DK144872B - PROCEDURE FOR THE PREPARATION OF PYRAZOLONE-CONTAINED TABLETS - Google Patents

Description

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The invention relates to a process for preparing small, mechanically stable and durable tablets containing one or more pyrazolones and optionally additional caffeine compounds, relative to the dosage of the active substance.

The preparation of tablets containing analgesically and antipyretically active pyrazolone compounds, with good pharmaceutical and mechanical properties, is difficult and can mostly be obtained only in part by the addition of high amounts of excipients.

Medically used pyrazolone compounds with and without the addition of caffeine compounds, e.g. dimethyl-aminophenyldimethylpyrazolone, phenyldimethylpyrazolone, isopropylanthipyrine, phenyldimethylpyrazolone methylaminomethanesulfonic acid sodium and combinations of dimethylaminophenyldimethylpyrazolone and phenyldimethylpyrazolone methyl-aminomethanes

The substances often exhibit poor flow conditions and must therefore be mixed with relatively high amounts of excipients. These compositions are processed according to the state of the art - mostly after prior wet or dry granulation - in known manner into tablets.

Due to the poor tableting properties of most tablets, weighing from 0.3 to 0.55 g containing relatively high doses of active substances, tablets manufactured according to the state of the art already show a tendency for low formation, high wear and tear at the time of manufacture, packaging and storage. and cracking. This also makes it very problematic to pack such tablets in modern push-through packs because the tablets when removing such packs often break.

When pressed at higher pressure, the mechanical properties of these tablets are only slightly improved. However, their degradation times increase quite significantly.

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The tendency for lid formation of the tablets is particularly strong when pressed with biconvex and not round pistons, so that generally only generally considered round tablets with 5 flat surfaces can be manufactured industrially.

Analgesic tablets containing pyrazole lones are mostly similar in size to their dosage. They have e.g. at an amount of active substance of 500 mg a tablet final weight of up to 750 mg at 10 a diameter of 13 mm. Such tablets can only be badly swallowed whole. Their degradation time depends on the pressure of the pressure. In addition, they also show an uncommon tendency to harden during the course of storage.

Numerous attempts to avoid the above drawbacks, ie. on optimizing the mechanical properties, degradation and size of the pyrazone tablets, over the years has not yielded any significant results.

Pyrazolones tend to be discolored under the influence of oxygen, light and / or acids of any kind and to form eutectics. For these reasons, the choice of suitable excipients for the preparation of tablets with these active substances is of particular importance for the stability of the preparation.

From the literature, for example. known (H. Bohme, 25 K. Hartke, Deutsches Arzneibuch, 7th edition 1968, commentary, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 1969, page 1241 penultimate paragraph) that polyglycols are incompatible with a number of substances. For aminophenazone (dimethylaminophenyldimethylpyrazolone) as a prototype for the 30 pyrazolones, discolourations with polyglycols are described in the above literature.

According to the state of the art, therefore, it could not be expected that polyglycols known per se as water-soluble adjuvants (binder) for tablets could be suitable for the tableting of pyrazolones.

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Contrary to what is known from the literature, it has now surprisingly been found that with small amounts of excipients, also in vaulted oblong form, durable pyrazolone tablets, which can be aspirated as much as 5 and with respect to the dosage of active substance, are small, according to the method of The invention is characterized by the addition of polyethylene glycols 2000 to 20,000 in concentrations between 5 and 40% and optionally a lubricant, and the mixture, after prior granulation, is compressed into tablets. The addition of polyglycol is preferably less than 25%. Each tablet preferably contains 300 to 600 mg of active substance.

The tablets thus prepared can be suctioned virtually without any aftertaste and without flushing with water. They decompose in artificial gastric juice at 37 ° C for a few minutes during the release of the active substance as the added excipient is well water-soluble.

Their durability is also immutable in the usual trope-like stress test and, above all, these tablets show virtually no tendency to stain discoloration. Also the mechanical properties which are understood include no tendency for lid formation or cracking is excellent, so that even a pack in 25 modern penetration gaskets is possible.

