DE1492011A1 - Enterally coated dextran sulfate ester tablets and process for their manufacture - Google Patents

Description

MÖNCHEN NUSSBAUMSTRASSE 10 DIPL.-ING. W. NIEMANN phone = 55547 «

HAMBUeO

W. 10956/62 7 / Nope.

Meito Sangyo Kabushiki Kaisha Nagoya (Japan)

Enteral coated dextran sulfate tablets and methods of making them

The invention relates to enterally coated Tablets made from water-soluble salts of extrane sulfate ester, which are useful for oral administration and a method for their preparation. In particular the invention relates to dextran sulfate ester in tablet form, i.e. the form which is best suited for the oral administration of this drug, which is

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possesses excellent medicinal properties, in particular since it has essentially no effect as an itnticoagulant, but rather has a very high lipolytic activity, and on the process of making these tablets. Until now · became this water-soluble salt of duxtran sulfate ester never administered orally and especially not in tablet form, but it was called directly into the bloodstream

k administered intravenous or intramuscular injection.

More particularly, the invention relates to enterally-coated Dextransulfatestertabletten, with a water soluble salt of dextran sulfate esters, which is uniformly and evenly coated with an enteric o ^r berzugsmaterial which / ert in an imitation or simulated lia ^ enflüssigkeit having a pH V below 3, 0 is insoluble, but dissolves or disintegrates in an imitation or simulated intestinal fluid with a pH value of 5.0 - 8.0, and a method for producing this

* Tablets.

Bieher was believed to be a water-soluble "salt of dextran sulfate ester would only be effective when administered parenterally and consequently it became exclusively direct administered into the bloodstream by intravenous or intramuscular injection. However, if a water soluble salt

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of dextran sulfate ester for the purpose of treating hyperlipemia is used, it turns out that - even if the dose used is lower than when used as Anticoagulant, since its use must be continued during an extended period of time - this continued Administration inevitably creates an obstruction which occurs in the coagulability of the blood. Consequently the clinical application of sulfated polysaccharides in the treatment of arteriosclerosis is hindered been.

In this context, it was found that a water-soluble salt of dextran sulfate ester which meets the specific conditions of a value within a specific range, ie a value of 0.020 to 0.050 (in a 0.7 molar salt solution at 25 ^° C.) ) and with a sulfur content within a certain range, ie an S content between 2.0 and 13 »0 wt.

In further investigations in the field of water-soluble baizeh of dextran sulfate ester, in particular with regard to a procedure to enable oral

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administration of these water-soluble salts of dextran sulfate ester, which so far have not been clinically for the various intended purposes for an extended period of time could be used with certainty, it was found that while maintaining their medicinal properties as Anticoagulant or llpolytisches agent when administered orally, the inactivation of these salts in the stomach can be prevented if these salts are used to prepare enterally coated tablets which are uniformly coated with a enteral coating material, which in a mimicked Gastric fluid with a pH below 3.0 is insoluble, but dissolves in or dissolves in an imitation intestinal fluid with a pH of 5.0 to 8.0 disintegrates, are overspray.

In surprising catfish it was also found that in the case of these enterally coated tablets, even when using a dextran sulfate ester with this property, that it was not useful as a lipolytic agent, whereby a high level of anticoagulant activity occurs naturally »if it is used as before, i.e. when it is fed directly into the bloodstream by parenteral administration, such as by intravenous or intramuscular injection, or even if the administration is for an extended period of time, which is convenient for the same reasons was not feasible, carried out, the intended medicinal properties are effectively retained, and Although there was no bad reaction, this medical property wore off adversely affect or hinder what the

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Oral administration of these tablets is made outwardly convenient.

So far, associations have been carried out for the oral administration of sulfated polysaccharides, whereby they were used in combination with certain salts of ethylenediaminetetraacetic acid (EBTA) in order to thereby make use of the Ca ⁺⁺ and Mg ⁺⁴ "* - scavenging activity of ethylenediaminetetraacetic acid ( iJDTA) is capable of removing the metal ions from the polysaccharides, which could have an influence on the inactivation of the polysaccharides Gastric juices could not be adequately protected, the presence of many factors making a simple decision that the mechanism of inactivation necessarily due to the activity of the Ca ⁺⁺ or Mg ⁺⁺ ions alone more difficult} it has also been found that if not a considerable amount of E DTA is used, it was not even possible at all to prevent the effects of these metallic ions to a satisfactory extent.

