EA010981B1 - Preparation of antimicrobial action - Google Patents

Abstract

The invention relates to chemico-pharmaceutical industry, in particular, to preparing an antimicrobial agent as a suppository comprising iodine, and can be used in clinical practice for the treatment of inflammatory diseases of female genital region.The preparation of antimicrobial action manufactured as a suppository comprises iodine as an active substance and an excipient, characterized in that the active substance made in the form of iodine-dimethylsulfoxide in ratio 1:(1-10), and as the excipient it comprises a fat-soluble base, wherein the iodine content in the suppository is 10 to 20 mg.The suppository offers a wide range of antimicrobial action.

Description

The invention relates to the pharmaceutical industry, in particular to the creation of an antimicrobial agent in the form of suppositories containing iodine, and can be used in clinical practice in the treatment of inflammatory diseases of the female genital area.

An urgent problem not only of modern gynecology, but also of medicine in general, is the antibiotic resistance of pathogenic microorganism strains. The adaptive capabilities of pathogenic microflora lead to the rapid development of resistance not only to antibiotics, but also to sulfanilamides, nitrofurans, etc. Resistance practically does not develop only to bactericidal agents, since most of them are based on the lysis of protein structures and the destruction of vital cellular elements of bacteria. But it is precisely this property that limits the possibilities of their use in clinical practice. As a rule, antiseptics are toxic to the host, in addition, they do not penetrate the source of infection.

Many pathogens of uroginetic infections have stages of "rest" in their life cycle; when adverse conditions occur, they penetrate the host cells, become inaccessible to most antibiotics, etc., provoking chronic forms of the disease and the persistence of microbes.

The “targeted” route of drug delivery allows not only to increase the effectiveness of treatment, but also to avoid many of the adverse effects of taking the drug.

The genitourinary system is known to be difficult to access for most drugs; to create the necessary concentrations of drugs in the focus of inflammation often increase the dose.

Iodine is a well-known antiseptic. Iodine is widely used in medical practice for inflammatory and other diseases of the skin and mucous membranes, however, the use of iodine to create drugs is limited by its solubility. For external use, usually 5-10% iodine solutions are used. For the treatment of gynecological diseases, 20 mg per suppository is enough.

Known drug "Betadine" - vaginal suppositories. The active substance - iodine is in the form of a complex with polyvinylpyrrolidone (povidone). 1 suppository contains 200 mg of iodine povidone and 2.8 g of macrogol. The concentration of active iodine is 0.1-1%. (The Register of Medicines of Russia - Radar, 2003, p.236)

The drug is a broad spectrum antiseptic against bacteria, viruses, fungi and protozoa.

Indications for use:

infectious and inflammatory diseases of the female genital organs caused by iodine-sensitive microorganisms;

acute and chronic vaginitis;

mixed infections (infections caused by Sagbpsgsia ναβίηαΐίκ. fungi, trichomonads).

The drug can be used as a prophylactic before surgical operations in the vagina or diagnostic procedures.

In acute vaginitis, 1 vaginal suppository is prescribed 2 times a day for 7 days. For subacute and chronic vaginitis, 1 suppository per day is prescribed for 14 days. If necessary, the course of treatment can be extended.

Also known is the drug "Iodoxide" - vaginal suppositories. 1 suppository contains 0.2 g of iodine-povidone and a base (polyethylene oxide 1500 and polyethylene oxide-400) up to 3 g (Radar, 2003, p. 489).

Known drugs have side effects - they cause itching, flushing at the place of use and allergic reactions. In addition, it is not recommended to use polyethylene oxides on the mucous membranes.

Refusal of treatment is often caused by intolerance to drugs containing iodine.

The objective of the present invention is to expand the arsenal of antimicrobial agents for the treatment of gynecological diseases.

