Antifungal agent "brasil"

 

The invention relates to medicine and concerns based tools terbinafine, which has antifungal activity. Proposed antifungal agent, executed in the form of tablets containing as active substance terbinafine hydrochloride in an amount of 60-80% by weight of the tablet and the excipient is microcrystalline cellulose, hypromellose, sodium starch glycolate, Aerosil or lactose, magnesium stearate. Tablets have good raspadaemost and solubility, which leads to proper therapeutic result. 5 tab., 2 Il.

The invention relates to the field of medicine and concerns based tools terbinafine, which has antifungal activity.

Terbinafine representing allylamine, has a broad spectrum of activity against fungi causing diseases of the skin, hair and nails, including dermatophytes, such as Trichophyton (e.g., T. rubrum, T. mentagrophytes, T. verrucosum, T. tonswans, T. violaceum), Microsporum (such as M. canis) Epidermophyton floccosum, Candida (e.g., C. albicans) and Pityrospomm.

Activity against yeast fungi depending on their type, may be fungicidal or fungistat to a deficiency of ergosterol and to the intracellular accumulation of squalene, what causes the death of cells of the fungus. Effect terbinafine is carried out by inhibiting the enzyme scaleability in the cell membrane of the fungus. This enzyme does not belong to the system of cytochrome P450. Terbinafine does not affect the metabolism of hormones or other drugs.

Well-known antifungal preparations "lamisil", "Activin", containing one tablet 250 mg terbinafine hydrochloride (Reference Vidal drugs in Russia, ed. 8, M., 2002).

The closest in technical essence and the achieved result is containing terbinafine hydrochloride pharmaceutical compositions described in the international application WO 01/52895, a 61 K 47/02, 2001, Tablets represent a multicomponent system with active substance 37-68%.

The aim of the present invention is to provide on the basis of terbinafine hydrochloride antifungal agents in the form of tablets with raspadaemost and solubility, improved due to selection of auxiliary ingredients and their quantitative ratio.

To solve the problem proposed antifungal agent, named "Brasil". It contains the active substance - terbinafine gidrolichesky cellulose, the hypromellose, sodium starch glycolate, Aerosil or lactose, magnesium stearate.

Example. Getting pills "Brasil" the Composition of 1 tablet g: Terbinafine hydrochloride 0,28125 Microcrystalline cellulose - 0,05026 the Hypromellose - 0,00452 Sodium starch glycolate - 0,05007 Aerosil - 0,00195 Magnesium stearate - 0,00195 the Components are mixed and damp granulation. The obtained granules are dried in the installation of the fluidized bed. This is followed by dry granulation, powder sodium starch glycolate, Aerosil, magnesium stearate. Next, the powdered mixture tabletirujut on a tablet press using punches with a diameter of 11 mm with polyglobulia sphere. The obtained tablets "Brasil have a lot of 0.39,

A study of the experimental drug - pills "Brasil" in comparison with the tablets lamisil" company "Novartis Pharma, Switzerland.

Spent determining the absorption spectrum of the studied tablets. In Fig. 1 and 2 presents an overview of absorption spectra of the solutions of the tablets "Brasil" and "lamisil". As seen in the drawings, the absorption spectra of both drugs is exactly the same. Optical activity is observed at intervals of wavelengths from 200 to 300 nm. There are three peaks of absorption at glioblasts from 300 to 320 nm optical density monotonically decreases to zero.

The obtained data suggest spectrophotometric identity of the experimental drug and the comparator drug.

Definition raspadaemosti tablets conducted in accordance with the requirements of the global Fund XI (article "Tablets" and Annex 3). The results obtained are presented in table.1. Studies have shown that pills "Brasil" broke up for 6 min 52 with42 and tablets lamisil for 7 min 3139 C. In all cases, the time raspadaemosti tablets ranged from 6 to 8 min, which is significantly less than normal GF (15 min).

Determination of the dissolution was carried out on the device type "rotary basket" by Erweka. After 45 min the solution was transferred (902,2)% of active substance from the tablets "Brasil" and (89of 3.1% from the tablets lamisil".