Furthermore, it is new and surprising to those skilled in the art that only an addition of small amounts of polyglycols in an amount ratio of from 5 to 40% leads to optimal tablets in any desired form (e.g. in the form of 30 easily visible, vaulted oblong tablets ) can be pressed and possess both good mechanical and pharmaceutical properties.

Finally, the present process is simplified in relation to the prior art, in addition to using only one lubricant, namely polyethylene glycol, supplementary auxiliaries are used in GB Patent No. 1,033,684 in addition to polyethylene glycol.

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The tablets can be coated with a film or a coating coating optionally with aromatic additives for protection against external influences and for flavor camouflage.

Example 1

Tablets with 0.5 g of phenyldimethylpyrazolone methylaminomethanesulfonic acid sodium are prepared.

composition:

Phenyldimethylpyrazolone methyl-10-aminomethanesulfonic acid sodium 500 mg

Polyethylene Glycol 4000 47 mg

Magnesium stearate 3 mg 550 mg Preparation

Phenyldimethylpyrazolone methylaminomethanesulfonic acid - sodium is granulated with polyglycol to a grain size between 2 mm and 0.3 mm. Magnesium stearate can be added to the mixture or granulate.

The granulate is pressed into vaulted oblong tablets (length 16 mm and width 8 mm) with a final weight of 550 mg.

The tablets have excellent mechanical properties.

They completely decompose in artificial gastric juice according to the method described in "Deutsches Arzneibuch" after a maximum of 8 to 10 25 minutes.

Example 2

Tablets are prepared from 0.2 g of dimethyl-aminophenyldimethylpyrazolone and 0.3 g of phenyldimethylpyrazolone methylaminomethanesulfonic acid sodium.

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composition;

Dimethylaminophenyldimethylpyrazolone 200.0 mg

Phenyldimethylpyrazolone methylamino methanesulfonic acid sodium 300.0 mg Polyethylene glycol 4000 97.0 mg

Magne s in vims tear at 3.0 mg 600.0 mg

manufacturing

The mixture of dimethylaminophenyldimethylpyrazolone and phenyldimethylpyrazolone methylaminomethanesulfonic acid sodium is granulated with polyglycol to a grain size between 2 mm and 0.3 mm.

The mixture or finished granules are added to the magnesium stearate.

The granulate is pressed into oblong tablets (length 16 mm and width 8 mm) with a final weight of 600 mg.

The tablets have excellent mechanical properties and can be conveniently sucked whole. They are broken down in gastric juice according to the method described in "Deutsches Arzneibuch" over approx.

20 10 minutes.

Example 3

Tablets with 500 mg phenyldimethylpyrazolone with caffeine citrate are prepared.

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composition;

Phenyldimethylpyrazolone with caffeine citrate 550.0 mg

Polyethylene glycol 4000 74.0 mg

Magnesium stearate 1.0 mg 30 6 2 5 mg

manufacturing

Phenyldimethylpyrazolone with caffeine citrate is granulated with polyglycol to a grain size between 3 mm and 0.3 mm.

35 Magnesium stearate is added to the mixture or granulate.

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The granulate is pressed into oblong tablets (length 17 mm and width 8 mm) with a final weight of 625 mg.

The tablets have excellent mechanical properties and can easily be swallowed whole. They are completely decomposed in artificial gastric juice according to the method described in "Deutsches Arzneibuch" after a maximum of 10 minutes.

Example 4

Tablets with 0.3 g of dimethylamino-phenyldimethylpyrazolone are prepared.

composition:

Crystalline dimethylaminophenyldimethylpyrazolone 300 mg

Polyethylene glycol 6000 117 mg Magnesium stearate 3 mg 420 mg

Preparation:

Dimethylaminophenyldimethylpyrazolone is granulated with polyglycol to a grain size between 2 mm and 0.3 mm.

Magnesium stearate can be added to the mixture or granule.

The granulate is pressed into vaulted oblong tablets with a final weight of 420 mg.

The tablets have excellent mechanical properties.

The tablets are completely decomposed in artificial maize juice according to the method described in "Deutsches Arzneibuch" after 8 to 10 minutes.