KR100797557B1 - Compositions for prevention or treatment of varginal infections - Google Patents

Abstract

Antimicrobial compositions are provided to prevent or treat vaginal infections including external genital vaginosis, vaginal candidiasis and bacterial vaginosis by inhibiting growth of Candida albicans and Neisseria gonorrhoeae without side effects. An antimicrobial composition for prevention or treatment of varginal infections comprises 0.2-0.5 wt.% of catechin, 1-2 wt.% of lactic acid and 1-3 wt.% of oletron which is triclosan, further comprises a buffer for maintaining pH of the composition between 3-5.5 for several hours and including boric acid, lactic acid, ascorbic acid, citric acid or acetic acid, and is formulated as solution, cream, ointment, gel or tablet for vagina administration.

Description

Compositions for prevention or treatment of varginal infections}

1 is a graph showing the effect of quercetin dihydrate on Candida albicans,

2 is a graph showing the effect of oletron on Candida albicans,

3 is a graph showing the effect of lactic acid (blue) and Lactic acid on Lactobacillus ashidophilus (green) on Candida albicans,

4 is a graph showing the effect of catechin and 1% lactic acid (green) on candida albicans, the effect of catechin and 2% lactic acid (grey),

Figure 5 is a graph showing the effects of catechin ( C ) and oletron ( O ), lactic acid ( L ) on Candida albicans.

A: C- 0.2% + O- 1% + L -1% B: C- 0.2% + O- 2% + L -2%

Arch Personal Care Products, 1996, Specification Sheet

2. BUKO Pharma-Brief, 1996, Oletron, Nr. 7

3. Choi OJ., 1994, Ingredients and Uses of Herbs, Ilwol Seokgak, Seoul, 371

4. Cibley LJ., Vulvovagivitis: Current approach to diagnosis and treatment. The female patients 42; 45-48, 56

5.Dragon, S., Gee, J., Bennett, R., Valoti, M. and Sgaragli, G. 2006, Red wine alcohol promotes quercetin absorption and directs its metabolism towards isorhamnetin and tamarixetin in rat intestine in in vitro , British J. Pharmacology 147, 765-771.

6. Fidel PL., 1994, Effects of preinduced Candida-specific systemic cell-mediated immunity on experimental vaginal candidasis. Infect . Immun . 62; 1032-1038

7. Hook I. EW., Brady WE ., Reichart CA., Upchurch DM., Sherman LA., And Wasserheit JN., 1989, Determinants of emerhence of antibiotic-resistant Neisseria gonorrhoea. J. infect Dis . 159 (5): 900-907

Jang SY., Ryu SY., And Kim SD. 2003, Antifungal activity of plant Extracts against Pityrosporum ovale and Candida albicans , Kor . J. Pharmacogn. 34 (4): 303-307

9.Nakachi, K., Suga, K., Imai, K. 1995, Preventive Effects of Drinking Catechin on Cardiovascular Disease and Cancer, Kor . J. Foodscience 28 (4); 11-16

10. Lind I. 1990, Epidemiology of antibiotic resistant Neisseria gonorrhoea in industrialized and developing countries. Scand J. Infect Dis. 69: 72-82

11. Macher, AM 1988, The pathology of AIDS. Pub . Health Rep . 103: 246-250

12.Odds FC, 1988, Candida and Candidosis, 2nd ed., London, Bailire Tindall

13. Poh CL., Ocampo JC., Sng EH., And Bygdeman SM. 1989, Rapid in situ generation of DNA restriction endonuclease patterns for Neisseria gonorrhoea . J. Clin . Microbiol . 27 (12): 2784-2788

14. Toschi, TG. Bordoni, A., Hrelia, S ,. Bendini, A., Lercker, G., Biagi, PL. 2000, The protective role of different green tea extracts after oxidative damage is related to their catechin composition, J Agric Food Chem. 48 (9): 3973-8

15. Wei, PH., Chen, LR., Wei. YQ., Yuan, JR., Ma, JP., And Chen, LX. 2002, Determination of alkaloids from Coptis chinensis Franch and Phellodendron amurense Rupr. Decocted together in baitouweng decocta by high perfomance capillary electropohoresis. Se Pu. 20 (6): 554-556

