CN112773780A

CN112773780A - Composition for vagina and vulva and application thereof

Info

Publication number: CN112773780A
Application number: CN201911091878.XA
Authority: CN
Inventors: 曾忠铭
Original assignee: Sunze International Pte Ltd; Singapore Ze&z International Pte Ltd
Current assignee: Sunze International Pte Ltd; Singapore Ze&z International Pte Ltd
Priority date: 2019-11-11
Filing date: 2019-11-11
Publication date: 2021-05-11

Abstract

The invention relates to a composition for vagina and/or vulva, which has the strong effects of inhibiting candida, escherichia coli, staphylococcus aureus and the like, has the effect of promoting the growth of lactobacillus in the vagina, and can be used for sanitary nursing and health care of the vagina or vulva and preventing and treating vagina infectious diseases. The invention also relates to the application of the organic acid in preparing compositions or products for vagina and/or vulva, which can be used for preparing therapeutic or non-therapeutic compositions or products for vagina or vulva. The invention further relates to a method for inhibiting candida, escherichia coli and staphylococcus aureus and promoting lactobacillus in vagina, which can be used for regulating vaginal flora, maintaining acidity and acidity, eliminating vaginal vulva discomfort and preventing or treating vaginal infectious diseases.

Description

Composition for vagina and vulva and application thereof

Technical Field

The invention relates to a composition for vagina and/or vulva, which has the functions of inhibiting candida, escherichia coli, staphylococcus aureus and the like, has the function of promoting the growth of lactobacillus in the vagina when being used for the vagina, and can be used for sanitary nursing and health care of the vagina or vulva, and preventing and treating vagina infectious diseases. The invention also relates to the application of the organic acid in preparing compositions or products for vagina and/or vulva, which can be used for preparing therapeutic or non-therapeutic compositions or products for vagina or vulva. The invention further relates to a method for inhibiting fungi, escherichia coli, staphylococcus aureus, and promoting lactobacilli in vagina, which can be used for regulating vaginal flora, maintaining vaginal acidity, eliminating vaginal vulva discomfort, and preventing or treating vaginal infectious diseases.

Background

The vaginal mucosa surface of female is suitable for inhabitation of microorganism such as bacteria, fungi, etc. In a healthy state, the bacteria inhabiting the vaginal mucosal surface of women are mainly large gram-positive bacilli, and are called as "normal vaginal flora". The large gram-positive bacilli belong to the category of lactobacillus mostly, mainly comprising lactobacillus, can metabolize glycogen to produce acid in vaginal mucosa epithelial cells, keep the vaginal acidity within the range of pH value of 3.5-4.5, and have the function of resisting germ infection.

Many factors can interfere with the normal flora and acidity of vagina, so that the capability of resisting bacterial infection of the vagina of women is reduced, and the vaginal microbial diseases of women are very common. Among them, fungal vaginitis (Candidal vaginitis), Bacterial vaginosis (Bacterial vaginosis), Cytolytic Vaginosis (CV), and the like are common.

Vaginal microbial diseases are currently treated primarily with antibacterial agents. Although antibacterial treatment can inhibit or kill pathogenic bacteria, beneficial lactobacilli in the vagina often have inhibiting or even killing effects, so that the anti-infection capacity is reduced, and the vaginal infection is repeated or delayed. How to protect lactobacillus and vaginal acidity in vagina and improve the prevention and treatment effect of vaginal infection still remains a hot problem of current medical research.

The inventor discloses a plurality of compositions comprising benzoic acid and/or salts thereof, propionic acid and/or salts thereof, dehydroacetic acid and/or salts thereof, sorbic acid and/or salts thereof, phenethyl alcohol and other bacteriostatic agents in a compatible manner, and the vaginal bacteriostatic preparation prepared by the composition can inhibit candida, escherichia coli and staphylococcus aureus, but has weak inhibitory effect on lactobacillus in vagina, so that the vaginal flora is favorable for recovering to be normal, such as ZL201080036139, US8765819, PCT/CN2017/105296 and other technical schemes.

In the technical scheme of the compatibility of the bacteriostatic agent disclosed above, the usage amount of the bacteriostatic agent is low, so as to avoid inhibiting beneficial lactobacilli in vagina. The concentration of sodium propionate is 0.25-0.70% (w/v) and sodium benzoate is 0.05-0.15% (w/v) as disclosed in PCT/CN2017/105296, and the concentration of sodium propionate is 0.05-1.00% (w/v) and sodium benzoate is 0.025-0.20% (w/v) as disclosed in ZL2010800-36139 and US 8765819. The bacteriostatic rate of the bacteriostatic agent on the candida albicans can be lower than the standard that the bacteriostatic rate of the bacteriostatic agent on the candida albicans is more than 50% required by the national standard of the people's republic of China (sanitary Standard for Disposable sanitary articles) (GB 15979-.

The concentration of the bacteriostatic agent in the bacteriostatic preparation is increased, the bacteriostatic effect of the bacteriostatic preparation or product on Escherichia coli, Staphylococcus aureus and Candida can be obviously enhanced, the bacteriostatic rate for inhibiting the Candida can reach the standard that the bacteriostatic rate in GB15979-2002 is more than 50%, but the inhibitory effect on lactobacillus is also enhanced, and the growth of lactobacillus in vagina can be inhibited after the bacteriostatic preparation or product is used for vagina, so that the vaginal flora is difficult to recover to normal. As shown in experimental example one of PCT/CN2017/105296, when the concentration of sodium propionate was 0.4%, 0.5%, the growth of lactobacillus was not significantly inhibited; the growth of lactobacilli was significantly inhibited when the sodium propionate concentration was 0.6%, in particular 0.7%.

