LT6763B - Use of probiotics or probiotic lysates together with galenic components and lysozyme for the symptomatic treatment of vulvovaginites of variuos ethiology, regeneration of vaginal epithelium - Google Patents

Abstract

The present invention is a pharmaceutical composition comprising probiotic, galenic components and lysozyme and is used for topical treatment. The composition has anti-inframmatory, antibacterial, antifungal, epithelial restorative effects. It can be used in combination with antibiotics for the treatment and/or prevention of bacterial vaginitis or candidiasis vulvovaginosis, as well as after a course of antibiotics in order to restore the natural balance of the vaginal microflora.

Description

FIELD OF THE INVENTION

The present invention relates to a probiotic composition comprising natural extracts (galenic preparations), lysozyme hydrochloride and probiotic bacteria or probiotic bacterial lysates and for use in the topical treatment of vaginitis and vulvovaginitis of various etiologies and their symptoms, as well as after the administration of antibiotics, dysbacteriosis and its symptoms and vaginal epithelial regeneration.

State of the art

Bacterial and candidal vulvovaginitis and vaginal epithelial changes are among the most common problems that women of working age seek medical attention. In the last 10 years, the number of women who develop bacterial or Candida fungal vulvovaginitis accounts for 30-45% of all infections of the external female genital organs and vagina. One of the most common symptoms of this infection is inflammatory processes and mucosal disorders.

Candidal vulvovaginitis is caused by a yeast of the Candida strain. More than 170 species of yeasts are currently counted. C. Albicans is one of the most common (85-90%) species of yeast causing candidiasis vaginitis. Other species include C. Glabrata (5-10%), C. Tropicalis (3-5%), C.parapsilosis (3-5%), and C. krusei (1-3%).

Many additional factors can lead to vulvovaginitis. Among such factors are long-term, uncontrolled use of antibiotics, corticosteroids, cytostatics, oral contraceptives, radiotherapy, severe infectious diseases, endocrine disorders, immunodeficiency, and many more. Prescribed broad-spectrum antibiotics inhibit not only pathological bacteria, but also representatives of the normal vaginal microflora: lactobacillus and bifidobacteria. This increases the pH of the vagina and disrupts cleansing processes. Also, yeasts of the Candida species may use some types of antibiotics as nutrients.

Wearing tight synthetic underwear achieves high temperature and high humidity, which is conducive to the development of candidal vulvovaginitis.

Bacterial vaginosis is also a common endogenous infection for which women seek medical attention. Vaginosis often causes complications of pregnancy and is associated with pelvic inflammatory disease or an increased risk of contracting the human immunodeficiency virus.

It is not yet known whether frequent bacterial vaginosis is a new-onset infection or the same but emerging episodes. However, research refutes the theory about the relationship between sexual intercourse and vaginosis. Studies also show that recurrent episodes of infection are likely to be relapses of the same infection. Women who develop relapses complain of abnormal vaginal discharge at the end of treatment. Even women who do not feel any symptoms and consider themselves healthy after treatment usually have altered vaginal flora. The more this flora is altered, the greater the chance of recurrence of the infection.

Bacterial growth in the vagina is controlled by pH and hormonal balance. Anything that upsets this balance increases the risk of recurrence of the infection. The balance may be affected by the use of antibiotics and contraceptives, diabetes, stress.

Sexually transmitted diseases such as gonorrhea or chlamydia can also cause altered vaginal discharge. Other possible symptoms, such as inflammation or itching, occur due to the use of scented cleansers, tampons, pads. These symptoms can also be caused by non-communicable diseases such as diabetes or menopause (atrophic vaginitis).

