A composition having antimicrobial activity

 

(57) Abstract:

The invention relates to medicine, namely to farmacie and for the creation of an injectable streptocide. Task is the creation of a drug for injection containing-form streptocide, does not cause side effects when used and has a high bioavailability. The essence of the invention lies in the fact that the drug for injection contains g-form streptocide with a particle size less than 0.1 μm, the low molecular weight polyvinylpyrrolidone, and water for injection in the following ratio, wt. %:

Streptocide g-form - 1,5 - 2,5

The low-molecular polyvinylpyrrolidone - 2,0-4,0

Water for injection - Rest.

7 table.

The invention relates to medicine, namely to farmacie and for the creation of an injectable streptocide, necessary for the effective treatment of bacterial infections in clinical practice.

Sulfa drugs successfully used for the treatment of infectious diseases, are produced mainly in tablet form, as the core group of these drugs insoluble in water. At the same time, injectable form sulfenic severe forms of bacteriostatic and bactericidal infections [1]

The creation of an injectable form of sulfonamides involves translating them into soluble salts, in particular the formation of soluble compounds through the primary aromatic group [1]

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But this structure is unstable to the introduction of the stabilizer - toxic sodium sulfite.

In addition, the antimicrobial action of sulfonamides is possible only in an open-amino group in paraprotein to sulfa group, and the degree of its exposure, and therefore the antimicrobial effect will depend on the time and state of physiological constants blood [2]

Streptocide soluble issued in the form of 0.5, 5, 10 solution containing streptocid, stabilizer sodium sulfite and water for injection [3] (prototype). Used to treat sore throat, erysipelas, cystitis, pyelitis and other infections in the case when the patient's condition (vomiting, unconsciousness) does not allow to assign the sulfonamides inside.

Thus streptocid soluble, produced at the present time, the pharmaceutical industry, has a number of negative properties: they are side effects associated with the introduction of toxic stabilizer, irritant action of the e described. Streptocide g-form is not found use as a drug for injection.

The aim of the work was the creation of a drug for injection with high bioavailability and does not cause side effects when used.

The essence of the invention lies in the fact that the drug for injection contains:

g-form streptocide with a particle size less than 0.1 μm, the low molecular weight polyvinylpyrrolidone, and water for injection in the following ratio, wt.

g-form streptocide 1,5 2,5

Polyvinylpyrrolidone 2,0 4,0

Water for injections the Rest

The essential features that characterize the invention, are: the choice of the g-form streptocide at the declared size of the microparticles, selection of solvent, the quantitative composition of the ingredients of the composition.

Only the particle size of the g-form streptocide less than 0.1 μm provides passage of a drug through a needle N 0840, i.e. allows you to enter the drug intramuscularly.

The combination of all features allows you to obtain a new result of reduced side effects, improved bioavailability.

Streptocide g-form was first used when is some activity g-form streptocide showed he possesses antimicrobial activity, is not inferior to the activity of the existing pharmacopoeial streptocide.

For the study of the specific antimicrobial activity g-form streptocide used the method of serial dilutions. The initial solution was 0.5 solution streptocide pharmacopoeial and g-forms of 0.01 N. the solution of sodium hydroxide. Preparing two-fold dilution of solutions streptocide in meat-peptone broth with the addition of culture of Staphylococcus aureus (Staphylococcus aucreus). Sowing was aged a day in thermostat. Was determined visually bacterial plankton static concentration.

Were used sterile and non-sterile solutions streptocide pharmacopoeial and g-forms.

The experiments were conducted on three series of solutions streptocide in triplicate.

The results are presented in table 1.

Analysis of the data presented in table. 1, suggests that g-form streptocide possesses antimicrobial activity, is not inferior to the activity of pharmacopoeial streptocide.

To study the toxic effects of the claimed form of streptocide compared with the prototype carried out pathological examination of the organs of animals with pontrelli the animals were killed after certain periods of time. Pieces of bodies were recorded 10 12 solution of neutral formalin, was filled with paraffin, sliced thick 8 to 10 mm was colored with hematoxylin-eosin.

Histological examination were subjected to the following organs: the hip muscles, heart, lungs, liver, kidney, spleen. Histological examination injectable form soluble streptocide (prototype) at the site of intramuscular injection in the thigh muscles detected hemorrhage different depths (from small to extensive). Muscle tissue hemorrhages changed, these changes are characterized by a disturbance of General structure structure of muscle fibers (disappears transverse striation), including necrosis.

With intramuscular injection of declared drug streptocide (g-shape) for injection of pathological changes in the muscle is not detected. Thus, the claimed medicinal drug no irritant effect inherent in the prototype.

Histological examination of the other organs showed no significant changes with the introduction of the claimed medicinal preparation in comparison with the prototype.

Thus, experiments on animals have shown in the introduction stated the Oh emission solution streptocide for injection (prototype) and the proposed drug for injection, containing g-form streptocide, sang and danced on rats male weighing 150 to 200 g of the First group of animals were injected intraperitoneally 2 ml of the drug for injection (prototype), the second group of 2 ml of the preparations, containing, g-form streptocide 2,0; low-molecular polyvinylpyrrolidone 3,0; water for injections the rest; the third 2 ml of water for injection. Spent observing animals for 10 days. Next expected value LD50.

The results of the experiment are presented in table 2.

Analysis of the data shows lower toxicity (by 54.4) of the proposed drug in comparison with the prototype.

