DE1937133C3 - Use of aluminum, calcium or magnesium mono-, di- or tristearate - Google Patents

Description

The invention relates to the use of aluminum, calcium or Magnesiummono- mono-, di- or tristearate in an amount of 0.001 to 0.2 wt .-% of the total mixture for the production of a pharmaceutical preparation with a bubble content of N-acetyl 'tyl -p-aminophenol in tablet form.

N-Acetyl-p-aminophenol is usually offered in the form of non-effervescent tablets. There are too Fizzy preparations known, which are available as powder or granules and in small bags or envelopes are packaged, such as from H e I w i g: Moderne Arzneimittel, Stuttgart 1967, page 47.

Tablets are of course more convenient for administration because nothing is spilled and Little letters or bags do not have to be torn open in a cumbersome way. Also in the Storage of tablets the oxidizing effects of z. B. atmospheric oxygen has a smaller surface exposed than when storing powders or granules. The disadvantage of the tablets, however, lies in their slow dissolution, which up to now has been accelerated by adding fizzy components. the However, effervescent tablets still do not dissolve quickly enough. Most of the time, undissolved particles float of the preparation on the surface or stick to the edge of the glass, so that they do not become Application.

The invention has set itself the task of overcoming these disadvantages. You achieve this by in the total mixture for the N-acetyl-p-aminophenol tablets 0.001 to 0.2% by weight of aluminum, calcium or magnesium mono-, di- or tristearate be used.

The effervescent preparation produced in this way, in the form of a tablet, has excellent solubility in water. It dissolves almost twice as quickly as the known preparations in tablet form.

It is known to use metal stearates, especially magnesium, calcium or aluminum stearates in def Manufacture of pharmaceutical tablets to be used as lubricants, sometimes mixed with Waxes, such as paraffin or beeswax, to increase the flowability of the granules to the feed and To facilitate tabletting and the exit of the tablets from the compression molds. Usually Magnesium stearate used is usually in amounts of 0.5 to 1.0 wt .-%, based on the Total mixture, used.

Metal stearates have not hitherto been used for soda preparations, since there is no need for this existed and the stearates of polyvalent metals are considered water-insoluble or water-repellent. For Conventional water-soluble tablets are known that the addition of stearates the dissolution of drug mixtures adversely affected (see. American Pharmaceutical Association, Scientific Edition, Volume 46, pages 236-239 and Journal of Pharmaceutical Sciences, Volume 52, December 1963, pages 1139 to 1144).

In contrast, it is surprising that the use of metal stearates in an amount which is too small to cause a dissolution, the dissolution a fizzy preparation with N-acetyl-p-aminophenol as an active ingredient in water has been significantly improved. In the Tablet production is generally an intimate mixture of all ingredients with a humectant, mostly water, processed into larger lumps, which are then ground into granules, the

κι is then compressed into tablets. One takes indicate that the metal stearate in the soda preparations according to the invention reduces the adhesion of the individual particles decreased within the granules and thus within the tablets, so that the tablets when Ingress of water will fall apart faster and due to the larger ones available Surface can be dispersed and dissolved faster.

If less than 0.001% stearate is used, the is Little effect. In addition, even

2 »Difficult compositions with such low levels Make additives. With more than 0.2% stearate, the hydrophobic effect of the stearate becomes noticeable and prevents the penetration of water into the tablet, so that the dispersion and dissolution time

2 '> rises again. Accordingly, according to the invention, 0.001 to 0.2 and advantageously 0.001 to 0.004 and in particular 0.01 to 0.02% by weight of stearate is used.

As already mentioned, aluminum, Calcium and magnesium stearates, namely as mono-,

jo di- or tristearates. Also commercial stearates that can also contain palmitates or sometimes oleates are suitable.

