Solid dosage form terbinafine hydrochloride

 

(57) Abstract:

The invention relates to medicine, specifically to means for the treatment of fungal diseases. The invention consists in creating solid dosage forms of terbinafine hydrochloride, which contains the active ingredient, filler, humectant and optimouse agent, and preservative at the ratio specified in the claims. The technical result of the invention consists in the use of less scarce and more accessible ingredients and reducing the cost of medication. table 2.

The present invention relates to medicine and can be used to produce solid dosage forms of terbinafine hydrochloride, used as a drug for the treatment of fungal diseases.

Terbinafine hydrochloride (E)-N-(6,6-dimethyl-2-hepten-4-inyl)-N-methyl-1-naphthalenemethanamine hydrochloride General formula C21H25N HCl m m 327,90 belongs to the group of allylamine and is a highly effective antifungal drug.

The drug acts at an early stage of the biosynthesis of sterols cytoplasmic membranes of fungal cells by inhibiting the enzyme skvalenepoksidazu mushrooms, cat the aqueous cellular Sterol of fungal membranes, and to the intracellular accumulation of squalene, which causes cell death of the fungus. Terbinafine hydrochloride has fungicidal effect on dermatophytes, mold and certain dimorphic fungi, yeast and yeast-like fungi. On some species of yeast fungi can act fungistaticeski. Active against pathogens ringworm (Trichophyton, including T. rubrum, T. mentagrophytes, T. tonsurans, T. verrucosum, T. violaceum; and Microsporum canis and Epidermophyton floccosum); yeast-like fungi of the genus Candida (mainly Candida albicans); Pityrosporum orbiculate (Malassezia furfur) as the causative agent of multi-colored lichen.

In Russia there are several dosage forms terbinafine hydrochloride for external use:

- Terbinafine (Lamisil) cream 1% (dose 15 g) Novartis Pharma, Switzerland;

- Activin (Exifine) cream 1% (dose 10 g) Dr. Reddy's Laboratories, India;

- Terbinafine (Lamisil) is a topical solution 1%, vial, 30 ml, Novartis Pharma, Switzerland;

- Terbinafine (Lamisil) spray for topical application of 1%, bottle of spray 30 ml, Novartis Pharma, Switzerland.

Closest to the claimed technical essence and the achieved result, selected as a prototype, is lamisil tablets manufactured by Novartis Pharma, Switzerland (Reference VIDAL, Lekarstvennyie 250 mg other ingredients include magnesium stearate, colloidal anhydrous silica, methylhydroxypropylcellulose, microcrystalline cellulose and karboksimetilirovaniya starch sodium.

Tablet containing terbinafine hydrochloride 125 mg in addition to the above ingredients also contains lactose.

The disadvantage of this drug is the use of some scarce ingredients in its composition, which increases the cost of the drug.

The problem solved by the invention, the expansion of raw materials for the production of solid dosage forms of terbinafine hydrochloride.

The technical result from the use of the invention is to use less scarce and more accessible ingredients and reducing the cost of the medication.

This result is achieved in that the solid dosage form of terbinafine hydrochloride, which contains the active ingredient, filler, humectant and optimouse agent further comprises a preservative in the following ratio of ingredients based on the weight of the tablet, wt %:

Terbinafine hydrochloride 72,23-79,83

(in terms of 100% substance)

Fillers - 10,1-23,0

Humidifier - 0,1-5,0

Apadravya Kai cellulose and Aerosil, humidifier - water solution Kollidon 30, as apadravya agents - Kollidon CL-M and magnesium stearate, as preservative - benzoic acid or sodium benzoate.

