DE1027847B - Process for the production of orally administrable medicaments - Google Patents

Description

GERMAN

The present invention relates to a method for the production of orally administrable medicaments, such as pills, tablets and the like, in which any fixed amount of an active ingredient with a gastric acid-resistant, enteric protective layer, consisting of a solid, non-brittle varnish is.

Orally administered medicaments provided with a protective layer are known. You're doing it with a varnish made from natural resins, balms, keratins, salol as well from synthetic resins containing free carboxyl groups, fatty acid esters or cellulose derivatives or Mixtures surrounded by it (see z. B. German Patent 575 792).

, Detailed studies have shown, however, that this ^one S meet certain conditions to use now retardants its purpose, it was that they take too little account of the PJJ ratios in the gastrointestinal and thus the active ingredients too early, too late or not at Development come, it is that the coating of the gastric resistant layers presents difficulties of a technical nature, in that the layers are drawn up irregularly, have cracks, or it is finally that the over-. After prolonged storage, traits are changed in such a way that they either lose their resistance to gastric acid or, on the other hand, are neither broken down in the stomach nor in the intestines.

It has now been found that these disadvantages can be avoided by using an alkyd resin made from an endoalkylene-tetrahydrophthalic acid and a polyhydric, especially dihydric alcohol, which also contains a liquid, unsaturated, higher fatty acid and shellac. Oleic acid, for example linoleic or linolenic acid, are particularly suitable as fatty acids. Endomethylene or endoethylene-tetrahydrophthalic acid glycol polyesters are preferably used as alkyd resins. The hydrophthalic acid components can carry substituents, e.g. B. alkyl radicals, such as methyl or isopropyl radicals. The alkyd resin made from 3-isopropyl-6-methyl-3,6-endoethylene- Δ ⁴ -tetrahydrophthalic acid and glycol has proven to be particularly favorable.

Said lacquer can have the three components in any proportions that result in a solid, non-brittle coating. Suitable mixing ratios are, for. B. 35 to 65% resin, 10 to 25 ° / ₀ fatty acid and 25 to 40 ° / ₀ shellac. An exceptionally good resistance to gastric juice, together with excellent solubility in the intestine, has the coating mixture from about 50 ° / ₀ alkyd resin of 3-isopropyl-6-methyl-3,6-endoäthylen-zl ^{4-tetrahydro-phthalic} acid and glycol, about 17 ° / ₀ oleic acid (9-octadecenoic acid) and about 33 ° / ₀ shellac.
The Pharmaceuticals Manufactured According to the Invention Process for Manufacture
of drugs that can be administered orally

Applicant:
CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney,
Hamburg 36, Neuer Wall 10

Claimed priority:
Switzerland on December 24, 1954 and November 30, 1955

Dr. Emil Lang, Riehen, Basel,

and Dr. Peter Speiser, Neue Welt, Basel (Switzerland), have been named as the inventor

can be any form suitable for oral administration, such as. B. of pills, tablets, coated tablets, Powder or the like, wherein the active ingredient is a medicament which is active or absorbable in the intestine is changed.

The drugs manufactured using the new process primarily consist of an active ingredient core, which is provided with the said lacquer coating. You can also use several layers in a manner known per se Contain medicines; so it is possible that a further layer of lacquer covering the active ingredient Acts off layer is present. In this way one obtains a preparation that can be used with the gastric juice before protective active ingredient contains a further dose of active ingredient combined, which already develop their effect in the stomach can. A dose of the medicinal product already present in the core can be used for the outer layer of active ingredient or another remedy can be used.

According to another embodiment of the method, granules and / or powder particles can also consist of Active substance can be provided with the paint mentioned. Such granules and / or powder particles, whose varnish coating is of different thicknesses can be combined to form an application unit, with which the duration of action is significantly influenced. If the onset of action is to take place quickly, it is preferable to set those units that, in addition to the particles coated with paint, also paint-free active ingredient, be it in powder or Granular form or as a shell of the lacquered parts included. The individual active ingredient parts can be made from

709 959/392

the same or different remedies.

These preparations can be produced by methods known per se. So the paint mixture can be used in one in a suitable solvent, such as chloroform-alcohol, can be applied by dipping the active ingredient core, pouring on and spraying or coating. By Correspondingly multiple or thicker applications of the lacquer layer, it is also possible to reduce the dissolving time in the intestine to influence and thus also to vary the development of the effectiveness of the core in the intestine over time. It is it is also possible, in order to increase the duration of action, to use individual particles of different thicknesses with an inventive To coat varnish, these more or less heavily coated granules or powder with to mix paint-free, granular or powdered active substance and in the usual way z. B. to tablets to process. As a variant of this embodiment, one can also use such mixtures instead of them To process tablets and the like, enclose them in capsules or wafers that are soluble in gastric juice.

