RU2293558C2 - Agent for treatment of gynecological and proctological diseases - Google Patents

Abstract

FIELD: medicine, gynecology, proctology, pharmacy.

SUBSTANCE: invention relates to medicaments made as vaginal and rectal suppository used in treatment of proctological, non-inflammatory and inflammatory diseases of female pelvis organs, among them complicated with suppurative-inflammatory processes. Invention relates to an agent used in treatment of gynecological and proctological diseases it is made as a suppository and comprises 2-ethyl-6-methyl-3-oxypyridine succinate as an active component and a base chosen from group involving polyethylene oxide-1500, polyethylene oxide-400, cacao butter and hydrogenated fats. Invention provides prolonged release of a curative preparation in mucosa and soft tissues and provides its effect for about 12 h. The procedure is suitable and easy in performance and can be carried out by patients independently under ambulatory conditions.

EFFECT: valuable medicinal and pharmaceutical properties of agent.

3 cl, 2 tbl, 2 ex

Description

The invention relates to medicine, namely to medicines made in the form of vaginal and rectal suppositories.

Vaginal suppositories can be used in the treatment of inflammatory diseases of the female pelvic organs, including those complicated by purulent-inflammatory processes:

- salpingitis and oophoritis (acute and chronic);

- inflammatory uterine disease (acute and chronic);

- endo (myo) metritis); metritis; myometritis; pyometer; uterine abscess;

- inflammatory disease of the cervix; cervicitis, endocervicitis, exocervicitis - with or without erosion or ectropion;

- Diseases of the bartholin gland (cyst, abscess, bartholinitis ......);

- other inflammatory diseases of the vagina and vulva (vaginitis, vulvitis, vulvovaginitis, abscess of the vulva, ulceration of the vagina and vulva;

as well as non-inflammatory diseases of the female genital organs:

- endometriosis;

- prolapse of female genital organs; cystocele, urethrocele, erythrocele, rectocele;

- fistulas involving female genitals;

- a polyp of female genital organs (uterus, cervix, vagina, vulva ...);

- erosion and ectropion of the cervix (decubital (trophic) ulcer);

- cervical dysplasia;

- other non-inflammatory diseases of the cervix uteri - leukoplasia, stricture and stenosis, insufficiency ......;

- other non-inflammatory diseases of the vagina (dysplasia, leukoplakia, stricture and atresia, leucorrhoea, ulcer .......

- Other non-inflammatory diseases of the vulva and perineum (dysplasia, leukoplakia), as well as after surgical interventions on the pelvic organs in order to prevent postoperative adhesions, the development of purulent complications; gynecological operations, including laparoscopic; in the postpartum period; after instrumental preventive examinations; diagnostic procedures in the vagina; intrauterine manipulations (including artificial abortion).

A known method for the prevention of suppuration of wounds of the perineum after its dissection or rupture in childbirth, including a single chipping of the wound with a 5% solution of Mexidol in an amount of 2 ml (RF patent 2146523, 2000).

A female swab with a prolonged therapeutic and prophylactic effect is known, the treatment membrane of which may contain Mexidol with other drugs (RF patent 2178312, 2002).

Known drugs are vaginal suppositories, which include antiseptic agents (povidone iodine - a complex of iodine with PVP, chlorhexidine bigluconate), which are used for infectious and inflammatory diseases of the female genital organs. However, they all have adverse reactions: allergies of various types, poorly compatible with other drugs, have only local antiseptic effects, not promoting epithelization and restoration of function of damaged tissues.

Vaginal suppositories are also known, which include ketoconazole and butyloxyanisole, used only as an antifungal (fungicidal, fungistatic) agent that does not exhibit anti-inflammatory and healing effects.

Vaginal suppositories are also known, which include antibiotics (nifurantel, nystatin, metronidazole, miconazole nitrate), used as antibacterial, antifungal, antiprotozoal agents (RLS, M., 2002).

The disadvantage of these funds is their unidirectional action - antimicrobial or antifungal. They have limitations for use due to frequent individual intolerance, as well as the danger of side effects with prolonged use - a decrease in the sensitivity of microflora, the appearance of resistant forms of microorganisms and fungi, the possibility of impaired function of internal organs with their systemic effects.

The objective of the invention is to expand the assortment of drugs with anti-inflammatory and antibacterial effects, used in gynecology for the treatment of inflammatory processes, injuries and postoperative complications of the organs of the female genital area.

