RU2199324C1 - Antibacterial agent "brifeseptol" - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: agent comprises sulfamethoxazole and trimethoprim as active substances and also Collidon CL, polyvinyl-pyrrolidone or polyvinyl alcohol, 1,2-propylene glycol, talk, magnesium stearate and potato starch taken in the definite ratio of components. Invention provides the broad spectrum of effect of agent, absence of toxicity and exhibits good analytical and physical-chemical indices. EFFECT: valuable medicinal properties of agent. 2 dwg, 4 tbl

Description

 The invention relates to medicine and relates to the creation of an antibacterial agent with a wide spectrum of action.

 A solid dosage form is known, made in the form of granules pressed together, containing the active substances sulfamethoxazole and trimethoprim and auxiliary substances mannitol, lactose, microcrystalline cellulose, talc (patent Fr 2321893, 04.29.1977).

 It is also known a medicine based on the same active substances, made in the form of granules, coated with a dusting layer and pressed together into a tablet. As auxiliary substances, it includes starch, polyvinylpyrrolidone, calcium or magnesium stearate (patent Ru 2141823, 1999).

 The closest in technical essence and the achieved result is the drug "Bactrim" (MD Mashkovsky. Medicines, Moscow, "Medicine", 1993, part 2, pp. 335-336). The tool is made in tablet form, is a combined preparation containing two active substances sulfamethoxazole and trimethoprim. Being an active antimicrobial agent, bactrim (produced in Poland under the name Biseptol-480 and Biseptol-120) can cause side effects when taken.

 The objective of the present invention is to provide a domestic drug based on sulfamethixazole and trimethoprim in the form of tablets with good disintegration, "dissolution", which does not give serious complications when taken orally.

 To solve this problem, a drug called Brifesptol containing 3- (para-amino-benzenesulfamido) -5-methylisoxazole (sulfamethoxazole) and 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine (trimethoprim ) As excipients, it includes potato starch, Collidone CL, polyvinylpyrrolidone or polyvinyl alcohol, 1,2-propylene glycol, talc and magnesium stearate.

 The composition of physiologically acceptable excipients and their quantitative content, selected experimentally, provide good analytical performance of the tablet and the prevention of a number of complications when taking the tablets inside.

Brifesceptol contains ingredients in the following proportions, wt.%:
Sulfamethoxazole - 40 - 75
Trimethoprim - 8 - 15
Collidone CL - 0.5 - 3.0
Polyvinylpyrrolidone or - 2.0 - 6.0
Polyvinyl alcohol - 0.2 - 0.6
1,2-Propylene glycol - 0.5 - 2.0
Talc - 0.5 - 2.5
Magnesium stearate - 0.5 - 1.0
Potato Starch - Else
The granulate is produced on a granulator model "Roto 600 R" (manufacturer - company "Zanchetta &C", Italy).

 The granulator is designed for vacuum single-stage granulation of substances. The agglomeration process takes place by injecting granulating liquid through a spray nozzle installed in the granulator body, under vacuum, with periodic mixing of the ingredients. In this case, heat exchange between the product and the inner surface of the water jacket of the granulator is used, as a result of which optimal drying of the granulate is achieved.

 The technological process includes the following stages.

 1. Vacuum loading of ingredients (sulfamethoxazole, trimethoprim, potato starch, collidone).

 2. Mixing the ingredients for 5 minutes at a rotor blade speed of 90 rpm.

 3. Primary granulation - by injecting granulating liquid from a mobile container using a spray nozzle at a high mixing speed of the product.

 The granulating liquid may be a mixture of starch paste, 1,2-propylene glycol and a solution of polyvinylpyrrolidone or starch paste, 1,2-propylene glycol and a solution of polyvinyl alcohol.

 4. Stirring without adding granulating liquid using a telescopic crusher.

 5. Vacuum drying of the granulate due to heat exchange between the product and the inner surface of the water jacket of the granulator with periodic mixing of the granulate until the moisture in the granulate reaches 2.5-3.5% (determination by K. Fischer method after every 30 minutes of drying).

 6. Unloading dry granulate in a bin. It is carried out with a rotating mixer through a pneumatic transport-granulation unit G-50 with simultaneous sifting through a sieve with a mesh size of 1.2 mm.