Quantitative content terbinafine should be 0,2375 - 0,2625 g, preferably 0.25 g on the average mass of one tablet or 76% terbinafine hydrochloride by weight of the tablet; the microcrystalline cellulose is preferably 0,0537 g or 14.5 percent; Kollidon CL-M - preferably 0,0111 g or 3%; Kollidon 30 is preferably 0,0110 g or 2,97%; Aerosil - preferably 0,0074 g or 2%; benzoic acid or sodium benzoate is preferably 0,0018 g or 0.49% magnesium stearate is preferably 0,0037 g or 1%. The weight of the tablet of 0.37 g of 5%.

Terbinafine hydrochloride may be used, for example, firms Chemo Iberica SA ND 42-11219-00 (Spain) or other imported, registered in the Russian Federation; microcrystalline cellulose, for example, FS 42-3728-99 or imported; Kollidon CL-M, for example, ND 42-8871-98, BASF, Germany; Kollidon 30, for example, ND 42-8482-98, BASF, Germany; Aerosil, for example, according to GOST 14922-77, grade a-300 or imported; benzoic acid, for example, according to GOST 10521-78 or GFH, S. 9; magnesium stearate, for example, on THE other 6-09-129-75 and THE 6-09-16-1533-90 or imported, sodium benzoate, for example, FS 42-2458-94.

As fillers can be used lactose, starch, magnesium carbonate basic, kollidon other modifications, polyplasdone. As the humidifier can be used water, aqueous solutions of collegenow other modifications, the starch solution, a solution of polyvinylpyrrolidone solution of gelatin, sugar syrup. As outrivaled agent can also be used calcium stearate, stearic acid, starch, talc, kollidon other modifications, polyplasdone. Below are examples of the manufacture of tablets terbinafine hydrochloride.

Example 1.

In Rotogravure download sifted powders 76,03 kg terbinafine hydrochloride, 14.51 kg microcrystalline cellulose, 2.0 kg of Aerosil, mix thoroughly for 5 minutes. Moisturize with a calculated amount of 5% aqueous solution of Kollidon 30 (59,4 kg) containing 2,97 kg Kollidon 30, again stirred until uniformly dissolved, and the 0 kg magnesium stearate,0,49 kg of benzoic acid and 3.0 kg of Kollidon CL-M and tabletirujut. Weight pills 0,370, the solubility of 80%, raspadaemost 5 minutes.

Example 2.

Analogously to example 1, but with the following amounts of ingredients: 72,23 kg terbinafine hydrochloride; 15,77 kg microcrystalline cellulose, 3.0 kg of Aerosil, the calculated amount of an aqueous solution of Kollidon 30 (1.0 kg of Kollidon 30), 1.0 kg of magnesium stearate, 2.0 kg of sodium benzoate, 5,0 kg Kollidon CL-m

Weight pills 0,370,

Solubility - 80%, raspadaemost 5 minutes.

Example 3.

Analogously to example 1, but with the following quantities of components: terbinafine hydrochloride - 79,83 kg microcrystalline cellulose - 13,87 kg of Aerosil - 0.2 kg, Kollidon 30 - 4.9 kg, benzoic acid and 0.1 kg of Kollidon CL-M - 1,0 kg of magnesium stearate and 0.1 kg.

Example 4.

Analogously to example 1, but with the following quantities of components: terbinafine hydrochloride - 76,03 kg microcrystalline cellulose - 10,97 kg of Aerosil - 2.5 kg, Kollidon 30 - 5,0 kg, benzoic acid is 1.0 kg, Kollidon CL-M - 4.0 kg of magnesium stearate and 0.5 kg.

Example 5.

Analogously to example 1, but with the following quantities of components: terbinafine hydrochloride - 74,0 kg microcrystalline cellulose - 23,0 kg, Kollidon 30 - 0,8 cicno example 1, but when the following quantities of components: terbinafine hydrochloride - 78,2 kg microcrystalline cellulose to 10.1 kg, Kollidon 30 - 3,9 kg benzoic acid - 1.6 kg, Kollidon CL-M - 5.3 kg of magnesium stearate is 0.9 kg

Example 7.