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With the biological toxicity (LDc ₀ ), which was determined by intravenous injection of mice below 50 mg per kg, the administration of such a substance is not only undesirable but actually quite dangerous in a considerable narrow and, moreover, for an extended period of time .

Accordingly, it is a general purpose of the invention to provide an enterally coated tablet which which enables the oral administration of water-soluble salts of dextran sulfate, which heretofore practically not was feasible.

Another purpose of the invention is to provide an enterally coated tablet of dextran sulfate ester, in which the water-soluble salt of the dextran sulfate ester, which was previously administered directly into the bloodstream by intravenous or intramuscular injection was absorbed through the digestive system and was safe and can be administered for an extended period of time while maintaining its medicinal properties be.

Another purpose of the invention is to provide a method of making these orally administrable ones Compositions

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Other purposes and advantages of the invention are also can be seen in the description below.

In general, the gastric juice is strongly acidic while the intestinal fluid is alkaline. With a more precise one Examination shows that the pH of the gastric juice is below 3.0, and if this acidic juice moves along and with the alkaline Darta liquid im Duodenum vermisolite, its pll-7ert reaches a height from about 3.6-6.6, and between the jejunum and ilium (from jejunum to ilium) from about 3.6 - 7.9 »while only near the öri jadarms (middle part of the large intestine "color") a pH above 7 is given. In any case it is certain that the gastric fluid does not calibrate suddenly changes from acidic to alkaline. Accordingly, with regard to the material, which is considered to be more enteric (Enterally soluble) film should be used, the requirement that it is such, which on the one hand at all is not subject to any changes in acidic medium with a pH value below 3 * 0 or at least 5 bie Is not attacked for 6 hours, while on the other hand it turns as quickly as possible in a weakly alkaline Medium, i.e. weakly acidic or at a pH value of approx

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7.9 dissolves or breaks down into components. In addition, it is required that it is not attacked by digestive enzymes (peptio enzymes) in the agar fluid and that it has no resistance to the constituent parts of the Daroflueeigkeit.

Although the mechanism by which the sodium or potassium salt replaces or inactivates the dextran sulfate ester in the stomach has not been fully clarified, it can be seen that this is not only due to the influence of the metal ions, such as Ca ⁺ or Mg ⁺ , alone in the gastric fluid , since the effects of the various enzymes must not be overlooked. Therefore, even if a substance such as EDTA is added to the administration of the above salts of dextran sulfate ester, satisfactory results may not be obtained either. It is actually quite dangerous to administer such a toxic substance in large quantities over an extended period of time.

According to the invention, the water-soluble salt of dextran sulfate ester, while being substantially unaffected at least in the stomach, becomes satisfactory in gut absorbed, and the use of the water-soluble salt of dextran sulfate as a lipolytic agent, welohe hitherto even when administered parenterally by intravenous

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or intramuscular injection, apart from its use ala coagulant, which was not feasible, has not only been made possible, but ee can also be continuous Administration of a dosage over an extended period of time which has not previously been used could now be carried out in a safer and more effective manner.

Dae enteral covering material which is used for this purpose is to be used, must be one which is in a fake liquid with a pH value is insoluble below 3.0, but dissolves in a simulated intestinal fluid at a pH of 5.0 - 8.0 or falls within it.

The cited here imitation or simulated gastric fluid has the following composition, whereby its pH V ^f ert means Hinetellung the amount of hydrochloric acid therein to less ALB 3.0 can be controlled:

NaCl 1.4 g KCl 0.5 g CaCl ₂ 0.06 g pepsin 3.2 Q HCl Appropriate amount Distilled water Rest to 1000 ml total quantity 1000 ml

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On the other hand, the one listed here has a counterfeit or simulated intestinal fluid the following composition, Weobei you pll-Vfert by regulating the amount of sodium carbonate ai f 5 »0 - 8.0 set v / ground kunn:

