RU2200003C1 - Solid medicinal form of terbinafine hydrochloride - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: invention relates to agents used for treatment of fungal diseases. Invention provides the development of solid medicinal form of terbinafine hydrochloride containing active substance, filling agents, wetting agent, powdering agent and preserving agent taken in the ratio given in the invention claim. Invention provides the use of less deficient and more available components and decrease of the preparation price. EFFECT: improved properties of agent, decreased cost. 2 tbl, 9 ex

Description

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

Terbinafine hydrochloride - (E) -N- (6,6-dimethyl-2-heptene-4-ynyl) -N-methyl-1-naphthalenemethanamine hydrochloride of the general formula C ₂₁ H ₂₅ N • HCl m.m. 327.90 belongs to the group of allylamines and is a highly effective antifungal drug.

 The drug acts at an early stage in the biosynthesis of sterols of the cytoplasmic membranes of fungal cells, inhibiting the enzyme squalene epoxidase, which is 10 thousand times more sensitive than a similar human enzyme. This leads to a deficiency of ergosterol, the main sterol of the cell membrane of fungi, and to intracellular accumulation of squalene, which causes the death of the fungal cell. Terbinafine hydrochloride has a fungicidal effect on dermatophytes, mold and some dimorphic fungi, yeast and yeast-like fungi. It can act fungistatically on some types of yeast. It is active against pathogens of dermatomycosis (Trichophyton, including T. rubrum, T. mentagrophytes, T. tonsurans, T. verrucosum, T. violaceum; as well as Microsporum canis and Epidermophyton floccosum); Candida yeast-like fungi (mainly Candida albicans); Pityrosporum orbiculate (Malassezia furfur) - the causative agent of colorful lichen.

In Russia, several dosage forms of terbinafine hydrochloride for external use are registered:
- Lamisil (Lamisil) - cream 1% (tube 15 g) Novartis Pharma, Switzerland;
- Exifine (Exifine) - cream 1% (tube 10 g) Dr. Reddy's Laboratories, India;
- Lamisil (Lamisil) - solution for external use 1%, bottle of 30 ml, Novartis Pharma, Switzerland;
- Lamisil (Lamisil) - spray for external use 1%, bottle with a spray of 30 ml, Novartis Pharma, Switzerland.

 The closest to the claimed technical essence and the achieved result, selected as a prototype, is Lamisil in tablets, manufactured by Novartis Pharma, Switzerland (VIDAL Handbook, Medications in Russia, M., AstraPharmService, 2001, p. B-305) .

 A tablet containing 250 mg terbinafine hydrochloride contains magnesium stearate, colloidal anhydrous silicon dioxide, methyl hydroxypropyl cellulose, microcrystalline cellulose and carboxymethyl starch sodium as other ingredients.

 A tablet containing 125 mg terbinafine hydrochloride in addition to the listed ingredients additionally contains lactose.

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

 The problem solved by the invention is the expansion of the raw material base 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 affordable ingredients and reduce the cost of the drug.

This result is achieved in that the solid dosage form of terbinafine hydrochloride, containing the active substance, fillers, moisturizer and dusting agent, additionally contains 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% of the substance)
Fillers - 10.1-23.0
Humidifier - 0.1-5.0
Dusting Agents - 0.1-7.0
Preservative - 0.1-2.0
Microcrystalline cellulose and aerosil can be used as fillers, Kollidon 30 aqueous solution as a humidifier, CL-M Collidon and magnesium stearate as dusting agents, and benzoic acid or sodium benzoate as a preservative.

 The quantitative content of terbinafine should be 0.2375-0.2625 g, preferably 0.25 g per average weight of one tablet or 76% terbinafine hydrochloride per tablet weight; microcrystalline cellulose - preferably 0.0537 g or 14.5%; Collidone CL-M - preferably 0.0111 g or 3%; Collidone 30 - preferably 0.0110 g or 2.97%; Aerosil - preferably 0.0074 g or 2%; benzoic acid or sodium benzoate - preferably 0.0018 g or 0.49%; magnesium stearate - preferably 0.0037 g or 1%. The weight of the tablet is 0.37 g ± 5%.