 7. Dusting of the granulate (starch, talc, magnesium stearate, collidone) is carried out in a bin on a bintambler.

 8. Tableting on a tablet press.

The resulting tablets have the following technological characteristics:
abrasion resistance - not less than 99.5%;
breaking strength of 40-120 N;
disintegration 4-6 minutes.

An example of the calculation of the load (per 200 kg) to obtain the tablets "Brifesptol", kg:
Sulfamethoxazole (99.77%) ser. 0100101 - 117.91
Trimethoprim ser. 00157 - 23.52
Potato starch - 47.32
Kollidon SL-M - 5.0
Polyvinyl alcohol - 0.45
1,2-Propylene glycol - 1.80
Talc - 2.0
Magnesium Stearate - 2.0
"Brifesceptol" includes two active ingredients - sulfonamide preparation - sulfamethoxazole and a derivative of diaminopyrimidine - trimethoprim (in combination 5: 1).

 The combination of sulfamethoxazole and trimethoprim, each of which has a bacteriostatic effect, provides high bactericidal activity against gram-positive and gram-negative bacteria that are resistant to sulfonamide drugs.

 The bactericidal effect is associated with a double blocking effect of the drug on bacterial metabolism. Sulfamethoxazole disrupts the synthesis of dihydrofolic acid in bacterial cells, and trimethoprim prevents the conversion of dihydrofolic acid to tetrahydrofolic acid. Thus, the drug blocks two successive stages of the biosynthesis of purines and, therefore, nucleic acids, which are necessary for the growth and reproduction of bacteria.

 Both components of the drug have a synergistic antimicrobial effect associated with the inhibition of two enzymes that catalyze sequential reactions in the biosynthesis of folic acid in microorganisms. Thanks to this mechanism of action, Brifeceptol (sulfamethoxazole with trimethoprim) has a bactericidal effect even at such concentrations at which each component of the drug individually has a bacteriostatic effect. Therefore, the drug is also often effective against microorganisms that are resistant to one of its components. In addition, there is less likelihood of the formation of resistance of microorganisms to the drug.

 Microorganisms with a minimum inhibitory concentration (MPC) of less than or equal to 80 mg / L are usually sensitive to the drug; microorganisms with a MIC of 80-160 mg / L are partially sensitive.

It is shown that high concentrations of the drug are created in the tissues of the lungs, kidneys, prostate gland, bones, cerebrospinal fluid, and bile. "Brifesptol" is active against gram-positive microorganisms: cocci - Staphylococcus spp. (including those producing penicillinase), Streptococcus spp., including Sir. pneumoniae; bacteria - Corynebacterium diphtheriae;
gram-negative microorganisms: cocci - Neisseria gonohoeae; bacteria - Eschenchia coil, Shigella spp., Salmonella spp., Proteus spp., Enterobacter spp., Klebsiella spp., Yersinia spp .. Vibrio cholerae, Haemophilus influenzae; anaerobic non-spore forming bacteria - Bacteroides spp., Clamydia spp. The drug is also active against Toxoplasma gondi.

 Resistant to the drug are Pseudomonas aeruginosa, Treponema spp., Mycoplasma spp., Mycobactenum tuberculosis, as well as viruses and fungi.

 After oral administration, trimethoprim and sulfamethoxazole are rapidly and almost completely absorbed in the upper gastrointestinal tract (GIT). After a single dose of 960 mg of Brifesceptol, maximum plasma concentrations are reached after 1-4 hours and are 1.5-3 μg / ml for trimethoprim and 40-80 μg / ml for sulfamethoxazole. It was shown that with repeated administration every 12 hours, the concentrations of both components stabilize in the above ranges.

 Plasma protein binding is 66% for sulfamethoxazole and 42-46% for trimethoprim. The drug penetrates well into tissues. Both components easily penetrate the placenta, as well as into breast milk.

 Sulfamethoxazole is metabolized in the liver with the formation of inactive metabolites, and in the process of trimethoprim metabolism, oxymetabolites are formed, of which only a few are active.

 About 50-70% of the dose of trimethoprim and 10-30% of the dose of sulfamethoxazole are excreted unchanged. The half-lives of both components are on average 10-11 hours. Both substances and their metabolites are excreted mainly by the kidneys.

 It was found that with age in patients with impaired renal function, the half-lives of both components increase.