Candidiasis vulvovaginitis is currently treated with several groups of antifungal and antibiotic drugs. Imidazole antibiotics: clotrimazole, miconazole, oxiconazole, bifonazole, econazole, omoconazole, pheniconazole, isoconazole, terconzole, thioconazole, thioconazole, ketoconazole. Alkylamines: naftifinu. Polienais: amphotericin B, nystatin, levorin, natamycin. Triazolam: fluconazole, itraconazole or other fungistatic and fungicidal preparations (Bradshaw C S., Morton A N., Hocking J, Garland SM, Morris MB, Moss LM, Horvath LB, Kuzevska I, Fairley C K. (2006). recurrence rates of bacterial vaginosis over the course of 12 months after oral metronidazole therapy and factors associated with recurrence (J. Infect. Dis. 193, 1478-1486).

All of these antimicrobials are included in the pharmaceutical formulations for the topical treatment of vaginitis and vulvovaginitis.

Most antibiotics affect both bacterial and fungal vaginal fauna, which can affect the occurrence of gastrointestinal infections or the development of candidiasis of the vagina. The effects of the new macrolide antibiotics on the vaginal flora have not yet been studied, so no research has been done to determine their effects on vaginal lactobacilli. In a study, young women (18–45 years of age) who did not show any symptoms characteristic of vaginal pathologies were found to have anaerobic, aerobic, and fungal cultures in the vagina before starting antibiotics. After 4-6 weeks of antibiotic treatment, samples were taken from the study women and the results were compared. Lactobacteria, which accounted for 33% of the vaginal flora before treatment, remained. E. coli was 8% before treatment but increased to 17% after treatment. Enterococcus decreased from 25% to 8%. Candida yeasts, which are the most common and cause vaginosis, increased from 17% before treatment to 33% after treatment with antibiotics. These tests were performed with clarithromycin, but the results obtained are similar with older antibiotics (Wilson J: Managing recurrent bacterial vaginosis. SexTransm Infect 2004, 80 (1): 8-11).

Antibiotics can kill the bacteria that protect the vagina or change their balance. Vaginal fungal infection may develop during or after a course of antibiotic treatment. Due to the systemic action of antibiotics, vaginal fungal infection may also develop after treatment of angina with antibiotics.

Diabetes can reduce glycogen stores in vaginal wall cells. The disease can also raise the pH of the vagina, thus increasing the risk of developing a vaginal fungal infection.

Decreased levels of lactobacillus bacteria are associated with decreased levels of substrates due to increased pH due to the predominant multiplication of opportunistic bacteria, which are normally retained by lactic acid secretion.

Mechanical damage to the vaginal wall can be very dangerous. It can be one of the main conditions for infections and inflammatory reactions. Such lesions are possible due to decreased vaginal protective barrier function.

Vaginal disorders open access for pathological organisms to enter the uterus. As a result, patients may experience hormonal imbalances or other infections of the reproductive tract).

Modern society is increasingly choosing natural substances rather than chemical ones to fight bacterial infections. To avoid the adverse effects of antibiotics or synthetic antiseptics, biologically active natural plant compounds are chosen as an alternative to treatment. Vaginal suppositories have many advantages: the uniformity of the dosage form can be maintained, no large amount of fluid is required to release the drug substance. This has been demonstrated by the creation of double-layered vaginal suppositories containing an extract of Lactobacillus bacteria and yarrow (Achillea millefolium).

The efficacy of the use of lactobacilli in the treatment of bacterial vaginosis has been confirmed in clinical trials. Most of the studies that showed positive results were performed using high doses of lactobacilli. From this we can say that not only the characteristics of cultures, but also their quantity are important for the effectiveness of the preparation.

The essence of the invention

The object of the invention was to provide an effective composition for the symptomatic treatment and prevention of bacterial and candidiasis vulvovaginitis and for the treatment of vaginal dysbacteriosis caused by antibiotics or other factors. The result was achieved by using anti-inflammatory, antifungal and probiotic substances in the form of a vaginal suppository to cause local effects. Using this composition, a synergistic therapeutic effect is achieved: the normal vaginal microflora is stimulated and colonies of the pathogenic Candida fungus are inhibited and eliminated.

The main goal is to develop a composition of probiotics, natural extracts and lysozyme hydrochloride for the prevention and / or treatment of gynecological infections.