This object is achieved by the fact that the proposed tool for the treatment of gynecological and proctological diseases, made in the form of a suppository and containing the active substance 2-ethyl-6-methyl-3-hydroxypyridine succinate and a base selected from the group polyethylene oxide 1500, polyethylene oxide 400, cocoa butter, hydrogenated fats, with the following ingredients per candle:

2-ethyl-6-methyl-3-hydroxypyridine succinate 0.1-1.0 The basis 1.0-6.0

The tool is intended for the treatment of hemorrhoids, anal fissures, inflammations and wounds after operations and manipulations in the rectum, as well as for the treatment of non-inflammatory and inflammatory diseases of the pelvic organs in women, including those complicated by purulent-inflammatory processes, as well as after surgical interventions.

Suppository bases used in the manufacture of candles:

1) lipophilic - cocoa butter, hydrogenated fats, products of their thermal fractionation - are used for the manufacture of suppositories by pouring;

2) hydrophilic bases - a) gelatin-glycerin, b) soap-glycerin and polyethylene oxide bases, including a mixture of polyethylene oxide 1500 and polyethylene oxide 400.

Using this basis, it is possible to obtain suppositories by both pouring and pressing. The disadvantage of this basis is that due to osmotic activity, it causes dehydration and irritation of the vaginal mucosa and rectum.

3) diphilic bases: lanol (Lanolum), vitepsol (Witepsolum), lazupol (Lasupolum), parkhil, uniliver, hartfet, etc.

Diphilic bases are used for the preparation of suppositories by pouring.

Suppositories were mainly prepared by the usual pouring method adopted in the pharmaceutical industry.

Composition for the preparation of a vaginal suppository:

2-ethyl-6-methyl-3-hydroxypyridine succinate - 0.125 per 1 candle (or 5% by weight); the basis is diphilic - parchil or hartfet, or uniliver, or witepsol until a suppository weighing 5.0 is obtained.

Clinical trials were conducted on volunteers:

Example 1:

Patient V., 33 years old. Diagnosis: cervical erosion. Conducted cryodestruction. The treatment was carried out using vaginal suppositories with an active substance content of 5% and based on Vitepsol, which were administered 2 times a day (morning and evening) for 5 days.

During treatment, the process of mucosal regeneration was successful, the mucosa on the wound surface has fully recovered.

Palpation pain in the postoperative wound area disappeared on the 2nd day after surgery. There were no postoperative complications.

Example 2. Patient K., 60 years old. Diagnosis: prolapse of the anterior vaginal wall.

Surgical plastic surgery of the anterior vaginal wall was performed. The treatment of sutured wounds was carried out using vaginal suppositories (the same composition), which were administered 2 times a day for 5 days.

After 5 days, the wounds healed completely, without scars, the structure and functioning of the microcirculatory system and the vaginal mucosa were restored; pain on palpation in the area of the postoperative wound disappeared on the 2nd day of treatment. There was no temperature reaction in the postoperative period.

During bacteriological examination of the vaginal contents in the patient, IgKOE Enterococcus fecalis was 5.2 per 1 ml; IgKOE Escherichia coli - 5.4; Candida sp. - 5.2; St. epidermidis 4.4; Pseudomonas aeruginosa - 4.2; Streptococcus sp. - 4.7.

Colonization resistance of vaginal microorganisms (logKOE / ml) before surgery and on the 5th day after treatment (see table 1).

Table 1

Microorganism Before surgery After treatment Candida sp. 5.2 2.9 Enterococcus fekalis 5.2 2.7 Escherichia coli 5,4 3.0 St. Epidermidis 4.4 3.2 Streptococcus sp. 4.7 2.6 Pseudomonas aeruginosa 4.2 4.0

In all diseases where an inflammatory reaction is present as an essential component, the leading role in damage to cells and tissues of the body is played by the active forms of oxygen (ROS) produced by leukocytes, mainly neutrophils. Although the most destructive forms of ROS generated by myeloperoxidase act in the leukocyte phagolysosomes, neutrophils are able to secrete this enzyme into the extracellular space at the site of inflammation. The destruction of the infectious agent during the development of the inflammatory process can be provided at the cost of incidental damage to their own tissues in the focus of inflammation, while oxygen-dependent tissue damage is both direct and indirect. The latter is realized when ROS acts on regulatory and effector molecules, for example, on proteinases and proteinase inhibitors.

Phagocytic cells with powerful specialized ROS generation systems are also a source of reactive oxygen species in inflammation. When phagocytes come into contact with foreign particles, cells are activated to form superoxidion radicals. This phenomenon is called the “superoxide” or “respiratory” explosion. The bactericidal effect of phagocytes is carried out by the action of ROS inside the phagolysosomes, and the cytotoxic effect by action on objects located outside the phagocyte, and is carried out by the release of ROS from the cell into its microenvironment. Phagocyte activation is associated not only with bacterial aggression, but also with other types of effects (xenobiotics, allergens, pollutants).