Furthermore, several small ones, for example cylindrical ones, can also be used to extend the duration of action a varnish according to the invention, layers coated tablets on top of each other and that way The resulting plug-shaped structure is provided with a coating which is soluble in gastric juice.

The invention is described in more detail in the following examples.

example 1

Tablet tablets with an active ingredient content of 5 mg phenyl - cyclohexyl - oxy - acetic acid - dimethylamine - ethanol ester bromomethylate, a diameter of 6 mm and a gross weight of 80 mg are mixed in portions with a chloroform-containing alcoholic solution of 50% alkyd resin made from S-isopropyl- o-methyl-Sjö-endoethylene- ^! ^4- tetrahydrophthalic acid and glycol, 17% oleic acid (9-octadecenoic acid) and 33% shellac by pouring on, later painted by spraying in a coating pan. Between the individual additions of lacquer, small amounts of coating powder must be dusted in order to prevent the compacts from sticking together. The compacts are treated in portions with lacquer solution until the dried compacts have an average gross weight of 105 mg, where experience has shown that the layer thickness of the lacquer layer is 160 μ ± 10%.

The coated compacts are then, as is customary in coating, with a solution of gum arabic and sugar applied up to a gross weight of 110 mg; then with a solution of the above Active ingredient and sugar in water, which have been worked up with talc to form a suspension, further coated, until each coated tablet has a total of 5 mg phenyl-cyclohexyl-oxy-acetic acid-dimethyl-amino-ethanol ester-bromomethylate on the outer shell having. At the end, sugar is applied as usual.

In this dosage form of the active ingredient in the outer tablet coating during the active ingredient in the inner, protected by the varnish layer tablet core is only made freely about 2 _^1/2 to 4 hours after passage of the pylorus is cleared immediately after taking, as due to X-rays could be detected in many test subjects.

A similar result is obtained if, in place of the paint described, a paint consisting of 38% alkyd resin composed of 3-isopropyl-6-methyl-3,6-endoethylene / I ⁴ -tetrahydrophthalic acid and 1,2-propanediol, 24 % Oleic acid and 38% shellac were used.

Example 2

Tablet tablets with an active ingredient content of 250 mg of a-phenyl-a-ethylglutaric acid imide, a diameter of 10 mm and a gross weight of 335 mg are poured on in portions with a chloroform-containing alcoholic lacquer solution of the composition described in Example 1, later by spraying in a coating pan painted. Between the individual additions of lacquer, small amounts of coating powder must be dusted in order to prevent the compacts from sticking together. It is treated with lacquer solution until the dried compacts have a gross weight of 425 mg, where experience has shown that the layer thickness of the lacquer layer is 200 μ ± 10%.

A gum arabic-sugar-talc suspension is then applied in the usual way to a gross weight of 545 mg and finally the sugar-coated finish is carried out as usual. The active ingredient in the tablet core, which is protected by the stomach-resistant lacquer, is only released 2 ¹ ₂ to 4 hours after passing through the pylorus, as has been demonstrated on the basis of X-rays in many test subjects.

Example 3

A certain amount of sugar globules, so-called scatter globules, with an average weight of 50 mg, are treated in a coating pan with an alcoholic solution of phenyl - cyclohexyl - oxy - acetic acid - dimethylamino - ethanol ester bromomethylate, so that each globule contains 0.25 mg of this active ingredient having. A quarter of the resulting beads is removed from the kettle and the remaining three quarters are coated with a chloroform-containing alcoholic solution of 50% alkyd resin made from 3-isopropyl-o-methyl-3,6-endoethylene-Zl ⁴ -tetrahydrophthalic acid and glycol, 17% linoleic acid ( 9,12-octadecadienoic acid) and 33% shellac until the evenly applied and dried lacquer layers on the beads are about 60 μ thick, which corresponds to a resistance time of about 30 minutes in the artificial gastric juice. The second quarter of the beads is then removed and the remainder treated in an analogous manner with the gastro-resistant varnish until the layer thickness is about 110 μ, which corresponds to a resistance time of about 1 hour in artificial gastric juice. The third quarter of the coated beads is then removed from the coating pan and the remaining quarter is coated in the usual way until the coating thickness is about 160 μ, which corresponds to an approximate resistance time of 2 hours in artificial gastric juice at 37 ° C.

The unpainted beads and those with different paint layer thicknesses are mixed and filled in push-fit capsules or wafers made of natural or hardened gelatine or starch, the Ratio of the various proportions, such as the total amount of active ingredient, adapted to the type of action can be.

