2 shows the release rates of emulsifier-containing active substance preparations, each of which had been dried at 20 ° C. and annealed at 70 ° C. for 15 hours and had been stored at a temperature of 20 ° C. for different periods of time.

From Fig. 2 it can be seen that the respective release rates of the merely annealed sample have the lowest values, while the release rates of the samples stored at 20 ° C. over a longer period of time are clearly above those of the completely untreated matrix and the only annealed matrix.

FIG. 3 shows the release rates of emulsifier-containing active substance preparations, each of which had been dried at 20 ° C. and heat-treated at 70 ° C. for 15 hours and, in contrast to FIG. 2, had been stored for different lengths of time at a temperature of 40 ° C. .

In principle, an analogous behavior of the different active substance preparations can be demonstrated from FIG. 3.

Fig. 4 shows the release rate of an active ingredient preparation analogous to FIG 2 treated underlying preparation -. In contrast to this, however, at 40 ° C dried - had been. It can also be seen from FIG. 4 that the release rates increase with the increasing storage time of the samples, so that the sample that had been stored at 20 ° C. for 6 months has the highest release rates. In contrast, the immediately measured sample (0 months) has the smallest release values.

FIG. 5 shows the release rate of an active substance preparation which had been treated analogously to the preparation on which FIG. 3 is based - but in contrast to this had been dried at 40.degree. In principle, the corresponding tendencies can be seen in FIG. 5, as could already be seen in FIG. 4.

Fig. 6 is the release characteristic of an emulsifier polyvinylpyrrolidonhaltigen matrix shows the composition: 1 wt .-% clonidine, 20 wt .-% polyvinylpyrrolidone and 79% acrylate (Eudragit NE 30 D ^R) which had been dried at 20 and 40 ° C, in tempered or untempered form.

The measurement data of the respective release rates were based on following sample treatment:

• 1) 1 hour in artificial gastric juice pH: 1.2;  
• 2) 1 hour in artificial intestinal juice - pH: 6.5;
• 3) another 2 hours in artificial intestinal juice - pH: 6.5;
• 4) another 2 hours in artificial intestinal juice - pH: 6.5.

Also from Fig. 6 shows that, notwithstanding the presence of polyvinyl pyrrolidone, the release rates of the annealed samples are consistently much lower than those of the unannealed drug delivery systems.

The influence of various drying conditions can be read from FIGS. 7a and 7b. The composition of all samples consists of 1.00% by weight clonidine, 20.00% by weight polyvinylpyrrolidone and 79% acrylate. The treatment of all samples to record the release characteristic was carried out in analogy to the method given in the description of FIG. 6.

Was FIG. 7a shows the release characteristics of an untreated sample, a sample for three hours at 70 ° C is melted and a sample melted for 3 hours at 70 ° C and 6 months had been stored at a temperature of 40 ° C. All samples were dried at a temperature of 20 ° C.

FIG. 7b shows the release characteristics of samples which were treated in analogy to that in FIG. 7a, with the difference that the drying was carried out at a temperature of 40.degree.

Fig. 8a is the release rates of a drug delivery system, again, the matrix of which has been freed from the emulsifier.

The release system consists of 1.00% by weight of clonidine and 99.00% by weight of emulsifier-free acrylate together. The Measurement data of the respective release rates were in each case recorded after the following treatment of the samples:

• 1) 2 hours in artificial gastric juice pH: 1.2;
• 2) another 2 hours in artificial intestinal juice - pH: 6.5;
• 3) another 2 hours in artificial intestinal juice - pH: 6.5;
• 4) another 2 hours in artificial intestinal juice - pH: 6.5;
• 5) another 16 hours in artificial intestinal juice - pH: 6.5.

The release rates of samples are shown at different temperatures (20 ° C and 40 ° C) had been dried and the untempered or after one-hour annealing at 70 ° C had been used.  

FIG. 8b illustrates the release behavior of an active ingredient release system (composition as described under FIG. 8a) based on an emulsifier-free matrix after 3 months of storage at a temperature of 40.degree.

Fig. 9a shows the release characteristics of emulsifier, polyvinylpyrrolidonhaltiger active ingredient release systems, which is composed of 1.00 wt .-% clonidine, 20.00 wt .-% polyvinylpyrrolidone, and 79.00 wt .-% of acrylate. The measurement data of the respective release rates were recorded after the following treatment of the samples:

• 1) 1 hour in artificial gastric juice pH: 1.2;
• 2) another hour in artificial intestinal juice - pH: 6.5;
• 3) another 2 hours in artificial intestinal juice - pH: 6.5;
• 4) another 2 hours in artificial intestinal juice - pH: 6.5;
• 5) another 18 hours in artificial intestinal juice - pH: 6.5.

The release rates of samples were recorded have been dried at different temperatures were and the untempered or after one hour Tempering at 70 ° C had been used.  

Fig. 9b, the release behavior illustrates a drug delivery system (composition as described under 9a) based on an emulsifier-free matrix after three months storage at a temperature of 40 ° C.

Fig. 10, the release behavior is shown a drug delivery system prepared directly from the aqueous dispersion (composition: 1 wt .-% clonidine, 99 wt .-% of acrylate), which immediately measured after preparation and after storage for three months at 20 ° C or at 40 ° C had been measured.

As from the diagrams of the emulsifier Drug release systems emerges are the Release rates from the thermal treatment of the Drug release system dependent.

The release rates of the unannealed samples are significantly higher than those which - in the case of FIG. 10 - had been annealed at 70 ° C. for three hours.