The technical result of the invention is that the claimed tool does not have side effects when using it (itching, hyperemia and allergic reactions) by reducing the active iodine on the suppository. When applied to tissues, the active complex, including iodine DMSO (dimethyl sulfoxide) penetrates the depths of tissues, selectively affecting microorganisms, thereby increasing the effectiveness of the treatment of gynecological diseases. In addition, while maintaining effectiveness, the course of treatment is reduced.

The problem is solved as follows.

The proposed antimicrobial agent, made in the form of a suppository, comprising the active substance iodine and a filler, characterized in that the active substance is made in the form of a complex iodine-DMSO (dimethyl sulfoxide) in a ratio of 1: (1-10), and as a filler it contains a fat-soluble basis, while the iodine content in the suppository is from 10 to 20 mg.

In a suppository weighing 1 g, the iodine content can be 10 mg.

In a suppository weighing 2 g, the iodine content can be 10 mg.

In a suppository weighing 2 g, the iodine content can be 20 mg.

The fat-soluble base may be cocoa butter or solid fat or witepsol.

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The claimed tool is called "Vagitrit."

The drug "Vagitrit" is prepared as follows.

Iodine in a ratio of 1: 1 is mixed with DMSO at room temperature until completely dissolved. Vitepsol brand N-15 (ND 42-9583-98) and / or Vitepsol brand \ U-35 (ND 42-9584-98) or cocoa butter or any solid fat for suppository base is melted at a temperature of 40-60 ° C. The base is cooled to a temperature of 35-36 ° C and iodine solution is introduced into DMSO so that the iodine content in the mixture does not exceed 1%. The suppository mass is poured into a blister strip packaging with a volume of 1 or 2 cm ³ at a temperature of 35 ° C. Hermetically sealed. Cool at a temperature of 5-8 ° C. Get suppositories weighing 1 or 2 g, the deviation in mass within ± 5%.

Appearance of the suppository: brown, hard, brittle on break, with a specific smell of iodine, torpedo-shaped.

More DMSO is not needed, as DMSO in large concentrations is toxic, causes the smell of garlic from the mouth, etc.

Iodine is readily soluble in DMSO at room temperature. A solution of iodine in DMSO can be introduced into the compositions with both fat-soluble bases and water-soluble ones. The solution of iodine in DMSO when applied to tissues ensures the penetration of iodine through biological membranes, including through the mucous membranes without damaging the latter. In addition, DMSO has a local anesthetic, local anti-inflammatory, antimicrobial effect.

Dimethyl sulfoxide belongs to the pharmacotherapeutic group - dermatotropic drugs. The pharmacological action is anti-inflammatory. It has a local anesthetic, local anti-inflammatory, antimicrobial (antiseptic) and fibrinolytic effects. It penetrates quickly and well through biological membranes, including through the skin and mucous membranes, and increases their permeability to other drugs. Changes the sensitivity of antibiotic-resistant microflora.

The drug in the conditions of the test (dilution 1:10) has an antimicrobial effect. Tests are carried out according to the Global Fund XIth ed., Issue 2 "Methods of microbiological control of medicines" and Changes No. 3 of 06/19/2003

The drug under the conditions of the test for microbiological purity (dilution 1:10) has an antimicrobial effect against Sapb1ba a1Ysapk, you. Segeik and Acre. shdeg.

Table 1. The antimicrobial effect of the drug "Vagitrit-10 mg" weighing 1.0 g

Dilution of the drug 81. aigeiz ATCC 6538-P E. SON ATCC 25922 Rz. aegid shock GISK 453 You. segeiz ATCC 10702 S. aNlsaps ATCC 885-653 Azr. Shdeg ATSS E-1119 1: 10 + + + - - - 1: 20 + + + - - - 1: 50 + + + - - + 1: 100 + + + + ± + I: 200 + + + + + + 1: 500 + + + + + + Culture control + + + + + +

Designation: "+" - the growth of the test microorganism is similar to control; "±" - weak or slow growth.

“-” - lack of growth.