16. Wenzel RP., 1995, Nosocomial candidemia risk factors and attributable mortality. Clin . Infect Dis . 20; 1531-1534

17.WHO, 1980, Sesceptibility testing of Neisseria gonorrhoea to antibicrobial agents. WHO / VDDDT / 80. 423, 1-17

18. Yokozawa, T., Cho, EJ., Hara, Y., Kitani, K. 2000, Antioxidative activity of green tea treated with radical initiator 2, 2'-Azobis (2-amidinopropane) dihydrochloride, J. Agric Food Chem . 48 (10): 5068-73

19. Yoo, SC. and Suh, JS. 1974, Antifungal Actions of Crude drug Water Extracts on Candida albicans , Kor . J. Pharmacog . 5 (3): 147-154

20. Young, H. and Reid, HG. 1988, Immunological diagnosis of gonococcal infection. In immunological diagnosis of sexually transmitted disease. Marcel Deker, inc., New York, Basel: 78-116

The present invention relates to a composition for treating genital inflammation. Such compositions can be applied or intravaginally administered to the vaginal and vulvar regions of a patient to alleviate the symptoms and treat vulvar vaginitis, vaginal candidiasis or bacterial vaginosis in an optimal state.

We are buried in a host of bacteria, viruses, and fungi. These pathogens cause many diseases in humans and cause significant harm to health.

The symptoms of genital disease are dangerous enough to cause complications, and sometimes even serious enough to be life-threatening. These genital diseases cause a variety of trichomonas parasites, such as bacteria. During menstruation or before and after menstruation, the resistance of the endometrium is weakened, and when bacteria invade, it infects rapidly. The endometriitis is infected by bacteria and causes inflammation. The main cause is staphylococcus aureus, streptococci, etc., and sometimes infected with gonococcus or tuberculosis. Mostly after childbirth or miscarriage, because the inner lining of the uterus falls off and bacteria are good to invade. There are many other causes for genital disease. Mild symptoms may end up with a fever, but in severe cases a lot of dark discharge comes out and sometimes blood is mixed. There are severe lower abdominal pain and back pain, and the entire lower back rings when walking or urinating.

Candida albicans , which is a fungus that causes genital vaginitis in Korea, accounts for more than 50% of infections in candida albicans, and the treatment is not easy (Ministry of Health and Welfare, 2001). Candida albicans infection is called candidiasis, and current statistics show that about 75% of women experience at least once in their lifetime and 45% of women experience at least twice a year (Odds). , 1988).

The cause of vaginitis is usually harmless to the human body, but is infected when long-term use of antibiotics or other drugs or when the function of the immune system, which is an infection defense device, is reduced. It is known to be an infectious bacterium (Wenzel, 1995). Bacterial vaginitis is vaginitis in which anaerobic bacteria multiply more than 100 times in the vagina due to the resistance of normal bacteria to the vagina for some reason (Fidel, 1994). Comes out and smells These odors are caused by a substance called "amine," sometimes fever and pain during urination. Bacterial vaginitis has a long incubation period of 1 to 3 weeks, and if symptoms are neglected, complications such as cervicitis or fallopianitis can lead to infertility or premature birth. When the balance of strength is maintained between bacteria and humans, the disease rarely occurs, but when the bacteria grow abnormally or the resistance is reduced, the disease occurs.

There are a lot of women who have a disease called Vagiritis that has a lot of vaginal fluid and smells from the vagina. However, 50% of these are bacterial vaginosis caused by excessive germs on the surface of the vaginal wall but not by inflammation of germs invading the vagina. Gonorrhea caused by gonorrhea bacteria has a frequency of 20 times higher than syphilis. Most of all, if left untreated, it is a serious disease that causes permanent damage and infertility of the reproductive organs.