The effervescence is applied in any way, usually with an alkali carbonate or alkali bicarbonate achieved in cooperation with an aliphatic polycarboxylic acid. Are particularly suitable Sodium and potassium carbonate or bicarbonate and citric acid or tartaric acid. One is also beneficial Addition of sorbitol, which according to GB-PS 10 02 393 the rate of absorption of N-acetyl-p-aminophenol elevated. It is true that sorbitol generally delays dissolution because of its sticky nature wet state, but this disadvantage does not occur when using the invention. As another

• r, constituents can in the use according to the invention z. B. codeine or caffeine, also lauryl sulfate as a surface-active agent, as well as sweeteners, ζ. Β. Saccharin and glutamic acid, which is particularly useful in the case of bitter-tasting active ingredients, as

-, o common substances in N-acetyl-p-aminopheno! containing Tablets are incorporated.

example

For producing a Hot Geyser Spring Y according to the invention, the preparation were the following substances after boiling intimately mixed together:

Components mg each
tablet kg each 65,000 500.0 Tablets N-acetyl-p-aminophenol 50.0 32,500 Sorbitol powder 10.0 3,250 Saccharin (sodium salt) 8.0 0.650 Codeine phosphate 30.0 0.520 Caffeine 0.9 1,950 Glutamic acid 0.1 0.059 Sodium lauryl sulfate 1346.2 0.0065 Sodium bicarbonate 87,500

This mixture was moistened with water and then mixed with 9?, 3.0 mg per tablet, corresponding to 60.00 kg per 000 tablets, of anhydrous citric acid. This mass was spread out on metal sheets, ^{dried at 80 °} C. and then sieved into a mixer and homogeneously mixed in an amount of "> 153.8 mg per tablet, corresponding to 10.00 kg per 65,000 tablet batch. The granules obtained were converted into tablets of about 3 g of compressed material was then dried at low humidity ι ο

The approaches were mixed with different stearates, the stearate together with the last added sodium bicarbonate was added. The tablet weight the thickness of the tablets and the Compression pressures were the same in all cases. Uniformly hard and brittle tablets were obtained. The solution quotes of the various tablets were measured. They are in Table I as average Dissolution speed in seconds depending on the amount of stearate listed 2 »

In Table II the maximum reduction in the solution time is given in%.

In particular, the following stearates were used:

2 ^r >

A) Magnesium stearate, probably a distearate according to U.S. P., 99.9% of which is a sieve with a clear mesh size of 0.053 mm passed. This material was up to an addition of 0.07% Suitable for stearate. At higher concentrations in, foam formed which settled on the container. As the stearate concentration increased, the bitter taste of the caffeine became noticeable, the with additions of more than 0.1% was noticeable unpleasantly. r>

B) Magnesium stearate, probably distearate according to BP with a bulk density of 0.16 g / cm ³ , with 99.9% passing through a sieve with a mesh size of 0.25 mm and 97 to 100% passing through a sieve with a mesh size of 0.075 . No deposits occurred in ^{4 <l of} the solution up to an addition of 0.05% stearate. As the stearate concentration increased, the bitter taste of the caffeine became noticeable. It was no longer acceptable above 0.05%. ^4>

C) Magnesium stearate, probably distearate, 100% of which is a sieve with a clear mesh size of 0.150 mm and at least 95% passed a sieve with a clear mesh size of 0.053 mm. The> o Solution was suitable with additives up to 0.05% stearate. The bitterness of the caffeine wore off unpleasantly noticeable at a content of over 0.08%.

D) Magnesium stearate, probably distearate, which '' only differed from stearate C in terms of grip and grip. Up to 0.05% gave good solutions, with higher additions considerable foaming occurred. The bitter taste of the caffeine made itself ^{unpleasantly noticeable at a content b} "of over 0.05%.

E) aluminum stearate, a distearate with 6.9% by weight of aluminum oxide, 1.5% of water, 14.8% by weight of fatty acid and 9.5 wt% ash content. 90% of the b5 material passed a sieve with a clear one Mesh size of 0.42 mm and 60% a sieve with a mesh size of 0.075 mm. the Solution showed no foam and no deposits in the entire area observed. However a slightly soapy taste was noticeable, that with a stearate content of over 0.03% resulted in an unacceptable product.