To determine acute toxicity used outbred white mice weighing 17-23 g each. Suspension preparations, prepared on the basis of 3% starch solution, was administered to mice per os through the probe in a volume of 1 ml.

Were used 48 nonlinear mice, divided into six groups of six animals each. Experienced drug and the comparator drug was administered at doses of 2, 3, 4 and 5 g/kg

Both subjects prepare dose 5 g/kg, it has proved to be of low toxicity. Dose 5 g/kg were totally portable, it is more therapeutic (25 mg/kg) 200 times.

Thus, both drugs LD50was not achieved even at the dose of 5 g/kg, a Statistically significant difference in the magnitude of LD50between experimental drug and the comparator drug was not found.

Subacute toxicity of the drugs studied in outbred white rats weighing 180-220 g each. The drugs were injected intragastrically in volumes and dilutions listed in table. 2. Based on the fact that therapeutic dose of 25 mg/kg, and ten times therapeutic dose of 250 mg/kg, laboratory animals were divided into 5 groups: group 1 - 10 times therapeutic dose of the drug "Brasil";
group 2 - therapeutic dose of the drug "Brasil";
group 3 - 10 times therapeutic dose "lamisil";
group 4 - therapeutic dose of the drug "lamisil";
group 5 - intact animals, saline.

The duration of drug injection was 14 days. During the experiment, the degree of intoxication was assessed by the General condition of the animal, condition of coat, the change in the number of uriasi, defecation, salivation, nest the slaughter of animals and their postmortem with subsequent weighing of the abdominal organs and the brain. For optical analysis, selected samples of kidney, liver, spleen, thymus and brain. In addition, in the blood of animals have been identified such biochemical and hematological parameters like total protein, glucose, urea, activity alanintransferzy (ALT), aspartokinase (ACT), alkaline phosphatase, hemoglobin concentration, platelets and leukocytes.

During the whole time of administration not reported any fatal accident. Both drugs as therapeutic and 10-fold therapeutic doses did not cause statistically significant deviations in the mass of internal organs or other visible signs of intoxication. Thus, when assessing the General toxic effect of the differences between drugs "Brasil" and "lamisil" was not found.

In table. 3 presents the results of determining the content of total protein, glucose, urea, the activity of both transaminases and alkaline phosphatase in the blood plasma of laboratory animals. As can be seen from these results, significant differences in the data of biochemical parameters between the test drug and the comparator drug is not observed neither when using therapeutic doses or when using 10-fold therapeu the control group of laboratory animals.

In table. 4 shows the results of determining the concentration of hemoglobin, number of erythrocytes, platelets and leukocytes. These results indicate that when comparing two drugs, Brasil" and "lamisil" in both doses integral hematological parameters in laboratory animals do not differ significantly. Values of the investigated biochemical and haematological parameters in the four experimental groups of animals show no differences from the data for the control group, where rats were injected instead of the drug with saline.

The results of the determination of leukocyte blood are presented in table. 5. From these data it is seen that as a result of the introduction of drugs in both the studied doses WBC blood in laboratory animals is practically unchanged.

As shown by the results of postmortem dissection, almost unable to detect pathological changes in the liver, spleen, thymus, kidney, brain tissue and the injection of drugs. Comparative histological analysis showed that the experimental drug and the comparator drug when administered to rats in therapeutic and 10-fold therapeutic doses did not cause cytoma the actions of drugs. Starch suspension drugs were administered intragastrically and condition of the gastric mucosa was evaluated irritant effect. Revealed that none of the control animals, neither in the experimental groups, ulcerative lesions of the mucosa were observed. Single small hemorrhages (petechiae) was observed in all groups of rats, their number is not depended on the dose of the administered drug.


Claims

Antifungal agent, characterized in that it is made in tablet form and contains as active substance terbinafine hydrochloride in an amount of 60-80% by weight of the tablet and the excipient is microcrystalline cellulose, hypromellose, sodium starch glycolate, Aerosil or lactose, magnesium stearate.

 

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