NaHCO, Appropriate amount

Pancreatic juice 2.8 g

Distilled tea V / ater Appropriate amount

Total amount 1000 ml

According to the invention, substances which are valuable as an enteral coating material comprise one or more the following substances listed as examples: sodium alginate, potassium alginate, ammonium alginate, cellulose acetate phthalate, Sodium cellulose acetate phthalate, potassium cellulose acetate phthalate, Ammonium cellulose acetate phthalate, cellulose acetate dialeate, sodium cellulose acetate maleate, potassium cellulose acetate maleate, Ammonium cellulose acetate maleate, polyvinyl alcohol phthalate, Sodium polyvinyl alcohol phthalate, potassium polyvinyl alcohol phthalate, ammonium polyvinyl alcohol phthalate, Polyvinyl alcohol raleate, sodium polyvinyl alcohol maleate, Potassium polyvinyl alcohol maleate and ammonium polyvinyl ~ alcohol aleate. In particular, however, are the water-soluble. Salts of alginic acid such as sodium alginate, potassium alginate and ammonium alginate are suitable.

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Any water-soluble salt of alginic acid, for example its sodium salt, is βineβ with an absolute viscosity of 500 cp in a 1 - ^ 'strength aqueous solution at 20 ⁰ C suitable. If rapid results in the intestine are desired, salts of low viscosity are preferred. Usually, however, a salt in the range of 60 to $ 00 cp is particularly suitable, the thickness of the coating having little effect on its solubility in the intestines or intestinal tract.

The water-soluble courtiers of alginic acid, as well as the others Enteral coating materials, to a minor extent, have the nature of a semi-permeable membrane. If so the i-iediain contained therein from a readily soluble substance exists, a certain diffusion takes place from the inside as well as from the outside, and it exists the possibility that exudation of the contained therein occurs. By looking at the surface of the foregoing Coating a solution of acetoglyceride (an acetylated product of an aliphatic glyceride with fatty acids, which usually have 12 to 20 carbon atoms) and one harmless wake-up substances, such as beeswax, cprnauba wax, Plant Waohs, Ibotawax, synthetic wax or the like. That is dissolved in an organic solvent, sprayed on,

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the semi-permeable & embrannatur <* ^ΘΓ alginates can be overcome.

The thickness of the coating layer of the enteric coating material is suitably 0.05 to 1.0 in particular between about 0.1 to 0.5 mm. Besides, it is in view of the fact that the water-soluble salts of dextran sulfate ester are extremely unstable in the stomach and that theirs Activity tends to decrease easily with moisture, particularly desirable that the LiberBugeechioht is uniform and that in the execution of the tJ a powdered layer is formed by coating with powdered material. In the process which consists in the fact that the coating material in an organic Solvent dissolves and then applies, occur in the formed coating on the surface of the manufacture Inconsistencies or malfunctions due to the phenomenon of heavy sticking which occurs during the volatilization of the solvent stops. As a result, the coating tends to be uneven and consequent poor training. If, in order to prevent this, the coating is made thicker, prevention can be achieved its rapid disintegration in the intestinal fluid.

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V / βηη Natrlumdeattransulfat tablets containing (which has an intrinsic viscosity of 0.02 to 0.05 in a 0.7 molar salt solution at 25 ⁰ C and a i, chwefelgehalt of 13.0 wt $ or above possess.) To enteral-soluble Preparations according to the method of the invention were formed and examined, the product produced according to the invention - although the untreated product, which is decomposed or inactivated by the gastric juice, was not suitable for oral administration - showed complete lipolytic activity and caused im If the dosage is favorable, there is no prolongation of the coagulation time.

Ee was thus made possible for the first time by the invention, oral administration of the water-soluble salt of dextran sulfate ester safely and for extended periods of time in the treatment of Hyperlipäi ^ Le or allied Diseases such as atherosclerosis or the like. apply.

In the experiment in vitro with this pharmaceutical preparation which changes its ZuBtandes been determined according to ^A ERIFICATION of enterically coated preparations, as described in the 6th edition of Japanese Pharmacopoeia, observed. It was found that there were absolutely no abnormalities such as abrasion, damage or the like. of the coating in

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a simulated gastric fluid was detected. On the other hand, the preparation disintegrated in an imitation liquid within 10 pounds 60 minutes. While trying with the simulated r.lagenflüHSigkeit, whereby a Examination in particular of the Ausechwitzung of the dextran sulfate ester, of the drug contained in the preparation, by means of the metachromatic reaction using Toluidine Blue (Toluidine Blue) was performed the result for at least a period of 2 hours negative.