Indications for use
Infectious and inflammatory diseases caused by microorganisms sensitive to the drug, including bronchitis, pneumonia, pleural empyema, lung abscess, pyelonephritis, cystitis, urethritis, prostatitis, gastrointestinal diseases, brucellosis, wound and surgical infections, scarlet fever, meningitis, brain abscess, osteomyelitis, sepsis, cholecystitis, cholangitis, in combination therapy )

 For adults and children over 12 years of age, the drug is prescribed at 960 mg 2 times / day, with prolonged therapy - at 480 mg 2 times a day. Children 6-12 years old are prescribed 480 mg 2 times a day.

 In acute infections, the duration of treatment is 5-6 days, in acute brucellosis - 3-4 weeks, with typhoid and paratyphoid - 1-3 months. In patients with impaired renal function, the dose of the drug depends on the creatinine clearance value: when clearance is more than 30 ml / min, average therapeutic doses are shown, when clearance is 15-30 ml / min, 50% of the therapeutic dose is used, when clearance is less than 15 ml / min .

 It was shown that the simultaneous use of "Brifeceptol" and thiazide diuretics leads to an increased risk of thrombocytopenia. The drug increases prothrombin time with the simultaneous use of warfarin. The drug can inhibit the metabolism of phenytoin in the liver, which leads to an increase in the half-life of phenytoin by 39%. The drug displaces methotrexate from binding to plasma proteins. In patients receiving both indomethacin and brifeceptol, an increase in plasma sulfamethoxazole level is possible.

When using the drug, side effects are possible:
- from the gastrointestinal tract - nausea, vomiting, diarrhea;
- from the hemopoietic system - thrombocytopenia, leukopenia, megaloblastic anemia;
- from the urinary system - crystalluria.

Contraindications
- the drug is contraindicated during pregnancy;
- Hypersensitivity to the components of the drug;
- Severe violations of the hematopoietic system;
- the period of breastfeeding (the issue of switching the feeding of the child to artificial nutrition should be resolved);
- deficiency of glucose-6-phosphate dehydrogenase due to the risk of hemolysis;
- severe damage to the liver parenchyma and severe renal impairment.

 The proposed tool "Brifeceptol" has passed preclinical studies. The study was conducted in comparison with the drug "Biseptolum" (Poland).

 To record the UV spectrum, a U1trospec-11 spectrophotometer manufactured by LKB Biochrom was used. When recording the absorption spectra, one tablet of both the experimental and control preparations was dissolved in 10 ml of distilled water, followed by filtration through a Millipore filter with a pore diameter of 0.45 μm, then the filtrate was diluted in a ratio of 1: 100 with distilled water.

 In FIG. 1 shows an overview absorption spectrum of a solution of a control preparation in the range from 200 to 300 nm. As can be seen from figure 1, reveals one clear absorption peak in the region of 260 nm, equal to 0.596 units. optical density.

Figure 2 shows the absorption spectrum of the solution of the experimental drug in the same interval (from 200 to 300 nm). The spectrum also reveals one peak of absorption at 260 nm, equal to 0.579 units. optical density
Thus, the absorption peak values of the optical density of the experimental and control preparations differ by less than 5%, which indicates the equality in them of the concentration of all ingredients, including the active principle.

 Tests for disintegration and dissolution of tablets in accordance with the requirements of Global Fund XI. The test was carried out on tablets of Brifezeptol 0.48 mg and tablets of Biseptol 480, manufactured by the Pabyanicki Pharmaceutical Plant Polfa, Poland.

The analysis of the test "Disintegration" was carried out on the apparatus "swinging basket" manufactured by ERWEKA. As the solvent used distilled water, the volume of solvent 1 l, a temperature of 37 ^o C.

 For testing, the tablet was placed in a basket with a mesh diameter of 2 mm. The basket was immersed in the dissolution medium and translational movement was carried out in a vertical plane with a frequency of 60 Hz. When the tablets completely disintegrated, the device was turned off, after which the timer readings were read.

 The decay time of the experimental and control tablets is given in table. 1. As follows from the above data, the tablets of the experimental batch disintegrated in 4'38 "± 24", and the control lot - in 5 "05" ± 34 ". In all cases, the disintegration time of both experimental and control tablets is from 4 to 6 minutes, which is significantly less than the requirements of the Global Fund XI, according to which the disintegration time should not exceed 15 minutes.

