An antimicrobial agent tarifaire

 

The invention relates to medicine. The tool is made in the form of tablets, coated. The core includes ofloxacin, lactose, corn starch, hydroxypropylcellulose or methylcellulose, croscarmellose of sodium and crosspovidone and magnesium stearate, and the shell contains hypromellose, triacetin or polyethylene glycol 6000 and the ink suspension "White lake". The tool provides good absorption in the gastrointestinal tract, allatoxin and therapeutic effect is not inferior to foreign analogues. 6 tab., 8 Il.

The invention relates to the field of medicine and for the creation of tools antimicrobial action on the basis of ofloxacin.

Known tablet (patent US 4639458, 1987 ), obtained by direct pressing, containing as an antibacterial agent negidrirovannogo quinoline-carboxylic acid, and also notes the possibility of using ofloxacin.

The closest in technical essence and the achieved result is patent EP 855183, 1998, which describes antibacterial drugs - derivatives of quinoline.

The present invention is the creation of medicines on the basis of ofloxacin in nomu and quantitative selection of components.

To solve the problem proposed an antimicrobial agent called Tarifaire in the form of tablets, coated tablets contain the active ingredient ofloxacin and excipients lactose, corn starch, hydroxypropylcellulose or methylcellulose, croscarmellose of sodium and crosspovidone and magnesium stearate at a ratio, wt.%: Ofloxacin - 35-70 corn Starch - 6-15 Hydroxypropylcellulose or methylcellulose - 2-4 Croscarmellose sodium or crosspovidone - 1-3 Magnesium stearate 0.5 to 2.0 Lactose - the Rest of the film-coated Tablets comprising hypromellose, triacetin or polyethylene glycol 6000, ink suspension "White lake" when their ratio, wt.%: The hypromellose - 35-65 Triacetin or polyethylene Glycol 6000 - 6-12
Ink suspension "White lake" - 30-56.

A specific embodiment of the invention.

By the beginning of the medicinal product Tarifaire is ofloxacin(+-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4 benzoxazine-6-carboxylic acid.

An example of a specific embodiment of the invention.

The drug contains, g:
Ofloxacin (in terms of active substance) - 0,20
Lactose-earth - 0,0078
The hypromellose - 0,0049
Triacetin - 0,0008
Ink suspension "White lake" - 0,0043
Brief technology for preparation is as follows. Ofloxacin and excipients sift through a sieve, mix, granularit. The obtained granulate is dried, optivault and tabletirujut. The tablets covered with a shell in drazherovalnogo boiler or installing a fluidized bed.

The active substance of Tariverde is an antibiotic ofloxacin.

Ofloxacin has a broad antibacterial spectrum of action. Affects mostly gram-negative bacteria. Effective against microorganisms resistant to most antibiotics and sulfonamides. Bactericidal action. Used for infections of the respiratory tract, ear, throat, nose, skin, kidneys. Rapidly absorbed from the gastrointestinal tract (bioavailability over 95%). The maximum concentration in the blood is achieved within 30-60 minutes. The half-life of 6-7 hours. There is metabolized. 75-90% is excreted in the urine. Even after a single dose found in the urine within 20-24 hours.

Were conducted clinical trials of the drug Tarifaire, the tablets were coated with the spruce co., Ltd.", India, series-020020, release date, 11.00, shelf life of up to 10.03, registration number 008163, date of registration 14.02.97.

The research was conducted in 18 healthy subjects: 6 men and 12 women aged 18-45 years.

Taking drugs was carried out per os at 9 a.m. at the dose of 200 mg (1 tablet one of the study drug. Blood sampling was carried out from the cubital vein in an amount of 5 ml glass test tubes before taking the drug and after 0,25; 0,5; 0,75; 1; 1,5; 2; 4; 6; 8; 10; 12; and 24 hours after administration of the drug.

To 1 ml of plasma was added 500 μl of phosphate buffer and 5 ml of chloroform, shake for 15 minutes. Then the samples were centrifuged for 10 minutes at 3000 Rev/min the Organic layer was quantitatively transferred into a clean test tube and add 200 ál of 0.1 M sodium hydroxide solution. The samples were mixed on a "vortex" 1 minute, centrifuged for 5 minutes at 3000 rpm and 100 μl of the aqueous phase was injected into the column of the chromatograph.

The analysis was performed on the high performance liquid chromatograph "Shimadzi" with the fluorometric detector "Kratos" atex282 nm. Used reversed-phase chromatographic column: Bond ODS 4.6 mm15 see the Elution was performed with a mobile phase composition of acetonitrile - 0.01 M phosphate is alala of 1.4 ml/min.

Khromatograficheskie specifications are methods of quantitative determination of ofloxacin in plasma are presented in table 1.