Fig. 11, the release rates are one with Clenbuterol (8 wt .-%) loaded drug release system again. (Matrix: Eudragit NE 30 D).

Fig. 12 and Fig. 13 indicate the dependence of the diffusion coefficient on the load again using a non-extracted matrix (Fig. 12) and the other using an extracted matrix (Fig. 13) again.

At the same time it can be seen that the release rates of the - annealed as well as untempered - samples that had been dried at 20 ° C, larger values have than the corresponding values of those Samples that had been dried at 40 ° C.

The release functions shown graphically in FIGS. 2 to 5 demonstrate that regardless of the drying temperature (20 ° C. or 40 ° C.) and storage temperature (20 ° C. or 40 ° C.), the following trend occurs for tempered samples (70 ° C.) it can be determined:

The release rates of those samples that are immediately in the Following the annealing were measured with The lowest approval rates. These are well below the values that are for the corresponding untempered samples. With As the storage time increases, the release rates increase general varying degrees (depending on the drying and storage temperature).

FIGS. 6 and 7 show the influence of the emulsifier on the release rates in a polyacrylate / polyvinylpyrrolidone mixture, such as is sold commercially. The knowledge gained from FIGS. 1 to 5 are also confirmed by the release rates of these systems.

This is the release rate of the tempered samples below that of the untempered being in turn a dependence on the drying temperature is detectable. In these cases, too Release rates after several months of storage.  

In contrast, a completely different picture emerges in the corresponding investigations of the emulsifier-free active ingredient release systems (FIGS . 8a and 9a).

Regardless of the drying conditions, the Release rates - both in the PVP-containing and in the PVP-free system - just a few different ones Values, whereby also the difference to the values of annealed samples negligible in both cases is small.

FIG. 11 also provides clear evidence that the release from extracted matrices takes place much more slowly - with less scatter between the curves - than from the corresponding non-extracted matrix.

FIG. 12 shows the dependence of the diffusion coefficient on the load for a non-extracted matrix (Eudragit NE 30 D) - FIG. 13 shows this dependence for the corresponding extracted matrix material. It can clearly be seen that for the purified polymer ( FIG. 13) there are significantly smaller scatterings with respect to the diffusion coefficient than for the corresponding non-extracted acrylate.

By extracting the emulsifier, one of the thermal treatment of the release system independent release behavior can be achieved.

Furthermore, it has been shown ( FIGS. 8b and 9b) that the active ingredient release systems produced according to the invention have an improved shelf life, ie that the release rates have remained essentially unchanged even after the active ingredient release system has been stored for a long time.

The tasks mentioned at the beginning are carried out by the Process described in Example 1 solved. Different, different configurations of the Processes for those skilled in the art from the present Description visible. However, it becomes explicit noted that the example and this assigned description only for the purpose of Explanation and description provided and not as Limitation of the invention is to be seen.

example 1

30.0 g of the aqueous Eudragit NE 30 dispersion were frozen at -18 ° C and then by simple Let thaw at room temperature. After this complete thawing was carried out with stirring from Aqua dem. ad 300.0 g. This treatment comes through it to completely break the dispersion, taking over a loose white sediment a clear one Protrusion forms. (A possibly still existing Slight cloudiness can be achieved by separating suspended matter clarify using a suction device.) The supernatant was decanted and mixed with the same amount of aqua. replaced and thus the residue washed about 1 minute. Separating, supplementing and washing has been done so often (9 times) repeated until the last two separated aqueous washing media were each emulsifier-free. (Instead of adding 10 times the amount of Wash water is also possible 15 times with the wash three times the amount of water. Even then it is last wash water demonstrably free of emulsifier.)

Claims (10)

1. emulsion polymer, characterized in that it has been freed from emulsifiers or surfactants and other auxiliaries soluble in the solvent by using an extracting agent in which the emulsion polymer is not soluble. 2. Active substance release system based on a Emulsion polymer, characterized in that it is an emulsion polymer according to claim 1 contains. 3. Delayed drug release system Drug release based on Emulsion polymers, characterized in that the Emulsion polymer essentially free of Is emulsifiers or surfactants. 4. Delayed drug release system Active ingredient release based on esters of Acrylic and / or methacrylic acid, thereby characterized in that the emulsion polymer in essentially free of emulsifiers or surfactants which are extractable with water. 5. active ingredient release system according to claim 3 or 4, characterized in that as a carrier material serving emulsion polymer from the group Polylactide, polystyrene, polyvinyl acetate, Polyvinyl pyrrolidone, polybutadiene, polyacrylonitrile, the polyvinyl ester, the polyvinyl ether and their Copolymers and their mixtures was selected.   6. Active ingredient release system according to one of claims 3 or 4, characterized in that the as Emulsion polymer serving as carrier material Polymer based on methyl and / or Ethyl ester of acrylic acid and / or methacrylic acid embodies. 7. active ingredient release system according to one of claims 3 to 6, characterized in that it is active ingredient Clonidine (2 - [(2,6-dichlorophenyl) imino] imidazolidine) contains. 8. Active ingredient release system according to one of claims 3 to 6, characterized in that it is an active ingredient Clenbuterol (4-amino-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol) contains. 9. Process for producing a substantially of Free emulsifiers or auxiliary substances Emulsion polymer, characterized in that the emulsion polymer - if necessary after Remove volatile components - with a Extractant treated in the Polymer itself does not dissolve or does not dissolve significantly and emulsifiers or surfactants and others Excipients extracted. 10. Process for producing a Drug release system based on an or several emulsion polymers, thereby characterized in that one or more according to Claim 8 produced emulsion polymer (s) with one or more active ingredient (s) per se known way.