A method of manufacturing the solid pharmaceutical compositions

 

(57) Abstract:

Use: manufacture of solid pharmaceutical compositions, particularly tablets. The inventive method of manufacturing the solid pharmaceutical compositions comprising as active ingredients L-3,4-dihydroxyphenylalanine and L-alpha-hydrazino - alpha-methyl-3,4-dihydroxyphenylpropionic acid in their mass ratio (3,5 - 10) : 1, respectively, includes the following stages: the active ingredients are milled with lactose and/or microcrystalline cellulose, taken in an amount of 20 to 33 % by weight of the composition, and then, if necessary, mixed with the coloring agent. The resulting mixture is treated with stearin in the amount of 1,5 - 2 % by weight of the composition dissolved in an aliphatic alcohol containing 2 to 4 carbon atoms, dried, granularit, then if necessary, the dry granulate is mixed with targeted supplements and then pressed into tablets containing 55 to 70 wt.% active ingredients. On the surface of the tablets may be coated film coating. 1 C.p. f-crystals, 1 table.

The invention concerns a method of manufacturing the solid pharmaceutical compositions. In particular, the invention relates to a method of manufacturing tablets or tablets is as the active ingredient include a mixture of L-3,4-dehydrophenylalanine and L-alpha-hydrazino-alpha-methyl-3,4-digidrofolievoy acid in a mass ratio of (3,5 10) 1.

It is known that L-3,4-dehydrophenylalanine (levodopa) in combination with L-alpha-hydrazino-alpha-methyl-3,4-digidrofolievoy acid (carbidopa) is used in the treatment of Parkinson's disease (U.S. patent N 3, 769, 424).

Although the description has reference to the manufacture of pharmaceutical compositions containing as active ingredients a mixture of levodopa and carbidopa in a mass ratio of (0,2 8) 1 or the composition or method of manufacture of the above compounds is not disclosed.

In accordance with the requirements of tablets with improved release of the active ingredients (e.g., levodopa, in combination with carbidopa -), reflected in the Pharmacopoeia XXII USA (S. 226), which entered into force on 1 January 1990, at least 80% content of active ingredients, the tablets should be released in 0.1 n solution of florodora for 30 min, under certain conditions. The tablets comply with these requirements and the requirements of method, however, the above Pharmacopoeia is not provided.

The aim of the invention is to develop a method of making tablets that provide improved release of the active ingredients, in which 80% of the content of active ingredients in t which have the usual quality requirements, and it is not damaged and have a satisfactory appearance, proper hardness, etc., this goal is achieved by this method of manufacture of tablets or film-coated tablets with improved release of the active ingredients, where the tablets comprise as active ingredient a mixture of L-3,4-dehydrophenylalanine and L-alpha-hydrazino-alpha-methyl-3,4-digidrofolievoy acid in a mass ratio of (3,5 10) 1 by grinding the active ingredient with lactose and/or microcrystalline cellulose, taken in an amount of 20 to 33% by weight of the composition, then, if necessary, by mixing the coloring agent, processing the mixture stearine in the amount of 1.5 to 2% by weight of the composition dissolved in an aliphatic alcohol containing 2 to 4 carbon atoms, followed by drying, granulation and optionally mixing the dried granulate with targeted supplements and pressing into tablets containing 55 to 70% by weight of the active ingredients and, if necessary, applying a film coating on the surface of the thus obtained tablets.

Carbidopa is used preferably in the form of its monohydrate. The term "L-alpha-hydrazino-alpha-methyl-3,4-digidropiridinove cieniu, the rapid release of active ingredients is achieved by mixing one of the active ingredients or both of them with a hydrophilic solvent, preferably lactose and/or microcrystalline cellulose by grinding, which is created by passing the mixture through an impact mill or serrated flat crusher, or by applying a mixing impeller in the form of high-speed mixing machine.

Proper appearance and mechanical strength of the tablets in accordance with the invention is provided by performing aggregation with stearin, dissolved in an organic solvent, it is mainly used stearin in the amount of 1.5 to 2.5 wt. the finished tablets. As the solvent used, preferably ethanol or isopropanol. The organic solution stearin may also contain a binder such as a polymer ester methylmethacrylic acid. This stage refers to the rapid release of the active elements.