As can be seen from the table. 1 preparation of Vagitrit-10 mg vaginal suppositories weighing 1.0 g has an antimicrobial effect against VasShik Segeik, Sapb1ba a1Ysaik at a dilution of 1:50, and in relation to AkretdShik it goes - 1:20. The antimicrobial effect in relation to these test microorganisms is removed by dilution of the drug 1: 100.

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Table 2. The antimicrobial effect of the drug "Vagitrit-10 mg" weighing 2.0 g

Dilution of the drug 81. aigeez ATCC 6538-P E. SON ATCC 25922 Rz. aegidosis GISK 453 You. segeiz ATCC 10702 S. a1Ysap8 ATCC 885-653 Azr. shdeg ATSS R-1119 1: 10 + 4- + - - - 1: 20 + + 4- - - - I: 50 + + + ± ± ± 1: 100 4- + + + + 4- 1: 200 + 4- + + + 4- 1: 500 + + + + + + Culture control 4- 4- 4- + + 4-

Designation: "+" - the growth of the test microorganism is similar to control;

"±" - weak or slow growth;

“-” - lack of growth.

As can be seen from the table. 2 preparations of Vagitrit-10 mg vaginal suppositories weighing 2.0 g have an antimicrobial effect against VasShik Segeik, Sapb1ba A1eaik and AkregdShik Schdeg at a dilution of 1:20. The antimicrobial effect in relation to these test microorganisms is removed by dilution of the drug 1:50.

Table 3. Quantitative assessment of the antimicrobial effect of the drug "Vagitrit" in comparison with other antimicrobial drugs and drugs - analogues containing iodine.

A drug Test microbe E.coN Rz. aegidsoza 81 Aigeez C1. b1ysy1e S. a1Ysapz 8.1 ur1 zsz Vagitrit 2.0 2.0 0.2 0.2 2.0 2.0 Betadine 2.0 3.0 0.4 0.1 1.8 2.0 Iodoxide 3.0 3.0 0.3 0.3 1.6 2.0 Benzylpenicillin 15.0-60.0 * stable 0.003-60.0 0.018-6.0 stable 1.212.0 Erythromycin 10.0-100.0 * stable 0.1-100.0 * 0.1-5.0 stable 43.0 Oleandomycin stable stable 0.3-100.0 * 1.0-20.0 stable stable Streptomycin 0.5-100.0 0.5-200.0 * 0.5-200.0 1.0-200.0 stable 0.004- 20.0 Tetracycline 0.5-100.0 * 3.0-100.0 * 0.1-100.0 * 0.1-100.0 stable 1.0-2.5 Chloramphenicol 0.5-200.0 * 10.0-200.0 * 0.5-100.0 * 1.0-50.0 stable 0.8-5.0

* - and more; the second interval of minimal inhibitory concentrations of antibiotics is given for resistant strains of pathogens

Stock solutions for studies were prepared by diluting the compared preparations with a DMSO solution. The resulting solutions were poured into 6 2 ml tubes. A series of ten-fold dilutions were made from each tube in sterile saline to a concentration of 10,000 to 0.001 μg / ml (0.2 ml of the previous concentration was diluted with 1.8 ml of saline). The control was saline without the addition of drugs. To study the antimicrobial effect on six test strains of microorganisms, 6 rows of 8 tubes were poured with the following concentrations of each drug (μg / ml): 1000-100-10-1-0.1-0.01-Κι-Κ ₂ . Each dilution of the preparations was examined in triplicate.

For research, museum strains of microorganisms were used, occupying a different systematic position: gram-positive cocci - §1aG11ossossi5 aigeik-209 P; gram gram

- 3 010981 bacilli - Excepsoy soi-88; spore-forming bacilli - OoVpbypp bShsy1e-4938 and fungi Sapb1ba a1Yasap§-674, as well as field strains Rkeiboshoyak aetidshoka and 8a1shope11a Ινρΐιί cue.