Thus, the influence of various factors in inflammation caused, including by infectious agents, leads to an increase in the concentration of reactive oxygen species and the initiation of lipid peroxidation, which in turn is accompanied by the activation of AOS, which inhibits lipid peroxidation at an optimal level. AOS depletion leads to a significant and uncontrolled increase in lipid peroxidation, accumulation of peroxidation products (Vladimirov Yu.A., 1998), damage to biomembranes (Mokhnatkina N.S. et al., 1986), modification of proteins, lipids, nucleic acids (Reynolds ES, Mosien MT, 1980).

Modification of proteins leads to the appearance of antigenic properties in them, and lipid peroxidation leads to an increase in the production of chemotaxis factors (thromboxanes, leukotrienes), which increase the migration of phagocytes to the site of their formation (Fujimoto Y. et al., 1983). Therefore, the activation of phagocytes in the focus of inflammation has the ability to self-intensify, which helps maintain the inflammatory process and can lead to the formation of a vicious cycle of inflammation.

Free radical oxidation reactions of unsaturated fatty acids (EFAs) of phospholipids of cell membranes of tissue cells and plasma lipoproteins (LPO) lead to peroxidation of phospholipid molecules, which leads to a violation of the structure of cell membranes and lipoproteins. In relation to membranes, NLC peroxidation leads to disruption of the barrier and matrix functions, an increase in ion permeability, a decrease in transmembrane potentials, a decrease in ATP synthesis in mitochondria, and, as a result, cell death.

The free-radical mechanism of damage to plasma, mitochondrial and nuclear membranes, the nuclear and mitochondrial genome, blood lipoproteins leads to damage to blood vessels and histohematological barriers, impaired oxygen delivery to tissues, which plays a crucial, often crucial role in the pathogenesis of the most common inflammatory, toxic and autoimmune diseases nature.

The positive effect of antioxidants on the prevention of infection and the healing of purulent and gunshot wounds, burns, trophic ulcers (MF Kamaev. 1975; V.K.Sologub et al., 1979; Hinder, 1991; Haniwell, 1994) was previously known. .

Among the synthetic analogues of vitamins, aromatic and heteroaromatic phenols, the most promising antioxidants are 3-hydroxypyridine derivatives, which are structural analogues of the group of vitamins B6 (pyridoxol, pyridoxal, pyridoxamine), which play an important role in the life of the body and play the role of non-specific physiological antioxidants in it.

The most promising and studied antioxidant from the 3-hydroxypyridine group is 2-ethyl-6-methyl-3-hydroxypyridine succinate.

A wide spectrum of pharmacological activity of 2-ethyl-6-methyl-3-hydroxypyridine succinate is due to antioxidant and antiradical properties characteristic of aromatic phenols, structural similarity with vitamin B6 compounds, and the presence of succinate exhibiting antihypoxant properties.

2-ethyl-6-methyl-3-hydroxypyridine succinate has the ability to inhibit excessive free radical oxidation of lipids, as a result of which the viscosity of plasma membranes decreases, the content of polar fractions of lipids (phosphotidylserine and phosphotidylinositol, etc.) in the membrane decreases, the ratio of cholesterol / phospholipids decreases , decreases the viscosity of the lipid layer and increases the fluidity of the membrane. Initially, when it acts on the plasma membrane of a cell, the microenvironment of membrane receptors located mainly on the cell surface and, in most cases, are lipid-dependent, changes. As a result, the conformation and ability of membrane receptors to bind biologically active substances changes.

At the second stage, as a result of the diffuse distribution of the antioxidant throughout the cell, its direct effect on the membrane structures occurs, due to which lipid peroxidation is inhibited and their exit from the membrane slows down.

The protective effect of 2-ethyl-6-methyl-3-hydroxypyridine succinate on blood cells, detected during hypotonic and oxygen hemolysis, plays an important role in microcirculation disorders.

2-ethyl-6-methyl-3-hydroxypyridine succinate inhibits the free radical stages of prostaglandin synthesis catalyzed by cyclooxygenase and lipoxygenase, and thereby increases the prostacyclin / thromboxane A2 ratio. An increase in the antiaggregatory activity of the vascular wall leads to an improvement in microcirculation.

It has been established that 2-ethyl-6-methyl-3-hydroxypyridine succinate also has antiglucocorticoid activity, blocks glucocorticoid receptors, hindering the realization of the effect of glucocorticoids, and, therefore, limits the realization of the stress response, thereby reducing the activity of LPO processes.

Studies have shown that 2-ethyl-6-methyl-3-hydroxypyridine succinate inhibits both enzymatic and non-enzymatic lipid peroxidation, and their antioxidant activity is approximately the same in both cases.