Stearin is used as a lubricant in the manufacture of tablets (Amer. Pharm. ACC. 45 (1), 51 (1956); 49 (1), 35 (1960)) in an amount of about 1 wt. preferably in a quantity not exceeding 1% In the e which is unusual, that, thanks to his use of this phenomenon can be prevented. In addition, it can be expected that in the presence of stearin release of the active ingredient will be difficult. In accordance with the invention stearin is used in an amount of not less than 1.5% relative to the weight of the finished tablet.

After treatment, a hydrophilic solvent, such as lactose and/or microcrystalline cellulose, as usual auxiliary substances used subsequent solvent, cellulose, disintegrity agent, preferably carboxymethylcellulose or nizkozameshhennoj hydroxypropylcellulose; and a binder, preferably a polymer ester methylmethacrylic acid.

It is considered preferable to use nitrosamines cellulose, which can act both as a binder and as dezintegriruetsja substance.

In the case of processing the hydrophilic solvent (a solvent) of both active ingredients for the manufacture of tablets are only used for the above-mentioned excipients. If the active ingredient alone, especially carbidopa treated hydrophilic solvent (solvents), another ingredient, and further Vassa granulation in the process of manufacturing tablets typically use the following excipients: for example, disintegrant, preferably carboxymethyl cellulose; anti-adhesive substance, preferably talc; substances promoting sliding, preferably colloidal silicone dioxide, or lubricants, preferably magnesium stearate.

Thus obtained tablets may optionally be coated with a film by known methods.

In the production of colored tablets coloring agent is preferably introduced with the active ingredient (or ingredients) and the hydrophilic solvent (solvents) by grinding. Then also can be followed by first staining the hydrophilic solvent (solvent) in an aqueous solution of the coloring matter, and then after drying, mixing the thus obtained mixture with the active ingredient (or ingredients) by applying a crushing force. In both cases, the procedure continues by depositing a mixture of excipients and thoroughly mixing them with a solution of stearin.

Staining is also carried out by using a film coating.

The method according to the invention provides for the manufacture of tablets with improved release of the active ingredient. Good quality tabla concentration of active ingredient in the tablets according to the invention can reach 70%

Example 1. The mixture 1720 g of lactose and 1720 porous microcrystalline cellulose is thoroughly moistened with an aqueous solution of 2 g of Indigo Carmine, and then dried. Painted thus the mixture is combined with 10 kg of levodopa and 1080 g carbidopa in the form of a monohydrate, and then passed through a flat toothed plate crusher type Alpin 800 g of polymer ester methylmethacrylic acid (Eudtagit L100) and 160 g transverse cross-linked carboxymethylcellulose add in this way the resulting crushed product and mix it all into the General mass in the mixing machine with a solution of 280 g of stearin in 2200 g of ethanol. Then dried and regranulated 400 g of talc powder, 80 g of magnesium stearate, 20 g of colloidal silicone dioxide (Aerosil, manufactured by Degussa) and 140 g of cross-linked carboxymethylcellulose is mixed with a dry granulate and the mixture is pressed into tablets of 10 mm in diameter. Thus, the obtained tablets weigh 0,41005 g and have the following composition,g:

levodopa 0,250

carbidopa monohydrate 0,027

lactose 0,043

microcrystalline cellulose 0,043

coloring agent (Indigo Carmine) 0,00005

the polymer ester methylmethacrylic acid 0.020

cross-linked carboxymethylcellulose 0,0075

stearin 0,007

talc 0,010

the magnesium stearate 0 is the R thus tablets studied by way described in the Pharmacopoeia XXII USA (S. 226). 85 the active ingredient was released within 5 min.

Example 2. The mixture 1204 lactose and 3393,6 g microcrystalline cellulose is thoroughly moistened with an aqueous solution of 8.4 g of Indigo Carmine and dried. Painted thus the mixture is mixed with 7 kg of levodopa and 756 to carbidopa in the form of a monohydrate, and then passed through a flat toothed plate crusher type Alpine. In this way the resulting crushed mixture was added 560 g of polymer methylmethacrylic acid (Eudragit L100) and 434, nitrosamines hydroxypropylcellulose, and the whole product is mixed in a mixing machine with a solution of 224 g of stearin in 2200 g of ethanol, dried and granularit. To the dry granulate add 336 g of talc, 70 g of magnesium stearate, 14 g of colloidal silicone dioxide, and the mixture is pressed into tablets of 8 mm in diameter. Thus, the tablets weigh 0.2 g and have the following composition, g:

levodopa 0,1000

carbidopa monohydrate 0,0108

lactose 0,0172

microcrystalline cellulose 0,04848

coloring agent (Indigo Carmine) 0,00012

the polymer ester methylmethacrylic acid 0,0080

nizkozameshhennoj hydroxypropylcellulose is 0.0002

stearin 0,0032

talc 0,0048

the magnesium stearate 0,0010

the m way tablets studied by way described in the Pharmacopoeia XXII USA (S. 226). 83 wt. the active ingredient was released within 5 min.