 Terbinafine hydrochloride can be used, for example, by Chemo Iberica SA according to ND 42-11219-00 (Spain) or another import registered in the Russian Federation; microcrystalline cellulose, for example, according to FS 42-3728-99 or imported; Kollidon CL-M, for example, according to ND 42-8871-98, BASF, Germany; Collidon 30, for example, according to 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, C.9; magnesium stearate, for example, according to TU 6-09-129-75 and TU 6-09-16-1533-90 or imported, sodium benzoate, for example, according to FS 42-2458-94.

 Terbinafine hydrochloride tablets are prepared by mixing the sieved terbinafine hydrochloride powders and excipients, followed by wetting with a calculated amount of humidifier. Next, the moistened granulate is dried to a residual moisture content of at least 1-3%. The resulting tablet mass is passed through a calibrator and treated with a mixture of dusting agents, which subsequently allows you to get a tablet that meets the requirements of the State Pharmacopoeia X1 ed.

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

 Example 1

 Sifted powders of 76.03 kg terbinafine hydrochloride, 14.51 kg of microcrystalline cellulose, 2.0 kg of aerosil are loaded into a rotogranulator, thoroughly mixed for 5 minutes. Humidify with the calculated amount of 5% aqueous solution of Collidone 30 (59.4 kg) containing 2.97 kg Collidone 30, re-mixed until the moisture is evenly distributed and dried to a residual moisture content of 1-3%.

 The granules are dried, ground, dusted with 1.0 kg of magnesium stearate, 0.49 kg of benzoic acid and 3.0 kg of Collidone CL-M and tableted. The weight of the tablet is 0.370 g. Solubility is 80%, disintegration is 5 minutes.

 Example 2

 Analogously to example 1, but with the following amounts of ingredients: 72.23 kg of terbinafine hydrochloride; 15.77 kg of microcrystalline cellulose, 3.0 kg of aerosil, the calculated amount of an aqueous solution of Collidone 30 (1.0 kg Collidon 30), 1.0 kg of magnesium stearate, 2.0 kg of sodium benzoate, 5.0 kg of Collidone CL-M .

 The weight of the tablet is 0.370g.

 Solubility - 80%, disintegration - 5 minutes.

 Example 3

 Analogously to example 1, but with the following amounts of components: terbinafine hydrochloride - 79.83 kg, microcrystalline cellulose - 13.87 kg, aerosil - 0.2 kg, Collidona 30 - 4.9 kg, benzoic acid - 0.1 kg. Kollidona CL-M - 1.0 kg, magnesium stearate - 0.1 kg.

 Example 4

 Analogously to example 1, but with the following amounts of components: terbinafine hydrochloride - 76.03 kg, microcrystalline cellulose - 10.97 kg, aerosil - 2.5 kg, Collidona 30 - 5.0 kg, benzoic acid - 1.0 kg, Collidona CL-M - 4.0 kg, magnesium stearate - 0.5 kg.

 Example 5

 Analogously to example 1, but with the following amounts of components: terbinafine hydrochloride - 74.0 kg, microcrystalline cellulose - 23.0 kg, Kollidona 30 - 0.8 kg, benzoic acid - 0.6 kg, Kollidona CL-M - 0.9 kg, magnesium stearate - 0.7 kg.

 Example 6

 Analogously to example 1, but with the following amounts of components: terbinafine hydrochloride - 78.2 kg, microcrystalline cellulose - 10.1 kg, Kollidona 30 - 3.9 kg, benzoic acid - 1.6 kg, Kollidona CL-M - 5.3 kg, magnesium stearate - 0.9 kg.

 Example 7

 Analogously to example 1, but with the following amounts of components: terbinafine hydrochloride - 73.35 kg, microcrystalline cellulose - 10.3 kg, aerosil - 4.1 kg, Kollidona 30 - 4.85 kg, benzoic acid - 0.4 kg, Kollidona CL-M - 6.2 kg, magnesium stearate - 0.8 kg.