The incubation period for the Gram-negative dicocci, Neisseria gonorrhoeae , is 1 to 3 days for men and 3 to 10 days longer for women. Mostly transmitted by sexual activity, and pregnant women can infect the fetus at birth. Although infected, some patients have no symptoms but can infect others. In addition, it can be a throat infection, schizophrenia, abdominal pain, etc. may occur together, pus-like discharge flows from the end of the urethra, and the above symptoms, which may occur in the genitals, may gradually spread around the anus. Gonorrhea is commonly known to men and women of the urethra, urethra, anus or rectum, cornea, mouth or throat, women's uterus and fallopian tubes, and epididymis. In women, white, green or yellow vaginal discharge, pain during urination, irregular bleeding, excessive menstrual bleeding, fever, etc. Infections can reach the endometrium, fallopian tubes and cause dysmenorrhea, lower abdominal pain, and uterine pain. . The problem is that as the gonorrhea enters a woman's urinary system, complications occur in different ways, such as urethritis, bartholinitis, endometritis, tubal infections, pelvic peritonitis, cystitis, arthritis or dermatitis.

Men appear to have gonorrhea infections quickly, unlike women with incubation periods. The cloudy yellow discharge from the penis comes out and you feel pain during urination. In many patients, urinary tract infections and rectal infections occur, causing symptoms of urination and rectal disorders. If left for more than 1 to 2 weeks, it causes urethral stenosis and can become infertile due to gonococcal epididymitis.

Treatment of diseases caused by such genital infections aims to extinguish bacteria or fungi. However, treating candidiasis is not simple. In the meantime, even if many treatments have been developed, there is a problem that recurrence occurs well. In addition, when the inadequate antibiotics are used to prevent sexually transmitted diseases, or inadequate amounts of antibiotics, the pathogens that cause sexually transmitted diseases do not die and are more difficult to treat due to resistance.

In addition to candidiasis, sexually transmitted diseases caused by gonorrhea, Neisseria gonorrhoeae , are also serious. More than 200 million infections per year are reported worldwide (WHO, 1980; Lind, 1990). Gonorrhea is usually treated with antibiotics, but symptoms often return to the point that treatment continues until the bacteria are completely cleared. The cause of this was found to be re-infection rather than inadequate treatment. Penicillin, tetracycline, etc. are recommended by WHO, but they have strong resistance to bacteria due to misuse of antibiotics (Hook et al., 1989; Poh et al., 1989). Moreover, the cure for disease is mainly chemicals, which always have side effects.

Therefore, the present invention candida albicans mainly causing genital diseases And As a fungicide for gonorrhea Nigeria Neisseria gonorrhoeae , it aims to develop a therapeutic or prophylactic agent by searching for a treatable substance without side effects.

In addition, an object of the present invention is to develop a therapeutic or preventive agent that functions to preserve the beneficial bacteria of the vagina in addition to the function of sterilizing Candida albicans and gonorrhea bacteria which are the main causes of genital diseases.

Experimental results of bactericidal activity against Candida albicans (C. albicans ) and N. gonorrhoea ( N. gonorrhoea ) and the detection of infected tissues showed that the test substance was effective by concentration. Among them, bactericidal activity was significant in oletrons containing anti-inflammatory substances. The bactericidal effect of catechin, a polyphenol, was also great. The bactericidal activity of quercetin against Candida albicans and Nigeria gonorrhea was slightly shown, but not significantly. In addition, it was confirmed that lactic acid should be used as a material that does not affect L. acidofillus , which is necessary for preventing tissue infection.

The use of natural new materials that have no side effects and excellent bactericidal effects on genital tissues requires 0.2 ~ 0.5% of catechins and 1 ~ 2% of lactic acid to prevent infection and recurrence of biological tissues.

The bactericidal effects of catechin, quercetin, oletron, and lactic acid were examined as polyphenols that have anti-inflammatory, anti-cancer, and antioxidant effects in the treatment of diseases caused by Candida albicans and gonorrhea in Nigeria.