As can be seen from the table. 3, the minimum inhibitory concentration of Vagitrit for all tested strains of microorganisms is 0.2-2.0 μg / ml, i.e. comparable to the effect of known antibiotics. However, unlike benzylpenicillin, erythromycin, oleandomycin, streptomycin, tetracycline and chloramphenicol, Vagitrit has a much wider spectrum of action, as it is able to suppress the vital activity of fungi (C. a1Ysap§).

Thus, the new domestic drug has a pronounced antimicrobial effect in concentrations comparable to effective doses of antibiotics. It has a wider spectrum of action compared to most antibiotics used in medical practice.

Clinical trials were carried out on volunteers at the base of Clinic of the Family Doctor, Nizhny Novgorod.

The invention is illustrated by the following examples:

Example No. 1. Patient M.N. - diagnosis: bilateral salpinopharyitis in the acute stage, ureaplasmosis, adhesive disease, severe pain.

“Vagitrit” was used in complex therapy (cycloferon, e-phoresis, lidase, myhomax) for vaginal debridement of 5 suppositories at night. Treatment showed that the tolerance of suppositories is good, suppositories are compatible in complex therapy. As a result, a smear of the II degree of purity with preserved normoflora.

Example 2. Patient R.I. - diagnosis: nonspecific colpitis. Treat only Vagitrit suppositories (5 suppositories in the vagina at night). Tolerance is good.

In the smear before treatment: no - 20-30 in the s / s, a lot of mucus, a lot of conditionally pathogenic g + -coccal flora.

In the smear after treatment: no - 6-8 in the s / s, gr + stick units with normal normoflora preserved.

Example 3. Patient V. O. - diagnosis: nonspecific colpitis, cervical erosion.

The vagina was sanitized in front of the cervical cancer of the uterus only with “Vagitrit”, 5 suppositories at night. Tolerance is good. Before treatment, the degree of purity of the smear is 3-4; after treatment, 2.

Example 4. Patient R. E. - diagnosis: salpinitis, ureaplasmosis, chlamydia, adhesive process of the pelvis, bacterial vaginosis. “Vagitrit” was used in complex therapy (neovir, viloprafen, mykomax, lactofiltrum, wobenzym) for vaginal sanitation of 5 suppositories at night. Portability is good. As a result, garderells, mycoplasmas, ureaplasmas are eliminated. The degree of purity of the smear is 2.

Example 5. Patient Sh. N. - diagnosis: 6 weeks pregnancy, nonspecific colpitis.

The vagina was sanitized with “Vagitrite” 5 candles at night. Before treatment, a smear: no - 30-40 in the s / s, a lot of mucus, gr + fallen. - lot.

After treatment: no - 4-6 p / s, little mucus, gr + fallen - units.

The results of clinical trials have shown that suppositories exhibit a wide range of antimicrobial effects and can be used for vaginal debridement with nonspecific colpitis, bacterial vaginosis, ureaplasmosis, etc.

In addition, suppositories can be used in the complex treatment of chlamydia, viral infection, in preoperative preparation for the treatment of cervical erosion, while suppositories do not cause side effects

Claims (6)

FORMULA INVENTION 1. Means of antimicrobial action, made in the form of a suppository, including the active substance iodine and a filler, characterized in that the active substance is made in the form of a complex iodine-DMSO (dimethyl sulfoxide) in a ratio of 1: (1-10), and as a filler it contains fat-soluble base, while the iodine content in the suppositories from 10 to 20 mg. 2. The tool according to claim 1, characterized in that in a suppository weighing 1 g, the iodine content is 10 mg. 3. The tool according to claim 1, characterized in that in a suppository weighing 2 g, the iodine content is 10 mg. 4. The tool according to claim 1, characterized in that in a suppository weighing 2 g, the iodine content is 20 mg. 5. The tool according to claim 1, characterized in that the ratio of iodine and DMSO in the complex is 1: 1. 6. The tool according to claim 1, characterized in that as the fat-soluble base may be cocoa butter, or solid fat, or witepsol.