TABLETS CONTAINING S-CARBOXYMETHYLCYSTEINE

Abstract: Tablets or tablet kernels containing more than 10% by weight of S-carboxymethylcysteine are made of a blend of adjuvants comprising 1-5 parts by weight of mannitol, 0,2-2 parts of talcum, 0,2-2 parts of colloidal silica, 0,1-1 part of stearic acid or a salt thereof and 0,2-4 parts of starch on 1 part by weight of crospovidone.

Description: TABLETS CONTAINING S-tARBOXYMETHYLCYSTEINE AND PROCESS FOR THE PREPARATION THEREOF. Said invention relates to a tablet or tablet kernel containing S-carboxymethylcysteine and carrier and adjuvants known in carriers and adjuvants. Tablets containing S-carboxymethylcysteine are i.a. known from U.S. patent specification 3 891 749 (and German patent specification 2 006 486 corresponding thereto). S-carboxymethylcysteine has various activities of which thinning and dissolving phlegm in the bronchi (thus a diminution of the symptoms of bronchitus and pneumonia) is the most important one. (Vide French patent specifications 2 398 497, 2 430 945 and 2 506 614 and Belgian patent specification 887 922). Beside this it also decreases seborrhee (vide U.S. patent specification 3 671 643 and 3 950 542, British patent specification 1 051 870 and Dutch patent specification 152 169). As relatively high amounts of S-carboxymethylcysteine should be aministered (generalLy 2-2.5 g daily, often divided in 3 dosages) tablets with high contents of said substance are desired. Such tablets are hard to prepare. The properties of tablets or tablet kernels with modest content of active principle (up to about 1-2%) are completely determined by the lactose or the mixture of lactose and saccharose of which the tablet substantially consists in most cases, but for tablets and kernels with high contents of active principle the properties of the active principle itself are determining when compressing. In the above-mentioned U.S. patent specification 3 891 749 tablets are mentioned which per 100 mg of S-carboxymethylcysteine contain 100 mg of saccharose, 45 mg of starch and 5 mg of magnesium stearate. It appeared, however, that a granulate having this composition could not be compressed according to the practice of the art into tablets, the mass kept sticking to the dies. Also blends having closely similar compositions could not be processed at all into tablets or kernels. Moreover it may be expected the formulation described in U.S. patent specification 3 891 749, on account of the lack of tablet adjuvants for desintegration of the tablet according to the requirements of the international pharmacopeias, that the active principle will be insufficiently available to attain the clinical effect aimed at. This is supported by the fact that nowadays compositions containing S-carboxymethylcysteine are exclusively commercially available as mixture or capsules, having an equivalent biological availability. Consequently, in view of their pharmaceutical and technological possibilities to process high doses of S-carboxymethylcysteine,drinks, suspensions and capsules containing S-carboxymethylcysteine are still the obvious administration forms for high doses of S-carboxymethylcysteine. Now it was found that said objections are removed by a well realizable tablet ot tablet kernel if the adjuvants therein are a blend of 1-5 parts by weight of mannitol, 0.2-2 parts by weight of talcum, 0.2-2 parts by weight of colloidal silica, 0.1-1 parts by weight of stearic acid and/or salts thereof such as magnesium, calcium or aluminium stearate, and 0.2-4 parts by weight of starch on 1 part by weight of crospovidone, the S-carboxymethylcysteine content being from 10 to 90 % by weight. Preferably said adjuvants for tablets or tablet kernels are a blend of 1-3 parts by weight of mannitol, 0.2-1 part by weight of talcum, 0.2-1 part by weight of colloidal silica, 0.1-0.5 parts by weight of stearic acid or salt thereof and 0.5-2 parts by weight of starch on 1 part by weight of crospovidone,and preferably the content of S-carboxymethylcysteine is between 40 and 80X by weight. The best results are obtained with a tablet containing 375 mg of S-carboxymethylcysteine, about 50 mg of mannitol, about 10 mg of talcum, about 10 mg of colloidal silica and about 5 mg of magnesium stearate on about 25 mg of crospovidone, beside some starch for granulating and bringing the tablet at weight. This corresponds to 2 parts by weight of mannitol, 0.4 parts of talcum, 0.4 parts by weight of colloidal silica, 0.2 parts by weight of stearic acid or a salt thereof and 1.5 parts by weight of starch on 1 part by weight of crospovidone. Apart from the taLcum, the colloidal silica, the crospovidone, the starch and the stearic acid or salt thereof, said tablets are completely soluble in water and in gastric and intestinal juices. The tablets quickly fall apart, within the 15 minutes required by the international pharmacopeias. The decomposition time of the composition according to the invention is generally from 0.5 to 5 minutes. The biological availability of S-carboxylmethylcysteine after administration of tablets containing 375 mg S-carboxymethylcysteine was compared with those after administration of the same amount of S-carboxymethylcysteine in the form of capsules and mixtures to 9 healthy volunteers. It can be shown that the developed tablet formulation of S-carboxymethylcysteine has the same biological availability as a mixture or a capsule containing S-carboxymethylcysteine. Thus the biological availability of the S-carboxymethylcysteine in the tabLets is complete All components are known substances, of course they should be of a quality which is acceptable for pharmaceutical compositions. The presence of a slight amount of accidental diluents, such as adsorbed water is acceptable, provided that said casual diluents are pharmaceutically inert. Crospovidone is branched polyvinylpyrrolidone, it should meet the specification of the American Pharmacopee (in the edition of January 1, 1985 on page 554-5). Also the remaining adjuvants should meet the requirements of the Dutch,resp. European or American Pharmacopeia. The invention also relates to a process for preparing tablets of tablet kernels having high contents of pharmaceutical or other substances such as S-carboxymethylcysteine which are difficult to granulate andlor compress. In said process the substance which is difficult to process is mixed with mannitol, is granulated with a blend of starch and water, is dried, sieved again and after adding the remaining adjuvants is compressed to tablets or tablet kernels. The novel process is characterized in that for granulating and compressing as adjuvants for every part by weight of crospovidone 1-5 parts by weight of mannitol, 0.2-2 parts by weight of talcum, 0.2-2 parts by weight of colloidal silica, 0.1-1 part by weight of stearic acid and/or a salt thereof such as magnesium, calcium, or aluminiumstearate and 0.2-4 parts by weight of starch are used. Preferably per 1 part by weight of crospovidone 1-3 parts by weight of mannitol, 0.2-1 parts by weight of talcum, 0.2-1 part by weight of colloidal silica, 0.1-0.5 part by weight of stearic acid or salt thereof and 0.5-2 parts by weight of starch are used. Beside the use on S-carboxymethylcysteine said process is also useful in the formulation of amino acids and some antibiotics. The invention also relates to thus prepared tablets or tablet kernels. Example A blend of 375 g of S-carboxymethylcysteine and 50 g of mannitol was moistened with 125 ml of a 10% starch suspension and granulated by a sieve of 8 mm. The moistened mass was dried, sieved again through a sieve of 1 mm, and after mixing it with 26 g crospovidone, 5.2 g of magnesium stearate, 10.4 g of talcum and 10.4 g of colloidal silica and starch up to 520 g almost 1000 tablets were formed of it. This happened without difficulty and interruption. The dies kept completely clean.