Catechin (C ₁₅ H ₁₄ O ₆ ), one of the polyphenols, is known to have anti-inflammatory and anti-cancer effects, and has a superior effect of inhibiting aging compared to tocopherol because it inhibits the formation of lipid peroxide that promotes aging. (Nakachi et al ., 1996, Valcic et al ., 2000). Its anti-inflammatory action has also been shown to be effective in preventing tooth decay and has been shown to be good for tooth conservation. Colorants such as catechins are effective in preventing adult diseases such as high blood pressure and arteriosclerosis by lowering cholesterol and blood pressure, and because they have a strong binding property to heavy metals and nicotine, they are not absorbed by the intestines or lungs and are released into the body. have.

Quercetin also blocks many toxic heavy metals and acts as an antioxidant.

Oletron is a triclosan substance and is used as a skin anti-inflammatory substance as a raw material for the treatment of dermatitis or skin disinfectant, and is widely used as a raw material for bathing agents or cosmetics by utilizing such effects (BUKO Pharma-Brief, 1996).

Lactic acid is an in vivo substance produced by pyruvate reduction when muscle glycogen is broken down during exercise or as the end product of the circuit. It is used in medicine because it has antibacterial effect to prevent the growth of various bacteria.

The environment inside the vagina is a very good condition for germs to grow because it is moist, warm and free from sunlight. There are many bacteria in the disease-free vagina, Lactobacillus These bacteria, such as acidofillus , do not inflame, but rather acidify the vagina to defend against other germs. Therefore, in order to protect genital tissue cells from various germs, Lactobacillus ashdophylls should be controlled to survive (Cibley, 1986).

Candida albicans against biosynthetic substances such as catechin, quercetin, oletron, and lactic acid To show the viability of Lactobacillus ashdophilus, which has a bactericidal effect against gonorrhea and protects the tissues. Each was examined.

The present invention is 0.2 to 0.5% by weight of catechin (hereinafter, unless otherwise specified,% means weight%), lactic acid 1-2%, oletron 1-3% by weight as an active ingredient It relates to a pharmaceutical composition for the prevention or treatment of genital inflammation, comprising a pharmaceutically acceptable carrier.

In addition, the present invention is characterized in that the composition is a liquid, cream, ointment, gel, pessary or tablet for vaginal administration.

The genital inflammation refers to endometritis, candidiasis, vaginitis, gonorrhea or urethritis.

In addition, the present invention relates to a cleaning composition for preventing or treating genital inflammation, containing 0.2 to 0.5% by weight of catechin, 1 to 2% by weight of lactic acid and 1 to 3% by weight of oletron as active ingredients.

Each of the above composition ranges exhibit sufficient bactericidal effects against Candida albicans and Nigeria Gonoroa, and are limited to concentrations suitable for preserving Lactobacillus ashidophilus.

In addition, the composition of the present invention is characterized in that it is applied locally to the infection site.

In addition, the composition of the present invention is characterized in that the liquid, cream, ointment, gel, pessary or tablets for vaginal administration.

In addition, the composition of the present invention is useful for the prevention or treatment of genital inflammation, such as endometritis, candidiasis, vaginitis, gonorrhea or urethritis.

For practical use, the pharmaceutical compositions of the present invention may be formulated in various formulations, such as liquid, cream or ointment forms, pessaries or vaginal tablets and the like. In addition, the detergent composition of the present invention can be prepared in the form of a liquid, cream, gel or the like.

In a preferred embodiment of the invention, the pharmaceutical composition may contain a buffer which can maintain a stable vaginal pH between 3 and 5.5 for several hours after administration. The buffer may be selected from a pharmaceutically acceptable inorganic or organic weak acid, such as boric acid, lactic acid, ascorbic acid, citric acid or acetic acid, with a weak acid selected from the respective sodium salt or another pharmaceutically acceptable salt of the conjugate base of the weak acid used. It may contain in combination. Preferably, the pH is maintained at 4.2 to 5.0.

The detergent composition of the present invention is a liquid formulation, cream, gel, containing the surfactant of the present invention as an active ingredient, and containing a surfactant safe to the human body, as is well known to those skilled in the art It can be prepared in various forms such as lotions.

Other components that may be included in the formulation of the present invention include flavoring agents, menthol, eucalyptus extract, methyl salicylic acid or salicylic acids, hydrocortisone and the like as topical refreshing agents.