Aluminum stearate probably a distearate with 8% by weight of free fatty acid and a bulk density of 0.288 g / cm ^3. 100% of the material passed a sieve with a mesh size of 0.42 mm and 99.1% a sieve with a mesh size of 0.80 mm. The solution was excellent in the entire concentration range observed and was also not objectionable in terms of taste.

G) Aluminum stearate namely tristearate with a melting point of 105 "C, 33% by weight of free fatty acid, a specific density of 1.0 and a bulk density of 0.416 g / cm ^3. 100% of the material passed a sieve with a mesh size of 0.075 mm and 99% a sieve with a mesh size of 0.42 mm. The solution was free of foam and deposits in the entire concentration range observed. The bitter caffeine taste was unpleasant with additions of more than 0.04%.

H) aluminum stearate, namely a distearate with something Monostearate, 99% of which passed a sieve with a mesh size of 0.150 mm. the Solution was excellent across the concentration range. The bitter taste of caffeine became uncomfortable with a stearate content of 0.08% addition.

I) Aluminum stearate, namely a monostearate according to USP. This formed during the bubbling a foam that quickly collapsed. The solutions were up to an addition of 0.08% acceptable. The bitter taste of the caffeine became too strong at concentrations above 0.04%.

J) aluminum stearate, namely distearate with a bulk density of 0.32 g / cm ³ . Excellent solutions were obtained over the entire concentration range observed. As the stearate concentration increased, the bitter taste of the caffeine became noticeable. In 0.04% it was uncomfortable; however, it improved in the range of 0.08%.

The various magnesium stearates behaved similarly, but types A and B were the best. There were considerable differences in the aluminum stearates. Types I and J were the best. the Stearate solution is significantly influenced by the appearance and taste of the solution. In the case of magnesium stearates the preferred upper limit was 0.04% while aluminum stearate concentrations were up to 0.1% led to excellent results, provided that one of the influence on the taste of the Caffeine. In practical cases, a compromise must be made between the speed of the solution and the deterioration of the appearance and the taste of the solution are closed. Are best Concentrations from 0.01 to 0.02% and, in general, tablets containing aluminum stearate are better than such with magnesium stool.

Table I.

Wt%
Cfnorat Average B. : Speed of solution, D. Sec. E. F G H I. J o lea Γα ι A. 142 C. 142 142 142 142 142 142 142 0.0 150 103 H2 98 117 130 117 104 104 111 0.005 103 118 101 126 101 134 113 88 96 0.01 135 96 110 99 118 100.4 123 115 84 95 0.02 87 87 97 94 120 1OU 116 108 78 90 0.03 85 91 89 90 123 99 116 99 88 85 0.04 86 91 95 113 89.1 107 97 82.5 88 0.05 80 79 0.07 80 83 77 79 105 90 98 96 81 78 0.08 0.1 80 Table 11 Maximum Ver Stearate reduction of the Solution time in%

A Magnesium stearate (distearate) 46.7

B Magnesium stearate (distearate) 41.5

C Magnesium stearate (distearate) 45.75

D Magnesium stearate (distearate) 44.3

E aluminum stearate (distearate) 26

F aluminum stearate (distearate) 37.3

G aluminum stearate (tristearate) 31.0

H aluminum stearate (distearate and 32.3

some monostearate)

I aluminum stearate (monostearate) 45.1

J aluminum stearate (distearate) 45.1

Claims (1)

I.
Claim: Use of aluminum, calcium or magnesium mono-, di- or tristearate in one Amount from 0.001 to 0.2% by weight of the total mixture for the preparation of a pharmaceutical Fizzy preparation with a content of N-acetyl-paminophenol in tablet form.