Analysis of the Dissolution test was carried out on a rotating basket instrument manufactured by ERWEKA with six rounds. Samples were placed in cylindrical mesh baskets with a diameter of 25 mm with a diameter of mesh openings of 2 mm. The baskets were completely immersed in a dissolution medium (0.01 M hydrochloric acid solution) of 0.5 liter volume at a temperature of (37 ± 1) ^o С (water bath) and rotationally moved in a horizontal plane at a speed of 100 rpm.

 After 30 minutes, aliquots of the solution (5 ml) were taken from all cartridges, which were then filtered through a Millipore filter (pore diameter 0.45 μm), after which the concentration of the active substance was determined by spectrophotometric method at 260 nm.

 According to the table. 2 after 30 minutes of dissolution of the experimental tablets, 94.5 ± 4.6% passes into the solution, and control tablets - 92 ± 5.8% of the active principle, which is significantly more than the requirements of ND, according to which this value should be at least 75%.

 Acute toxicity of "Brifeceptol" was studied on white outbred mice weighing 17-23 g. The drug for administration was prepared as follows. The tablets were ground in a porcelain mortar and a suspension was prepared on the basis of a 3% starch solution. The suspension was administered per os through a probe in a volume of 1.0 ml.

 A total of 72 non-linear mice weighing 20 ± 3 g were used. Laboratory animals were divided into six groups, six animals in each group. The experimental and control preparations were administered at doses of 1 g / kg, 2 g / kg, 4 g / kg, 6 g / kg, 8 g / kg and 10 g / kg. Both test drugs (both the experimental and the comparison drug) did not cause the death of laboratory animals within 12 days after a single injection of even a maximum dose of 10 g / kg, i.e. turned out to be non-toxic. However, dyspeptic disorders are noted at high (more than 6 g / kg) doses of both the experimental and control drugs.

Subacute toxicity of the drug was studied on outbred white rats weighing 180-220 g. The drugs were administered intragastrically (Table 3). Laboratory animals were divided into five groups:
- Group 1 - 10-fold dose of the drug Brifesptol;
- Group 2 - therapeutic dose of the drug Brifeptol;
- Group 3 - 10-fold dose, Biseptol
- Group 4 - therapeutic dose of the drug Biseptol
- Group 5 - intact animals, saline.

 The duration of drug administration was 14 days. During the experiment, the degree of intoxication was assessed by the general condition of the animals, the condition of the coat, the onset of tremor, seizures, changes in the frequency and rhythm of respiration.

 After the end of drug administration, a postmortem examination of the animals was performed. For light-optical analysis, samples were taken of the kidneys, liver, spleen, thymus, and brain. In addition, biochemical and hematological parameters such as total protein, glucose, urea, alanine transferase (ALT) activity, asparagin transferase (ACT), alkaline phosphatase concentration, hemoglobin concentration, platelet and white blood cell counts, and white blood cell counts were determined in animals.

 As studies have shown, a 2-week administration of drugs (Table 4) does not cause a significant change in the mass of organs such as the liver, kidneys, spleen, thymus, stomach, and brain. During the entire time of administration, not a single fatal case has been recorded. There was no change in the state of the coat, no impaired coordination of movements, tremor, changes in the rhythm and respiratory rate, as well as pathological changes in other physiological parameters. Both drugs in both therapeutic and 10-fold therapeutic doses did not cause visible signs of intoxication.

Claims (1)

An antibacterial agent containing the active components sulfamethoxazole, trimethoprim and excipients, characterized in that it contains Collidone CL, polyvinylpyrrolidone or polyvinyl alcohol, 1,2-propylene glycol, talc, magnesium stearate and potato starch in the following ratio of ingredients, wt. .%:
Sulfamethoxazole - 40 - 75
Trimethoprim - 8 - 15
Kollidon CL - 0.5 - 3.0
Polyvinylpyrrolidone or - 2.0 - 6.0
Polyvinyl alcohol - 0.2 - 0.6
1,2-Propylene glycol - 0.5 - 2.0
Talc - 0.5 - 2.5
Magnesium stearate - 0.5 - 1.0
Potato Starch - Rest

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