The composition of the present invention may be administered or washed once to several times a day. It is also possible to administer tablets, creams or pessary preparations containing the composition of the invention before bedtime and then wash the next morning.

Hereinafter, the configuration of the present invention will be described in more detail with reference to the following examples. However, it is apparent to those skilled in the art that the scope of the present invention is not limited only to the description of the following examples.

Experiment method

Candida albicans, the world's most common cause of parasites, bacteria, and fungi that cause vaginitis And in Nigeria in Kono O (Neisseria gonorrhoeae) Lactobacillus ash FIG filler's (Lactobacillus bacteria to protect against, while the tissue has a sterilizing effect as the natural substances acidofillus ) was tested to find out whether they could survive.

<Example 1>

Candida albicans (Pamed, Korea National Institutes of Health) was used to proliferate, and the medium was YM medium (DIFCO) as a base, catechin, quercetin, oletron, lactic acid was added to each experiment was tested. Optimal concentration was searched by quantitative analysis of colonies of bacteria cultured in each medium at a rate of 10 ⁻³ and 10 ^{−4 in} the dark at 37 ° C. for 48 hours.

<Example 2>

Lactobacillus ashdophyllus for substances with optimal concentration of bactericidal effect In order to test the eligibility of the survival conditions were tested in the same manner as in 1) in the ratio of 10 ^-3 and 10 ^-4 in YM medium, and cultured for 48 hours at 37 ℃ quantitative analysis of residual survival.

Example 3

Neisseria gonorrhoea , which was sold by Samsung Biological Research Institute, In a similar manner, 100 ml of 2% (BBL in USA) of hemoglobin solution was added to chocolate medium (Cunlate medium, Union Lab, Inc.) by concentration, and incubated for 48 hours in a 5% CO ₂ incubator at 37 ° C. The concentrations showing the optimal bactericidal effect of catechin, quercetin, oletron and lactic acid were investigated.

Example 4

Lactobacillus ashidophilus, a beneficial bacterium, can be survived by screening the most effective concentrations of catechin, quercetin, oletron, and lactic acid. Candida albicans And two or three mixing effects suitable to sterilize Gonoroea, Nigeria.

Experiment result

Candida albicans In order to find out the optimal bactericidal effect of catechins, quercetin, oletron and lactic acid, the bactericidal substances against gonoroa nigeria were tested in low concentration step by step. As indicated in Table 1, the bactericidal effects of catechin, quercetin, oletron and lactic acid on Candida albicans were examined. Catechin, oletron and lactic acid showed a sterilizing effect of up to 100% in proportion to increasing concentration.

 Test substance concentration (%)  Catechin Quercetin  Oletron  Lactic acid 0.01 0.05 12.8 0.08 12.0 0.1 0.15 0.2 0.3 11.8 0.4 0.5 42.2 12.9 1.0 44.8 13.3 5.4 (-42.8) 2.0 87.7 14.2 9.2 (-15.4) 3.0 100 13.87 98.5 ( 100 ) 4.0 51.5 ( 100 ) 5.0 99.7 6.0 100 99.6 7.0 100 100 8.0 100 100

Catechin showed a low effect of 12.8% at concentrations of 0.15%, increased effect from 42.2% at 0.5%, 44.8% at 1%, and 87.7% at 2% to 3% to 100% complete. Bactericidal activity.

Quercetin showed an effect to some extent, but no bactericidal action was observed above it (FIG. 1). Despite several studies showing that quercetin has excellent anti-inflammatory and anti-cancer effects (Nakashi et. al ., 1995, Toshi et. al ., 2000) The bactericidal action was insufficient for Candida albicans.

Oletron showed an effect of close to 100% from 3% concentration, sterilized to 100% at a concentration of 6% or more (Fig. 2).

The effect of lactic acid on candida albicans was low from 1% to 5.4%, but gradually increased to 9.2% at 2% and 51.5% at 4% and nearly complete sterilization at 6%. Visible 99.6%, the concentration was more than 7% 100% effect.