Then in vivo experiments were carried out using four normal dogs, which weighed between 7 and 10 kg, which in the fasted state (in faet) that ^x preparation according to the invention was administered orally in amounts of 10 mg, 20 mg, 30 mg or 75 mg, given in mg of dextran sulfateater per 1 kg of body weight. Then blood was taken every two hours and the effectiveness of the enteral coating was assessed by examining the changes in the blood memory time with the passage of time and the lipoleptic activity at the respective dosages.

On the basis of these results it was observed that during the administration, given in amounts of dextran sulfate ester (with

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an intrinsic viscosity of 0.03 in a 0.7-raolaren chloride solution at 25 ⁰ O and with a kchwefelgehalt 18.0 #) 10 to 30 rag hardly any extension of the coagulation time showed the administration of a 75 mg bestimnte extension showed. On the other hand, it was confirmed that the lipolytic activity was clearly retained in all cases.

Regarding the determination method, the blood clotting time determined according to the Lee Whitis method, while the lipolytic activity by the ability of the so-called active plasma-containing lipoprotein lipase, which in the blood is established by the oral administration of the preparation according to the invention, the emulsion of composition described below in a test tube to clarify what constitutes the lipemia clearing factor, was measured.

Here, every two hours after the administration, blood was withdrawn by means of a syringe, into which 0.2 cm a 10- ^ igen citrate solution was introduced, whereupon this Was centrifuged for 5 minutes to separate the plasma. A cur of it became 10 cm of a 1/15 molar Phoe phosphoric acid buffer solution (pH 7t4) together with two drops a 20% sesame oil emulsion added, which is then 25

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human plasma (using dried normal human plasma). After mixing with 2 onr emulsion incubated for one hour at 37 ° C, the turbidity was measured at 630-650 μm using a photoelectric colorimeter, this measurement being designated A * Subsequently, after incubating this mixture for two hours at 37 ^° C., its turbidity was again measured in the same way, this measurement being indicated by B. The decrease in turbidity, ie AB (reproduced in "long T") gives the lipolytic activity.

On the other hand, when tablets of dextran sulfate ester without enteral coatings were orally administered to a normal dog so that the dosage was 75 mg / kg in terms of bextran sulfate ester, and the extent of the absorption was checked, there was neither prolongation of blood coagulation nor evidence of lipolytic activity observed. Moreover, from the results of experiments made when administering the DeKtraneulfate ester preparation according to the invention to humans, an interesting fact was observed that, depending on the amount administered, lipolytic activity occurs.

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could be caused without prolonging the clotting time.

In the manufacture of the enterally coated tablets γόη dextran sulfate ester according to the invention, become the Drug containing a water-soluble salt of dextran sulfate ester, diluent as base and Lubricants such as starch, lactose, glucose, dextrin, talc, etc. added and then according to common practice Tablets were prepared to form the uncoated tablets.

Once caulking and undersealing has been applied to the tablets in accordance with standard practice, they will be then evenly with an enteral coating material, which is mixed in with a sewn gastric fluid a pH below 3.0 is insoluble, but in a well-groomed intestinal fluid with a pH of 5.0 to 8.0 dissolves or disintegrates, coated. Furthermore, the outside of the tablets is coated with aoetoglyceride and a whitening substance.

According to the invention, coating with the above enteral coating material becomes extremely effective in this its powdery state carried out. In education the powder boil, after a seal and Unteraohioh-

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device has been applied to the surface of the uncoated tablets, a commonly used adhesive such as gelatin, gum arabic, sugar or the like is used. applied to the tablet surface. A powdered, water-soluble salt of alginic acid is then applied and, if necessary, the application of the adhesive and the above powder is repeated several times, whereby a continuous coating of a powder layer of the water-soluble salt of alginic acid is achieved and in this the desired thickness of the itilschlioht is formed. Up to now, the usual practice for this type of coating has been to dissolve the coating material and to form the film on the tablets either by spraying, brushing or other means, but this type of coating is not desirable in the case of the water-soluble salt of dextran sulfate ester.

Sealing, making sub-layers and smooth Coating, polishing, etc. can be carried out according to conventional methods, with the required ones as desired or necessary changes can be made.