The composition comprises at least one bactericidal component in a concentration of from 0.0001% to 3% (w / v) by weight of the composition.

The composition includes probiotics in a concentration of 0.5% to 20% (w / v) by weight of the composition.

The composition comprises natural anti-inflammatory extracts in a concentration of 0.0001% to 10% (w / v) of the composition.

Detailed description of the invention

The present invention relates to a composition comprising probiotics or probiotic lysates, lysozyme, aloe, carrot and sea buckthorn extracts, and excipients. The composition includes 10-30 mg of purified water, 10-40 mg of lysozyme hydrochloride, 30-70 mg of aloe vera extract, 10-30 mg of carrot extract, lū30 mg of sea buckthorn extract, 50-90 mg of probiotic lysate, 300-500 mg of emulsifier (sucrose stearate ), dye (titanium dioxide), 1000-1400 mg of excipients.

The above excipients are selected from triglycerides, purified water, hydrogenated soybeans and cottonseed oil.

In one embodiment of the invention, the pharmaceutical composition comprises 20 mg of purified water, 20 mg of lysozyme hydrochloride, 50 mg of aloe vera extract, 10 mg of carrot extract, 10 mg of sea buckthorn extract, 70 mg (min. 1.5x10 ⁹ ovules) of probiotic lysate, 400 mg of emulsifier (sucrose stearate), 1188 mg of white, odorless solid fat and vegetable impurities.

Experimental models and clinical trials to determine therapeutic effects

It is an object of the present invention to provide an effective composition comprising anti-inflammatory, epithelial regenerating and bactericidal / bacteriostatic agents in the form of a vaginal suppository. The invention comprises oils which coat the epithelium and form a barrier which mechanically protects against mechanical and biological damage. These oils also contain carotenoids, which have a strong regenerative effect.

Composition of the composition

The compound Composition Lysozyme hydrochloride 10-40 mg Aloe vera extract 30-70 mg Carrot extract 10-30 mg Sea buckthorn extract 10-30 mg Probiotic lysate 50-90 mg Sugar stearate 300-500 mg Emergent material 1000-1400 mg

Oils with carotenes are used to treat inflammation of the genital organs or uterus. Clinical studies performed with supercritical mass (carbon dioxide) oil have had a stimulating effect on serum lipids, lipoproteins, inflammatory markers, and platelet formation. To test this theory, a double-blind, randomized, multi-facility study of women suffering from Sjogren’s syndrome was conducted. The sea buckthorn extract used in this study was rich in beta carotenes to reduce land-related symptoms. The study also confirmed the effectiveness of sea buckthorn oil in restoring the vaginal normal state, including as an alternative to restoring the vaginal epithelium in women who cannot take estrogen replacement therapy in the presence of vaginal atrophy. This study is statistically significant (P = 0.08) and the vaginal health index was significantly increased in the sea buckthorn extract group [(0.8 (SD 2.8)] compared to the placebo group [-0.1 (SD 2.0)].

A significant increase in vaginal epithelial integrity was observed with beta-carotene oils compared to the placebo group. Patients who complained of vaginal pathologies and who complained (OR) = 3.1, 95% Cl (1.11-8.95) were included in the study. There was also a statistically significant trend (P = 0.008) in the increase in vaginal health index with beta-carotene oils [(0.8 (SD 2.8)] compared to placebo [-0.1 (SD 2.0)] .

Herbal anti-inflammatory substances inhibit inflammation and prevent the prolonged inflammatory process.

Purified aloe protein derived from aloe vera extract has antifungal effects and is active against Candida paraprilosis, Candida krusei and Candida albicans. In addition, these proteins also have anti-inflammatory effects, which are manifested by inhibition of the enzymes lipoxidase and cyclooxygenase. Because of these properties, it can be used as one of the ingredients in drugs for the treatment of these disorders.

Aloe has not only anti-inflammatory, but also a broad spectrum of antimicrobial activity. In vitro experiments with many microorganisms, such as Candida fungal strains or E. coli, have shown that aloe vera has both bacteriocidal and bacteriostatic effects.