Analogously to example 1, but with the following quantities of components: terbinafine hydrochloride - 73,35 kg, microcrystalline cellulose and 10.3 kg of Aerosil - 4.1 kg, Kollidon 30 - 4,85 kg benzoic acid 0.4 kg, Kollidon CL-M - 6,2 kg, magnesium stearate - 0.8 kg

Example 8.

Analogously to example 1, but with the following quantities of components: terbinafine hydrochloride - 76,03 kg microcrystalline cellulose trend of 15.87 kg, Kollidon 30 - 5,0 kg, benzoic acid, 0.5 kg, Kollidon CL-M - 0.1 kg, Aerosil - 2,5 kg

Example 9.

Analogously to example 1, but with the following quantities of components: terbinafine hydrochloride - 78,2 kg microcrystalline cellulose - 10,0 kg of Aerosil - 0.1 kg, Kollidon 30 - 3,9 kg benzoic acid - 1.6 kg, Kollidon CL-M - 5.3 kg of magnesium stearate is 0.9 kg Raspadaemost tablets was determined on the tester time decomposition dosage forms brand ZT-32 firms ERWEKA. The solubility of the tablets was determined on the device DT 60 by ERWEKA. B examples 3-9 solubility of tablets would be the m high-performance liquid chromatography (HPLC).

The obtained tablets are white or white with a yellowish hue. Quality tablets meet the requirements of the global Fund X1, issue 2, page 154.

The content of terbinafine hydrochloride in each tablet is determined by therapeutic dose. Reducing the amount of microcrystalline cellulose is less than 10% as well as increase of about 23%, impairs the flowability of the granules, the strength of the tablets and their raspadaemost. The increase in the number of Kollidon CL-M more than 5% technologically impractical, and a decrease of less than 0.1% affects raspadaemost tablets. When the number of Kollidon 30 less than 0.1% not achieved the required strength of the granulate, and when more than 5% worse raspadaemost tablets. The increase in the number of Aerosil more than 3% technologically impractical, and a decrease of less than 0.1% does not ensure the flowability of the granules. Increasing the amount of magnesium stearate was more than 1% technologically impractical, and a decrease of less than 0.1% impairs the flowability or fluidity of the granulate. With less than 0.1%, the amount of benzoic acid or sodium benzoate is not ensured stability of the tablet during storage, and the increase in amounts over 2% is impractical.

When tested on antimicrobe is owino, the medication possesses antimicrobial activity against all test strains (table 1). Determination of microbiological purity conducted in accordance with the requirements of the global Fund X1, issue 2, pages 193 and Change 1 dated 28.12.1995,, category 3 g, using the following dilution inoculation on nutrient medium: 1 and 11 - 1:300, 2 - 1:10. Legend: symbols (+), (-) or (-+) indicate the presence, absence or delay the growth of test strains of microorganisms on nutrient media.

Experimental-industrial batch studied in these conditions, microbiological purity comply with the requirements of the global Fund X1, issue 2, pages 193 and edit. 1. Table data on microbiological purity is attached (table 2).

Thus, the solid dosage form terbinafine hydrochloride according to the invention, is not inferior in their properties to foreign analogues, but unlike lamisil tablets containing methylhydroxypropylcellulose, carboxymethyllysine starch sodium, which is not registered in the Russian Federation is one of the available raw materials, which reduces the cost of the drug.

Solid dosage form terbinafine hydrochloride containing active substance, nacistickou pulp and Aerosil, as the humidifier aqueous solution of Kollidon 30, as apadravya agents Kollidon CL-M and magnesium stearate, and optionally as a preservative contains sodium benzoate or benzoic acid in the following proportions of ingredients based on the weight of the tablet, and Mac. %:

Terbinafine hydrochloride (in terms of 100% substance) - 72,23-79,83

Fillers - 10,1-23,0

Humidifier - 0,1-5,0

Apadravya agents of 0.1 to 7.0

Preservative - 0,1-2,0

 

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