Example 3. Tablets manufactured by the method described in example 2.

The composition of the tablets next,g:

levodopa 0,1000

carbidopa monohydrate 0,0270

lactose 0,0200

microcrystalline cellulose 0,0520

coloring agent (quinoline yellow) 0,008

the polymer ester methylmethacrylic acid 0,0100

nizkozameshhennoj hydropropylcellulose 0,0060

stearin 0,0040

talc 0,0040

the magnesium stearate 0,0010

colloidal silicone dioxide is 0.0002

Total 0,2300

Example 4. A mixture of 108 g of carbidopa in the form of a monohydrate and 172 g of lactose are passed through a flat toothed plate crusher type Alpin, then mixed with 1000 g of levodopa, 166 g of microcrystalline cellulose, 48 g of polymer ester methylmethacrylic acid (Eudragit L100) and 16 g of cross-linked carboxymethylcellulose in a mixing machine. The mixture is moistened with a solution of 28 g of stearin in 220 g of ethanol, thoroughly mixed, dried and regranulated. To the dry granulate is added 52 g of cross-linked carboxymethyl cellulose, 40 g of talc powder, 8 g of colloidal silicone dioxide (Aerosil, manufactured by Degussa) and 8 g of magnesium stearate, and the mixture is pressed the bathroom si 0,250

carbidopa monohydrate 0,0270

lactose 0,043

microcrystalline cellulose 0,040

the polymer ester methylmethacrylic acid 0,012

cross-linked carboxymethylcellulose 0,017

stearin 0,007

talc 0,010

colloidal silicone dioxide 0,002

the magnesium stearate 0,002

Total 0,410 g

The release of the active ingredient thus obtained tablets were studied by the method described in the Pharmacopoeia XXII USA (S. 226). 80 wt. the active ingredient was released within 5 min.

Example 5. The ratio corresponds to example 4, but using 24 g of polymer methylmethacrylic acid (Eudragit L100); 28 g of stearin dissolved in 192 g of a 12.5% solution of the polymer methylmethacrylic acid in isopropanol (Eudragit L12,5), and hydration occurs in the thus obtained solution.

Example 6. A mixture of 400 g of levodopa, 108 g of carbidopa in the form of a monohydrate and 104 g of lactose are mixed in a drum mill. Then mixed in a mixing machine with 96 g of microcrystalline cellulose, 32 g of polymer ester methylmethacrylic acid (Eudragit L100) 4 g of cross-linked carboxymethylcellulose and a solution of 16 g of stearin in 125 g of ethanol, dried and granularit. To the dry granulate is added 48 g cross-linked to the E. Thus, the obtained tablets weigh 0.21 g and have the following composition,g:

levodopa 0,100

carbidopa monohydrate 0,027

lactose 0.026

microcrystalline cellulose 0,024

the polymer ester methylmethacrylic acid 0,008

cross-linked carboxymethylcellulose 0,013

stearin 0,004

talc 0,006

colloidal silicone dioxide 0,001

the magnesium stearate 0,001

Total 0,210

The release of the active ingredient thus obtained tablets were studied by the method described in the Pharmacopoeia XXII USA (S. 226). 80 wt. the active ingredient was released within 5 min.

The data of examples 1 to 6 are summarized in table.

1. A method of manufacturing the solid pharmaceutical compositions comprising as active ingredients L-3,4-dihydroxyphenylalanine and L-hydrazino-a-methyl-3,4-dihydroxyphenylpropionic acid at a mass ratio (3,5 10) 1, respectively, characterized in that the said active ingredients are milled with lactose and/or microcrystalline cellulose, taken in an amount of 20 to 33% by weight of the composition, and then, if necessary, mixed with the coloring agent, the resulting mixture is treated with stearin in the amount of 1.5 to 2% by weight of the composition dissolved in alivechat with targeted supplements and then pressed into tablets, contains 55 to 70% by weight of the active ingredients.

2. The method according to p. 1, characterized in that the surface tablet is applied film coating.

 

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