To study the bioavailability of the claimed medicinal preparation in comparison with the prototype, studies have been conducted of the following indicators: 1) the maximum concentration of drug substance in the blood; 2) the time to reach maximum concentration; 3) the area under the curve of the change in concentration of a substance in plasma or serum in time.

The experiments were conducted on rabbits weighing 3 kg Calculation to streptocide was made with regard to therapeutic and amounted to 100 mg/kg taking into account the difference in molecular mass substances (equimolar Ovi and then the obtained sample was analyzed by the method of Propsting-Gavrilova [5]

The data obtained are summarized in table 3.

The data obtained indicate that the claimed medicinal preparation of streptocide has a bioavailability in 2,43 times larger than that of the prototype. This will allow, respectively, in 2,43 times to reduce therapeutic dose of the drug that will contribute to further mitigate the side effects of the drug. At the same time, the use of streptocide in its therapeutic dose, due to the high bioavailability may increase the bacteriostatic action of the drug, and thus its therapeutic efficacy.

The possibility of carrying out the invention is confirmed by studies on the selection of quantitative parameters ingredients of the composition, the use of which it is in the stated ratios makes it possible to achieve the goal.

Orientirovochnyi criterion concentration streptocide was its therapeutic concentration in the blood, which is from 2 to 20 mcg/ml [6], We have taken into account the concentration of streptocide soluble for intramuscular and subcutaneous injection, which is 1.0 to 1.5 [1]

To select the optimal concentration of studies have been conducted, achiev.

As can be seen from the presented data, in the stated concentrations of the required therapeutic concentration, close to the lower limits of therapeutic. At concentrations higher than 2.5 increases the load on the muscle tissue, which manifests itself in violation of the General structure of muscle fibers. At higher doses there is a risk of the appearance in the blood to toxic concentrations.

The choice of polyvinylpyrrolidone (PVP) as a solvent based on his indifference and providing the necessary sedimentation stability and absorbability of the composition. The time of sedimentation was established experimentally. This purpose was prepared 1 6 solutions of PVP, which made hanging streptocide. The mixture was shaken for 15 seconds and determined the optical density of the solution on fotoelektrokalorimetry FEC-56 M. the Results are shown in table 5.

As can be seen from the presented data, g-form streptocide without PVP quickly sedimentary. Increasing the concentration of polymer increases sedimentation stability. However, within 1 during 5 minutes (regulated minimum time) the lack of stratification of injectable drugs is not achieved. At a concentration of 3 4 6 the e optical density coincides with the original one.

Based on the analysis of the concentrations of streptocide in the blood stages of absorption and excretion of optimal boundaries should be considered 2 4

The dispersion of streptocide (g) form less than 0.1 μm provides a passage through the needle N 0840 (GF XI ed.).

The invention is illustrated by the following examples.

Example 1. The technological process is carried out under aseptic conditions.

2 g of low-molecular Polyvinylpyrrolidone (m 12000 m) was dissolved in a small amount of water for injection, the resulting solution was added 1.5 g of powder streptocide g-form with a particle size less than 0.1 μm, were shaken for 15 to 20 seconds and brought the volume of the resulting suspension with distilled water for injection to 100 ml, once again shook.

Thus obtained pharmaceutical preparation for injection is a suspension with an optical density of 2.3, after 5 minutes of settling, the optical density was 2.2, pH 6.5, T. O. the resulting suspension is stable, provides a passage through the needle N 0840 (GF XI edition).

Five rabbits weighing 3 kg was administered intramuscularly in a dose of 3 ml of the prepared suspension.

After 0.5, 1, 2, 4, 6 hours about the-Gavrilova).

The obtained experimental data were subjected to statistical analysis (p 95). Experimental data are presented in table 6.

The table shows that therapeutic concentration streptocide in the blood is maintained for 6 hours.

Histological inspection did not reveal changes of internal organs.

Example 2. The technological process is carried out under aseptic conditions.

4 g of low-molecular polyvinylpyrrolidone (m 12000 m) was dissolved in a small amount of water for injection, the resulting solution was added 2.5 g of powder streptocide g-form with a particle size of 0.1 μm or less were shaken for 15 to 20 seconds and brought the volume of the resulting suspension with distilled water for injection to 100 ml, once again shook.

Thus obtained pharmaceutical preparation for injection is a suspension with an optical density of 3.2, after 5 minutes of settling, the optical density was 3.0, pH 6,8, T. O. the resulting suspension is stable, provides a passage through the needle N 0840 (GF XI edition).

Five rabbits weighing 3 kg was administered intramuscularly in a dose of 3 ml of the prepared suspension.

Through 0,5, 1, 2, 4,� (Proebsting-Gavrilova).

The obtained experimental data were subjected to statistical analysis (p 95).

Experimental data are presented in table 7.

The table shows that therapeutic concentration streptocide in the blood is maintained for 6 hours.

Histological inspection did not reveal changes of internal organs.

The application of the proposed drug for injection with enhanced bioavailability and reduced side effects, will significantly reduce the treatment time and virtually eliminate side effects. TTT TTT TTT TTT TTT

A composition having antimicrobial activity, containing streptocid and water for injection, characterized in that it further comprises polyvinylpyrrolidon low molecular weight, and as streptocide form with a particle size less than 0.1 microns at the following ratios,wt.

Streptocide g-form 1,5 2,5

The low-molecular polyvinylpyrrolidone 2,0 4,0

Water for injections the Rest

 

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