Example 4

With starch, gelatine, milk sugar, a-phenyl-cc-piperidyl- (2) -acetic acid ethyl ester hydrochloride and a little water, a perforated disk granulate is produced in the usual way, which per 10 g of dry granulate in total Contains 10 mg of active ingredient. The dry granulate is then divided into several portions, of which one leaves a part unpainted. A second part is covered with a thin layer of gastro-resistant varnish as follows Coated: 100 g of granules are coated with an alcohol-chloroform solution that described in Example 1

Lacquer, which contains a total of 7.5 g of solid resin parts, processed so that the granules produced in this way has a resistance time of about 30 minutes in artificial gastric juice at 37 ° C. A third part of the Granules, e.g. B. 100 g, painted with a paint solution which contains a total of 12.5 g of solid resin. The granules produced in this way have a resistance time of about 2 hours in artificial gastric juice from 37 ° C. Finally, a fourth part of the granulate, for example 100 g, is mixed with an alcohol-chloroform solution of the paint mentioned, which contains a total of 18 g of solid resin, processed. That so treated granules have a resistance time of about 4 hours in artificial gastric juice at 37 ° C. Man Now mixes the unpainted with the various thickly coated granules and fills into capsules or other Container, the proportion of the various proportions as the total amount of active ingredient the various physiological requirements can be adapted.

Similar granulate mixtures are obtained if, instead of the varnish described, one consists of 55% alkyd resin composed of 3-isopropyl-6-methyl-3,6-endoethylene- / ^{I 4} -tetrahydrophthalic acid and glycerol, 16.7% linolenic acid and 28 , 3% shellac, used.

Example 5

One paints part of a z. B. granules prepared as in Example 1 with an alcohol-chloroform solution of a varnish, consisting of 45% alkyd resin of 3,6-endomethylene /] ⁴ -tetrahydrophthalic acid and glycol, 15% oleic acid and 40% shellac, the layer thickness of the Lacquer in turn can be adapted to the requirements for disintegration in the stomach and intestines by the lacquer according to the invention. The coated granulate is then mixed with the other auxiliaries required for tableting, such as lubricants, fillers, disintegrants, etc., and a multilayered tablet is produced in a manner known per se. The granules can optionally be provided with the same active ingredients or different active ingredients, with one layer of the tablet preferably consisting of granules coated with a highly gastric-resistant varnish, another layer of granules with a low gastric varnish, while a further tablet layer consists of granules, which has not been treated with the paint according to the invention.

Instead of the paint described in this example, you can also use a paint consisting of 60% alkyd resin from 3-isopropyl-6-methyl-3,6-endoethylene-zl ⁴ -tetrahydrophthalic acid and glycol, 10% oleic acid and 30% shellac .

Example 6

1 kg of active substance, for example 2- (N-phenyl-N-benzyl-aminomethyl) ■ imidazoline hydrochloride, is mixed homogeneously with 3 kg of lactose and four fifths of the mixture is spread out in a thin layer. A spray gun is used to spray 100 g of the ^{paint solution described in Example 1, diluted with 250 cm 3 of} alcohol, onto the mixture, which has to be repositioned frequently. This is followed by drying in a vacuum or circulating drying cabinet at 40 to 50 ° C, and material that has been stuck together is comminuted again using a beater or pin mill. As described above, the powder is further treated with varnish, removing one fifth of the powder that has already been varnished, until resistance times of about minutes, about 1 and 2 hours in the artificial gastric juice and about 2 hours in the artificial intestinal juice are achieved.

ίο By appropriately mixing not, weak and heavily coated powder is achieved that the active ingredient when taking such a powder partially is absorbed immediately, partly in the stomach and partly in the intestine.

The mixed unpainted and varnished powders are divided into cachets or capsules. However, they can also be processed into granules or tablets or in the usual way Press coated tablets.

Claims (6)

Claims = 1. Process for the production of orally applicable Medicinal products in which any fixed amount of an active ingredient with a gastro-resistant, enteric lacquer coating is provided, characterized in that for the production of the solid, but not brittle paint, an alkyd resin made from an endoalkylene-tetrahydrophthalic acid and a polyhydric alcohol, a liquid, unsaturated, higher fatty acid, and shellac are used. 2. The method according to claim 1, characterized in that one in the manufacture of the paint a dihydric alcohol such as B. glycol is used. 3. Process according to claims 1 and 2, characterized in that in the preparation of the Lacks used a dihydric alcohol and oleic acid. +0 4. The method according to claims 1 to 3, characterized characterized in that an alkyd resin from S-isopropyl-o-methyl-S ^ -endoäthylen- /] ⁴ -tetrahydrophthalic acid and glycol, oleic acid and shellac is used to produce the lacquer. 5. Process according to claims 1 to 4, characterized in that one is used to produce the paint 35 to 65% alkyd resin, 10 to 25% fatty acid and 25 to 40% shellac used. 6. Process according to claims 1 to 5, characterized in that about 50% alkyd resin from 3-isopropyl-o-methyl-3,6 - endoethylene - Zl ⁴ - tetrahydrophthalic acid and glycol, about 17% oleic acid and about 33% shellac used. Considered publications:
German Patent Nos. 699 574, 646 035, 575 792; French patents nos. 1 027 621, 956 797,
551215; Indian Patent No. 25,868;
Chem. Zentralblatt, 1939, II, p. 168.