Since Lactobacillus ashidophilus can survive in the presence of lactic acid to some extent, the concentration was tested, showing a proliferation rate from 1% to 42.8%, and from 2% to 15.4%. On the other hand, at a concentration of 3% or more, the bactericidal effect of 100% appeared, so that the concentration of lactic acid 1-2% was found to be suitable for the survival of Lactobacillus ashidophilus (Fig. 3).

In the past experiments, catechin, oletron and lactic acid exhibited a sterilizing effect of up to 100% in proportion to the effect of increasing the concentration. It was.

 Catechin 0.1%  Catechin 0.2%  Catechin 0.3%  Catechin 0.4%  Catechin 0.5%  Lactic acid 1% 66.2 65.1 85.1 89.2 91.2  Lactic acid 2% - - 86.6 95.6 94.5

Lactobacillus ashdophyllus was able to survive in tissues and sterilize genital infections. Experiments with Candida albicans in two mixtures showed that lactic acid 1% + catechin 0.5% to 91.2%, as shown in Table 2. The bactericidal effect of, showed excellent sterilization effect in lactic acid 2% + catechin 0.4% or 0.5% (Figure 4).

As a result of the experiments carried out so far, it is difficult to expect a perfect effect of close to 100%.

Lactobacillus ashdophyllus survived with catechin 0.2% + lactic acid 1% + oletron 2%, but Candida albicans was not completely sterilized. 100% of effects could not be seen at one time. However, Candida albicans bactericidal effect was clearly 100% in the material mixed with 2% lactic acid (Fig. 5).

We tested whether Candida albicans sterilized and Lactobacillus ashidophilus survived to a good bactericidal effect in Gonoroea, Nigeria. Meanwhile The bactericidal effect on Nigeria Gonoroa has a problem of quantitative analysis, so the results are simply indicated with or without bactericidal effect. As shown in Table 3, the sterilization effect was 100% at 7% of the oletron concentration, and the catechin at 100% at the concentration of 0.25%. Lactic acid showed a bactericidal effect at a concentration of 5% lower than that of Candida albicans (Table 3).

Test substance concentration (%) Catechin Oletron Lactic acid 0.2 x 0.25 o One x 2 x 5 x o 6 o / x o 7 o o 8 9

Like the experiment on Candida albicans Since the Lactobacillus ashidophilus should also be able to survive in the experiments of Nigeria Gonoroaea, it was tested with three mixtures obtained from the experiments on Candida albicans. It was confirmed that the bactericidal activity of Nigeria gonoroae in three mixtures of 0.1% catechin and 1% oletron added to 2% lactic acid. However, catechin 0.2% is required to obtain bactericidal action against Candida albicans, and as a result, the drug of choice for genital infection is lactic acid 1-2% + catechin 0.2-0.5% + oletron 1-3%.

       Catechin (%)   1% Oletron   2% Oletron  Lactic acid 0.1 o 2 0.2 o 2 0.3 x x One

As described above, the present invention candida albicans mainly causing genital diseases And Neisseria gonorrhoeae (Nisseria gonorrhoeae ) has been developed for the prevention and treatment of genital diseases.

In addition, the composition of the present invention, in addition to the function of sterilizing Candida albicans and gonorrhea, which are the main causative agents of genital disease, functions to preserve the beneficial bacteria Lactobacillus ashidophilus.

Claims (4)

A pharmaceutical composition for preventing or treating genital inflammation comprising 0.2 to 0.5% by weight of catechins, 1 to 2% by weight of lactic acid, and 1 to 3% by weight of oletron as an active ingredient and a pharmaceutically acceptable carrier. The method of claim 1, The composition is a liquid, cream, ointment, gel or vaginal administration, characterized in that the pharmaceutical composition for preventing or treating genital inflammation. The method of claim 1, The genital inflammation is endometritis, candidiasis, vaginitis, gonorrhea or urethritis, characterized in that the pharmaceutical composition for preventing or treating genital inflammation. Cleaner composition for preventing or treating genital inflammation comprising 0.2 to 0.5% by weight of catechin, 1 to 2% by weight of lactic acid, and 1 to 3% by weight of oletron as active ingredients.

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