The invention is explained in more detail below with the aid of the examples

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example 1

To 600 g of powdered sodium sal of dextran sulfate ester (intrinsic viscosity 0.025, sulfur content 16.9 IA , 432 g of starch and 120 g of lactose were added and the mixture was thoroughly mixed 12 g of stearic acid ester of polyoxyethylene and 12 g of isopropyl myristate dissolved in 100 g of anhydrous ethyl alcohol were added to this substance from the intestine and mixed thoroughly. After air-drying at room temperature, 24 g of talc was added as a lubricant and the mixture was then formed into tablets, each of which was 300 mg in size 15 g of the liquid mass from batch 1 were poured into the ng and lower layer. After the liquid evenly moistened or wetted the tablets and some of them began to dry and stickiness appeared,

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50 g of sodium alginate powder (with a particle size which through a sieve with a masoh number of about 2750 Mesh / cm (120 mesh) went, and with 60 op) sprayed or sprinkled over the tablets and poured into the container for 5 minutes in rotation, with warm, Dehumidified air was blown in and the powder excess was removed while at the same time drying was accelerated. After the first eribral coating was dried, the same liquid mass was used in increased amounts of 30 g and then 55 g, whereupon the sodium alginate powder was sprinkled over and the coating was dried. Several 45 g portions of the as Liquid Hasse shown in batch 2 was added and the drying process was repeated, as a result of which the semipermeable membrane nature of the sodium alginate coating was overcome grinding operations are carried out in accordance with well-known methods to thereby produce the finished products to obtain·

The weight of the enterally coated tablet prepared according to this process is 600 ag, where Your sodium alginate coating in the liquid about 30 - 50 ng weighs.

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These tablets showed no change in simulated gastric fluid, but somewhat disintegrated Minutes in a simulated Darrafluid.

Anaat »1

Gelatin 3 g

Gum arabic 3 g

Zuoker 28 g

Water 66 g

Total 100 g

Seed »2

Beeswax 10 g Acetyl monoglyceride 10 g Carbon tetrachloride 80 g

Total 100 g

If the tablets produced according to this example are given orally to patients suffering from arteriosclerosis continuously in an amount of 15 mg / kg, indicated as Dextrane sulfateeter «Terabreloht and the total cholesterol that free cholesterol «· and the o / p value were measured, the results in all lulls showed a remarkable decrease.

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would take. If on the other hand the effects of this drug contributes to the coagulation behavior of healthy living things continuous oral administration of these tablets over a period of 90 days in an amount of 50 mg / kg per day were observed, the results showed no prolongation of the coagulation period.

Example 2

The procedure of Example 1 was followed with the exception repeats that instead of clay sodium alginate, a total of about 80 g of sodium oellulose acetate phthalate was used.

The weight of the enterally coated tablet of dextran sulfate ester obtained was 600 rug and its thickness Powder layer of sodium cellulose acetate phthalate was about 0.1mm.

This tablet showed no change in simulated gastric fluid, but fell in about 30 minutes in simulated intestinal fluid. When this tablet was orally administered to patients suffering from atherosclerosis, the results were substantially the same as those of Example 1.

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Example 3

The procedure of Example 1 was followed with the exception repeats that instead of sodium alginic acid, about 150 g Sodium polyvinyl alcohol phthalate were used.

The weight of the enterally coated tablet obtained was 600 mg and the thickness of its 1 / ulverschiclit of sodium polyvinyl phthalate was about 0.2 mm.

The results of the in vitro and in The tests carried out in vivo were practically the same as in Example 1.

Example 4

To 600 g of powdered Hatriura salt of dextran sulfate ester (£> / _7Φ »(Η8, sulfur content 19.5 #) were added 432 g of starch and 120 g of lactose and thoroughly mixed with them the absorption of this substance into the system from the intestine a mass of 12 g of tftearic acid ester of polyoxyethylene and 12 g of isopropyl myristate, dissolved in 100 g of anhydrous ethyl alcohol,

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added and mixed thoroughly. A suitable amount of anhydrous ethyl alcohol was then added to the above mixture and the flake was granulated or granulated. Wax air drying at room temperature 24 g of talc was added as a lubricant, whereupon ron from the mixture tablets of a size were formed 300 mg. 1000 g of the thus obtained tablets, non-coated was placed in a shallow container coating and after the known sealing and sublayers is applied, hot air was eingeblaeen and heating the tablets to about 3O ⁰ C. Then the liquid Hasse from batch 3 was applied to the tablets by means of a spray device and after the tablets had dried, the spraying was carried out again. This operation was repeated several times, followed by application of a smoothing coating and grinding or polishing according to the known methods, whereby the finished product was obtained.