The potency of the aloe protein effect was compared with the control group treated with fluconazole. This test confirmed the antifungal effect of aloe. In the study, the concentration at which half of the bacteria (IC50) is inhibited was C. parapsilosis 252_M, C. albicans 75.61_M, and C. krusei 50.41_M.

Anti-inflammatory substances prevent the formation of pain, itching or foul-smelling vaginal discharge.

Aloe vera proteins inhibit C0X-2 and LOX enzymes, thus causing anti-inflammatory effects, and their potency and dissociation constant are compared with the well-known COX-2 inhibitor, a nonsteroidal anti-inflammatory drug, diclofenac.

Lysozyme has antibacterial activity against food safety related organisms, including Listeria monocytogenes and Clostridium botulinum. This study also found that Clostridium thermosaccharolyticum, Bacillus stearothermophilus and Clostridium tyrobutyricum are responsible for food spoilage and are also highly sensitive to lysozyme. However, gram-positive and gram-negative bacteria isolated during outbreaks of food poisoning such as Bacillus cereus, Clostridium perfringens, Staphylococcus aureus, Campylobacter jejuni, Escherichia coli 0157: H7, Salmonella typhimurium and Yersinia enterocolitica were resistant.

Lysozyme affects bacterial wall cells. This protein is most effective against gram-positive bacteria such as Staphylococci and Streptococci. Gram-negative bacteria like E. Coli and Sallmonella are also affected. This component can be used to inhibit both bacterial and viral infections.

Lysozyme is known to be an effective immune-boosting compound. It is used to treat infections of bacterial and viral origin. Lysozyme has an analgesic effect and can be used to enhance the action of antibiotics.

Studies were performed with fifteen normal and eighteen premature infants. They were given lysozyme extracted from egg white, together with a milk mixture (10mg / 100ml) from the first to the eighth week, as a substitute for lysozyme obtained with breast milk. Immunoglobulin synthesis was then monitored. Thirteen fully preterm infants as well as alternatively fed infants (milk formula, without lysozyme) and twenty breastfed infants were selected as controls. Judging by the fact that the baby consumes 600-900 ml of milk per day, the amount of lysozyme he receives is 60-90 mg. The infants did not experience any signs of disease. No significant difference was found between serum immunoglobulins compared to the control group. Secretory IgA was found in the feces of both lysozyme-fed and breast-fed infants. In the other groups (normally born, fed a lysozyme-free milk formula, premature-born fed a lysozyme-free milk mixture), only traces of secretory IgA were detected. No antibodies were detected in the samples from lysozyme-fed children in the studies.

Lysozyme has an analgesic effect and can be used to potentiate the effects of antibiotics. Another effect is the neutralization of acidic substances that occur during inflammation, thus suppressing it. This compound promotes wound healing, phagocytosis, inhibits degenerative and necrotic processes, reduces mast cell degranulation, inhibits histamine secretion and edema formation.

Lactic acid secreted by lactobacilli has a strong microcidal effect. Unfortunately, previous studies to determine the level of vaginal acidity provide incomplete results because they did not exclude women whose lactic microflora was not dominated by lactobacilli, nor did they take into account the high carbon dioxide and low oxygen environment in the vagina.

A more recent study looked at fifty-six women who scored 1 to 3 on the Nuget scale and had no symptoms of reproductive tract infections. Cervicovaginal sampling was performed by a method that does not require dilution, thus significantly reducing the likelihood of aerobic contamination. The pH of the samples was measured with a microelectrode, immediately after collection, the CO2 concentration was equal to the physiological vaginal level. The samples were also tested for lactate concentration. The mean pH was found to be 3.5 ± 0.3 and the mean lactate concentration was 1.0% ± 0.2% w / v. This is five times the concentration of hydrogen ions (pH) and lactate. The microbicidal form of lactic acid was eleven times more concentrated and significantly stronger than previous studies. From this, we can conclude that when lactobacilli dominate the vaginal microflora, there is significantly more lactic acid in the vagina, which prevents the pathological microorganisms from settling.