Claims: CLAIMS 1. Tablet or tablet kernel containing S-carboxymethylcysteine and carriers and adjuvants known for tablets, characterized in that the adjuvants in it are a blend of 1-5 parts by weight of mannitol, 0.2-2 parts by weight of talcum, 0.2-2 parts by weight of colloidal silica, 0.1-1 part by weight of stearic acid or salt thereof and 0.2-4 parts by weight of starch on 1 part by weight of crospovidone, the S-carboxymethylcysteine content being from 10 to 90% by weight. 2. Tablet or tablet kernel according to claim 1, characterized in that the adjuvants in it are a mixture of 1-3 parts by weight of mannitol, 0.2-1 part by weight of talcum, 0.2-1 part by weight of colloidal silica, 0.1-0.5 parts by weight of stearic acid or salt thereof and 0.5It parts by weight of starch on 1 part by weight of crospovidone, the S-carboxymethylcysteine content being from 40 to 80 % by weight. 3. Tablet or tablet kernel according to claim 2, characterized in that the blend of adjuvants in it is a blend of about 2 parts by weight of mannitol, about 0.4 parts by weight of talcum, about 0.4 parts by weight of colloidal silica, about 0.2 parts by weight of stearic acid or a salt thereof and 1.5 parts by weight of starch on 1 part by weight of crospovidone. 4. Process for preparing tablets or tablet kernels, in which S-carboxymethylcysteine or an other pharmaceutical substance is blended and granulated with a blend of starch and water, dried, sieved again and after adding the remaining adjuvants are compressed to tablets or tablet kernels, characterized in that as adjuvants for every part by weight of crospovidone 1-5 parts by weight of mannitol, 0.2-2 parts by weight of talcum, 0.2-2 parts by weight of colloidal silica, 0.1-1 part by weight of stearic acid or salt thereof and 0.2-4 parts by weight of starch are used. 5. Process according to claim 4, characterized in that as adjuvants for every part by weight of crospovidone 1-3 parts by weight of mannitol, 0.2-1 part by weight of talcum, 0.2-1 part by weight of colloidal silica, 0.1-0.5 parts by weight of stearic acid or a salt thereof and 0.5-2 parts by weight of starch are used. 6. Tablet or tablet kernel obtained in a way according to claim 4 or 5.

Inventors: BRON, JAN
Applicants: CEDONA PHARMACEUTICALS B.V.
Application year: 1986
Main classification: A61K31
IPC codes: A61K31, A61K9