Quantitative determination was performed by the method of calibration according to the peak areas using integrator "Schimadzu". The calibration relationship was linear in the concentration range of 0.1-5 ág/ml Calibration graph was described by a linear equation of the form: y=a+bx, where y is the concentration of drug in plasma (μg/ml); a=0,11858; b=0,00000274; x is the area of the chromatographic peak of the drug. The regression coefficient r=0,9943.

Pharmacokinetic parameters were calculated using KineticaTM2000 model-independent method. Was calculated the following parameters:
the maximum concentration of Cmax- the maximum value of the measured;
her achievements Tmaxthe time at which the measured maximum concentration;
the area of the pharmacokinetic curve is within the duration of the observation (AUC0-t) was calculated by the method of trapezoids, a (AUC0-) - by extrapolating to infinity, AUC0-= AUC0-t+Cthe half-life T 1/2 0,693/ kel;
the ratio of Cmax/AUC0-- individual values for the test drug and the comparator drug (as a characteristic velocity suction).

Expected relative (f) and maximum (f') the degree of absorption of the drug Tarifaire compared with drug Tarivid:
(f) = AUC0-(Tarifaire)AUC0-(Tarivid)
(f') = Cmax(Tarifaire)/Smax(Tarivid)
The obtained experimental data were subjected to statistical analysis using the package Systatw 5 for PC. Calculated statistical parameters: arithmetic mean (Mean), geometric mean (Geom Mean), standard deviation of the average (SD), standard error (SE), coefficient of variation (CV), median (Median). The significance of differences was assessed using ANOVA at a confidence level of 90% after logarithmic transformation of the values of pharmacokinetic parameters.

The dynamics of the concentration of ofloxacin in plasma of healthy volunteers after a single dose of 200 mg (tabla 1 the curves shown in Fig.1-2, and average pharmacokinetic curves in Fig.3 and 4.

These data indicate that the average concentrations of ofloxacin in plasma of volunteers for each time point is statistically not significantly different for the studied drugs.

When analyzing the average pharmacokinetic curves of drugs Tarifaire and Tarivid shows that they are almost the same. After taking as reference product and the test drug ofloxacin rapidly absorbed into the systemic blood flow from the gastrointestinal tract, reaching the maximum level to 1.5 hours (2,140.16, and 2,040,13 µg/ml, respectively). The coefficient of variation of individual values ranged from 31 to 93%.

The results of calculations of pharmacokinetic parameters of drugs Tarifaire and Tarivid shown in tables 4 and 5 and in Fig.5-8. As can be seen from the curves, the values of all the calculated parameters are statistically not significantly different, the maximum concentration of Cmaxfor Tariverde was 2.300.17 µg/ml, and for Tarivida - 2,40of 0.14 μg/ml; the time to achieve Tmax1,3P>
- 16,451,29 and 17,231,17 mcgh/ml, the half-life T1/2 of 7.60,6 and 7.90.6 hours, respectively. In the analysis of individual pharmacokinetic parameters noteworthy moderate variation (CV 33%).

From the above data it is seen that the values of the relative bioavailability of the drug Tarifaire in relation to the drug Tarivid range of 0.58-1,19. Noteworthy moderate scatter of individual values of the relative degree of absorption (CV= 17%). The average relative bioavailability of the drug Tarifaire in relation to the drug Tarivid 0.970,03.

The average value of the maximum extent of absorption of the drug Tarifaire in relation to the drug Tarivid is 0,960.04, and individual values vary in the range of 0.62-1,18. Is moderate individual variation in maximum absorption (CV=18%).

The values of the ratios of maximum concentration to the area under the pharmacokinetic curve Cmax/AUC0-for preparations of tar is 09 and 0,1450,008 respectively, and individual variation was moderate (CV 26%).

The calculated boundaries of the 90% interval is out of valid and are of 0.90-1.04 million for f and 0,89-1,03 f'. This interval is symmetric with respect to the equivalence point (the unit).

Thus, no statistically significant differences in the processes of absorption, distribution and elimination of drugs Tarifaire and Trifid, as well as in their relative bioavailability.


Claims

An antimicrobial agent, characterized in that it is made in the form of tablets, coated, while the core consists of ofloxacin and excipients lactose, corn starch, hydroxypropylcellulose or methylcellulose, croscarmellose of sodium and crosspovidone and magnesium stearate in the following ratio of ingredients, wt.%:
Ofloxacin - 35-70
Corn starch - 6-15
Hydroxypropylcellulose or methylcellulose - 2-4
Croscarmellose sodium or crosspovidone - 1-3
Magnesium stearate - 0,5-2,5
Lactose - Rest
and the shell comprises hypromellose, triacetin or polyethylene glycol 6000 and the ink suspension "White lake" at a ratio, by weight. %:
lake - 30-o

 

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