 Example 8

 Analogously to example 1, but with the following amounts of components: terbinafine hydrochloride - 76.03 kg, microcrystalline cellulose - 15.87 kg, Kollidona 30 - 5.0 kg, benzoic acid - 0.5 kg, Kollidona CL-M - 0.1 kg, aerosil - 2.5 kg.

 Example 9

 Analogously to example 1, but with the following amounts of components: terbinafine hydrochloride - 78.2 kg, microcrystalline cellulose - 10.0 kg, aerosil - 0.1 kg, Collidona 30 - 3.9 kg, benzoic acid - 1.6 kg, Collidona CL-M - 5.3 kg, magnesium stearate - 0.9 kg. The disintegration of the tablets was determined on the ERWEKA brand ZT-32 decomposition time tester. The solubility of the tablets was determined on an ERWEKA DT 60 instrument. In examples 3-9, the solubility of the tablets was from 75 to 80%, disintegration from 2 to 15 minutes. Impurities and terbinafine hydrochloride were determined by high performance liquid chromatography (HPLC).

 The resulting tablets are white or white with a yellowish tint. In terms of quality, the tablets satisfy the requirements of GF X1, issue 2, p. 154

 The content of terbinafine hydrochloride in one tablet is determined by the therapeutic dose. A decrease in the amount of microcrystalline cellulose of less than 10%, as well as an increase of more than 23%, impairs the flowability of the granulate, the strength of the obtained tablets and their disintegration. An increase in the amount of Collidone CL-M of more than 5% is technologically impractical, and a decrease of less than 0.1% affects the disintegration of the tablet. When the amount of Kollidon 30 is less than 0.1%, the required granular strength is not achieved, and when the amount is more than 5%, the disintegration of the tablet worsens. An increase in the amount of aerosil of more than 3% is technologically impractical, and a decrease of less than 0.1% does not provide granular flowability. An increase in the amount of magnesium stearate of more than 1% is technologically impractical, and a decrease of less than 0.1% affects the flowability or fluidity of the granulate. With less than 0.1% of the amount of benzoic acid or sodium benzoate, the stability of the tablets during storage is not ensured, and an increase in their amounts of more than 2% is impractical.

 When tested for antimicrobial activity in accordance with the requirements of Global Fund X1 in respect of 5 test strains of the microorganisms of the preparation, it was found that the preparation has antimicrobial activity in relation to all test strains of the microorganisms (table 1). The determination of microbiological purity was carried out in accordance with the requirements of Global Fund X1, issue 2, p. 193 and Change 1 of 12.28.1995, category 3 g, using the following dilutions when plating on culture media: 1 and 11 - 1: 300, 2 - 1:10. Legend: the signs (+), (-) or (- +) indicate the presence, absence or growth retardation of test strains of microorganisms on nutrient media.

 Experimental industrial series of the drug, studied under these conditions, according to microbiological purity comply with the requirements of Global Fund X1, issue 2, p. 193 and rev. 1. A table of data on microbiological purity is attached (table 2).

 Thus, the solid dosage form of terbinafine hydrochloride according to the invention is not inferior in its properties to foreign analogues, but unlike Lamisil tablets containing methylhydroxypropyl cellulose, carboxymethylated sodium starch, unregistered in the Russian Federation, is produced from available raw materials, which allows to reduce the cost of the drug.

Claims (1)

A solid dosage form of terbinafine hydrochloride containing the active substance, fillers, a humectant and a dusting agent, characterized in that it contains microcrystalline cellulose and aerosil as fillers, an aqueous solution of Collidone 30 as a humectant, and Collidone CL-M and magnesium stearate as a dusting agent and also additionally contains sodium benzoate or benzoic acid as a preservative in the following ratio of ingredients based on the weight of the tablet, wt. %:
Terbinafine hydrochloride (in terms of 100% of the substance) - 72.23-79.83
Fillers - 10.1-23.0
Humidifier - 0.1-5.0
Dusting Agents - 0.1-7.0
Preservative - 0.1-2.0

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