Bacterial vaginosis is one of the most common vaginal infections in the world and is characterized as a decrease in lactobacteria in the natural vaginal microflora. Antibiotic treatment is often ineffective. We argue that Bacillus coagulans can enhance the action of antimicrobial drugs and increase the rate of healing. The study looked at 40 women who were diagnosed with bacterial vaginitis and also showed symptoms: white discharge, an increase in pH of more than 4.7 times, a burning sensation, itching, swelling and redness in the external genitalia. A group that was treated with antibiotics alone was selected as a control. At the end of treatment, there was an 80% reduction in vaginosis symptoms in the prebiotic group compared with only 45% in the control group.

The study, which looked at the effectiveness of lactobacilli after taking antibiotics, looked at women taking antibiotics for 7 days. The women were divided into two groups. One group was taking antibiotics and probiotics, and the control was taking antibiotics only. Lactobacteria were chosen as the probiotic, and vaginal capsules were chosen as the pharmaceutical form. Samples were collected before treatment and 4 weeks after antibiotic treatment. A significant difference was obtained when comparing initial and final samples between groups (P <0.001). The mean difference between the samples in the test group was 6.61 and 4.13 in the control group. These data suggest that lactobacilli help to restore the vaginal flora more quickly after taking antibiotics.

A randomized, double-blind, placebo-controlled study was performed to assess colonization and clinical signs of vaginal lactic acid bacteria. Lactobacteria were administered in the form of a vaginal capsule immediately after treatment of vaginitis or vulvovaginitis with antibiotics. Vulvovaginal examinations and vaginal specimens were performed after drug administration, after the first and second menstrual cycles, and after six months. In summary, samples after five days of lactobacterial administration showed that the bacteria colonized the vagina, resulting in fewer relapses and altered secretions in women.

Although modern methods of treating infections are effective, many authors of scientific articles report that treatment of bacterial vaginitis is often unsuccessful. The most common failures are seen in the long-term post-infection study, when the "intermediate microflora" does not show the desired response to treatment, so the above composition helps to solve these problems.

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Claims (9)

A pharmaceutical composition comprising 20 mg of purified water, 20 mg of lysozyme hydrochloride, 50 mg of aloe vera extract, 10 mg of carrot extract, 10 mg of sea buckthorn extract, 70 mg (min. 1.5x10 ⁹ ovules) of probiotic lysate, 400 mg of emulsifier (sucrose stearate). ), 1188 mg of white, odorless solid fat and vegetable impurities. 2. The pharmaceutical composition of claim 1, further comprising anti-inflammatory, epithelial regenerating, bactericidal / bacteriostatic components. 3. A pharmaceutical composition according to claim 2, characterized in that it contains at least one bactericidal component in a concentration of 0.0001% to 3% (w / v) of the composition. 4. A pharmaceutical composition according to claim 1, characterized in that it contains probiotics in a concentration of 0.5% to 20% (w / v) by weight of the composition. 5. A pharmaceutical composition according to claim 1, characterized in that it contains oils containing substances which coat the epithelium and form a barrier against mechanical or biological damage. 6. A pharmaceutical composition according to claim 1, characterized in that it contains natural anti-inflammatory extracts in a concentration of from 0.0001% to 10% (w / v) of the composition. Pharmaceutical composition according to any one of the preceding claims, characterized in that it has anti-inflammatory, antifungal, prebiotic action and is prepared in the form of vaginal ovules. Use of a pharmaceutical composition according to any one of the preceding claims for the manufacture of a medicament for the prophylaxis and / or treatment of vaginitis and vulvovaginitis of various etiologies and their symptoms and vaginal dysbacteriosis and its symptoms. A pharmaceutical composition according to any one of claims 1 to 6 for use in the prophylaxis and / or treatment of vaginitis and vulvovaginitis of various etiologies and their symptoms and vaginal dysbacteriosis and its symptoms.