The anti-inflammatory and antitoxic effect of 2-ethyl-6-methyl-3-hydroxypyridine succinate is achieved by reducing the level of free radicals, sorption effects on the primary source of inflammatory endotoxemia by binding endo-and exotoxins, and enhancing the drainage function of the lymphatic system.

Against the background of stabilization of cell membranes and blood vessels, which provides the active substance, it prevents the penetration of pathogenic microflora, toxins and decay products into the blood.

The high therapeutic activity of 2-ethyl-6-methyl-3-hydroxypyridine succinate is due to the presence of immunomodulating and immunostimulating properties. Restoring the activity of non-specific humoral defense units, increasing local immunity by enhancing the phagocytic activity of leukocytes, it leads to the rapid elimination of the inflammatory process in damaged tissues, the destruction of pathogenic microflora, and contributes to a significant improvement in treatment results.

During conservative treatment during the reparative process, the following changes in the microcirculation in the area of inflammation occur:

edema decreases, rheology of blood flow in microvessels improves, opportunities for normal blood outflow arise, vascular resistance decreases, myocyte tone of preserved arterioles and precapillaries is restored, there is an increased neoplasm of the capillary network in the area of damaged microvessels and in non-vascular tissue sites.

The results of experimental and clinical observations allowed us to conclude that the anti-inflammatory effect of Mexidol is mediated through its ability to stabilize the redox potential of the body by involving homeostatic reactions of different levels of its integration: the drug increases the energy efficiency of redox processes, stabilizes hormonal and immune status, stabilizes biological defense mechanisms , and also has bactericidal activity. The study of the antimicrobial activity of 2-ethyl-6-methyl-3-hydroxypyridine succinate with respect to gram-positive and gram-negative microorganism strains, as well as fungi (6 strains of each type of microorganism), allows to reliably evaluate the results of the antimicrobial activity research. As can be seen from table 2, 2-ethyl-6-methyl-3-hydroxypyridine succinate has antimicrobial activity against both gram-positive and gram-negative flora, as well as Candida fungi.

The results of a study of the antimicrobial activity of 2-ethyl-6-methyl-3-hydroxypyridine succinate are given in Table 2.

table 2

Gram positive Growth retardation area in mm (M ± m) Gram negative Growth retardation area in mm (M ± m) Candida 1.29 + 1.36 Pseudomonas eureginosa 7.25 + 1.87 Streptococcus spp. 4.85 ± 2.64 Escherichia coli 6.68 ± 1.25 Staphylococcus epidermidis 2.64 + 0.95 Proteus spp. 3.95 ± 1.34 Staphylococcus aureus 2.38 ± 1.18

The effectiveness of the conservative treatment of inflammation and the prevention of postoperative complications using 2-ethyl-6-methyl-3-hydroxypyridine succinate is due to its antibacterial effect, restoration of vasomotor activity, antioxidant and antihypoxic effect on the capillary and postcapillary links of the microvasculature. The use of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the postoperative treatment of aseptic wounds can help to remove post-traumatic changes as soon as possible, prevent the development of purulent complications, stimulate the reparative process and help restore the structure and functioning of the soft tissue microcirculatory system.

Thus, the obtained data indicate a pronounced anti-inflammatory, antibacterial and immunostimulating effect of 2-ethyl-6-methyl-3-hydroxypyridine succinate.

The technical result from the use of the proposed tool leads to a reduction in the elimination of post-traumatic and local inflammatory disorders, prevents the development of purulent complications, helps to restore the structure and functioning of the microcirculatory system of soft tissues and mucous membranes, destroys pathogenic microflora and restores normal vaginal microflora.

The use of a dosage form in the form of suppositories provides a prolonged release of the drug into the mucous membrane and soft tissues and ensures its effect for about 12 hours, in contrast to rinsing and irrigation, the duration of which lasts less than 1 hour; however, the procedure itself is convenient and easy to perform and can be carried out by patients on their own on an outpatient basis.

Claims (3)

1. An agent for the treatment of gynecological and proctological diseases, characterized in that it is in the form of a suppository and contains the active substance 2-ethyl-6-methyl-3-hydroxypyridine succinate and a base selected from the group polyethylene oxide 1500, polyethylene oxide 400, cocoa butter, hydrogenated fats in the following ingredients per candle: 2-ethyl-6-methyl-3-hydroxypyridine succinate 0.1-1.0 The basis 1.0-6.0 2. The tool according to claim 1, which is intended for the treatment of hemorrhoids, anal fissures, inflammations and wounds after operations and manipulations in the rectum. 3. The tool according to claim 1, which is intended for the treatment of non-inflammatory and inflammatory diseases of the pelvic organs in women, including those complicated by purulent-inflammatory processes, as well as after surgical interventions.