The weight of the enterally coated, accordingly The tablet produced by this method was 600 mg and the polyvinyl alcohol phthalate coating had a thickness of 0.05 mm and a weight of about 2 - 3 mg.

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This tablet showed no change in simulated gastric fluid, but disintegrated in about 50 minutes a simulated intestinal fluid.

Anaate 3

Polyrinyl alcohol phthalate 10 g A 50 t 50 rental of Alcohol {acetone 90 g

100 g

In an in vivo association with the one according to this example manufactured, enterally coated tablets were at a Dosage, expressed as dextran sulfate ester, of 30 mg / kg a significant increase in clotting time was observed.

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Claims (8)

ι ι Patents claims \ i)) Enteral plated Dextransulfatestertablette with a water soluble salt of Bextransulfatester, dae evenly with a enteral transfer course material coated let, which 1st insoluble in an imitation or simulated Hagen liquid having a pH below -from 3.0, but simulated in a counterfeit or Intestinal fluid with a pH in the range of 5.0 to 8.0 dissolves or breaks down in it. 2. Tablet according to claim 1, characterized in that the enteral coating material is one or more of the substances such as sodium alginate, xalium alginate, ammonium alginate, Cellulose acetate phthalate, sodium cellulose acetate phthalate, Potassium cellulose acetate phthalate, ammonium cellulose acetate phthalate, cellulose acetate maleate, sodium cellulose acetate maleate, potassium cellulose acetate maleate, ammonium cellulose acetate maleate, polyvinyl alcohol phthalate, sodium polyvinyl alcohol phthalate, potassium polyvinyl alcohol phthalate, ammonium polyvinyl alcohol alcohol phthalate, polyvinyl alcohol maleate, sodium polyvinyl alcohol maleate, kailum polyvinyl alcohol maleate or ammonium polyvinyl alcohol maleate. 909807/0934 3. Tablet according to claim 1 or 2, characterized in that the thickness of the layer of the enteral coating material is 0.05 * 1.0 mm, preferably 0.1-0.5 ram. 4. Tablet according to one of claims 1 to 3, characterized in that the enteral coating material aua one Powder applied as a coating, which contains one or more of the following substances: sodium, potassium and Ammonium salts of alginic acid, sodium, potassium and ammonium salts of cellulose acetate phthalate; Sodium, potassium and Ammonium salts of cellulose acetate maleate; Sodium, potassium and ammonium salts of vinyl alcohol phthalate and sodium, Includes potassium and ammonium salts of polyvinyl alcohol maleate. 5. Process for the manufacture of enterally coated Dextran sulfate ester tablets, characterized in that a medical preparation which is a water-soluble Salt of dextran sulfate ester contains, presses and thereby a Manufactures uncoated tablet and this tablet uniformly with an enteral coating material, which in a simulated hagen fluid with a pH value below 3.0 is insoluble but is itself in a simulated intestinal fluid with a pH in the range between 5.0 and 8.0 100t or disintegrates in it, Coated. BATH ORIGINAL 909807/0934 U92011 - 2ü - 6. Verfaliren according to claim f), characterized in that that one or more of the Substances: Natriurial ^ inat, Kaliunalginat, Aiur; oniumalginat, Cellulose acetate phthalate, sodium cellulose acetate phthalate, Potassium cellulose acetate phthalate, arimonium cellulose acetate phthalate, Oellulose acetate tutraaleate, liatrium cellulose acetate maleate, Potassium cellulose acetate maleate, amnionium cellulose acetate maleate, Polyvinyl alcohol phthalate, sodium polyvinyl alcohol phthalate, Potash polyvinyl alcohol phthalate, ammonium polyvinyl alcohol phthalate, ] 'olyvinyl alcohol maleate, sodium polyvinyl alcohol maleate, Potassium polyvinyl alcohol maleate or acunon polyvinyl alcohol maleate is used. 7. The method according to claim 5 or 6, characterized in that that the coating is carried out as long as the thickness of the layer of the enteral / coating material 0.05 - Has reached 1.0 mm and preferably 0.1-0.5 mru. 8. The method according to any one of claims 5 to 7 ₍ characterized in that the enteral coating material is applied in powder form to the tablet as a coating by causing its adhesion or gluing nittele a suitable adhesive, the sticking operation necessary several times is repeated. 90980 7 / 093-4 BATH