As shown in experimental example three of ZL201080036139 and US8765819, wherein the fourth group used a formulation of "9% maltose + 0.1% sodium benzoate", the vaginal flora Nugent score of 13 of 16 patients (81.25%) dropped from > 7 to ≦ 3 after administration; the third group used a formulation of "9% maltose + 0.2% sodium benzoate" with 10 of 15 patients (66.67%) having a vaginal flora Nugent score decreasing from > 7 to ≤ 3. Nugent score is less than or equal to 3, which indicates that the vaginal flora is normal and lactobacillus is the dominant bacterium. It can be seen that the rate of vaginal flora recovery to normal decreases with increasing sodium benzoate concentration.

In other prior published technical documents, no bacteriostat compatibility method or composition which can meet the standard of GB15979-2002 that the bacteriostasis rate of candida is more than 50 percent, can promote the growth of lactobacillus in vagina and restore normal vaginal flora is found.

Disclosure of Invention

The invention aims to provide a composition for vagina or vulva, which has the functions of inhibiting candida, escherichia coli, staphylococcus aureus and the like, promoting the growth of lactobacillus in the vagina and restoring normal vaginal flora.

It is a further object of the present invention to provide the use of a compatible organic acid for the preparation of a composition or product for vaginal and/or vulvar use.

It is a further object of the present invention to provide a method for inhibiting candida, escherichia coli, staphylococcus aureus, and promoting lactobacilli in vagina, which can be used for eliminating or reducing vaginal vulvar itching, pain, dyspareunia, etc., and/or improving leucorrhea properties, and/or eliminating leucorrhea odor, and/or cleaning and caring vagina.

The compositions or methods according to the invention may be used for the prevention and/or treatment of vaginal infections, such as the prevention or treatment of candida vaginitis, or cytolytic vaginosis, or a dysbacteriosis of the vaginal flora, or bacterial vaginosis, or senile vaginitis.

The inventor finds out in the research that: the citric acid, malic acid and other dibasic acids and tribasic acids act independently, and the inhibition effect on candida albicans is weak; the inhibitor is compatible with bacteriostatic agents such as propionic acid and/or sodium salt thereof, benzoic acid and/or sodium salt thereof, phenethyl alcohol and the like, and has no obvious synergy, synergy or antagonism on the inhibition effect of the candida albicans.

However, citric acid is found to enhance the regulating effect of the combination of bacteriostatic agents such as propionic acid, benzoic acid, and phenethyl alcohol on vaginal acidity and vaginal flora, for example, the regulating effect of gel prepared from bacteriostatic agents such as 0.25-0.70% (w/v) sodium propionate, 0.05-0.15% (w/v) sodium benzoate, and phenethyl alcohol in PCT/CN2017/105296 on vaginal acidity and vaginal flora is enhanced. More particularly, when citric acid, malic acid, etc. are combined with higher concentration of bacteriostatic agent capable of inhibiting the growth of lactobacillus, such as sodium benzoate with concentration of more than 0.15% (w/v) and sodium propionate with concentration of more than 0.7% (w/v), etc., the vaginal flora can be quickly restored to normal after being applied to vagina, and the lactobacillus in the vagina is not inhibited by the higher concentration of sodium benzoate, sodium propionate, etc.!

This phenomenon is very abnormal and completely fails to meet the technical knowledge of the bacteriostat 'the bacteriostasis is enhanced along with the increase of the concentration' and the results of the in vivo and in vitro experimental researches, and fully shows the complexity of the vaginal micro-ecosystem. The mechanism of this phenomenon has not been elucidated, and one of the possible mechanisms is that triacids or diacids such as citric acid cause the abnormal phenomenon by changing the interaction relationship between different bacteria in the vagina.

Based on the findings, the composition and the preparation method creatively combine dibasic acid and tribasic acid such as citric acid and malic acid with organic acid bacteriostats such as propionic acid and benzoic acid and aromatic alcohol bacteriostats such as phenethyl alcohol, and the like, so that the composition can inhibit candida and protect lactobacillus, not only meets the standard that the bacteriostasis rate of the bacteriostasis preparation required in GB15979-2002 to candida albicans is more than 50%, but also can promote the growth of lactobacillus in vagina and restore vaginal flora to normal, and has important theoretical and practical significance in the field of female health.

The invention provides a composition for vagina or vulva, which is characterized by comprising the following organic acids and/or salts thereof in per hundred grams of the composition: (1) one or more dibasic or polybasic organic acids and/or salts thereof selected from the following group in a total amount of 0.3000 to 60.0000 mmol: citric acid, malic acid, succinic acid, tartaric acid, maleic acid; preferably 1.5000-33.0000 mmol of citric acid and malic acid; (2) one or more monobasic organic acid bacteriostats and/or salts thereof with the total amount of 0.3000-60.0000 mmol, wherein the monobasic organic acid bacteriostats are selected from the following group: acetic acid, glycolic acid, lactic acid, propionic acid and levulinic acid, preferably 10.4103-33.0000 mmol of propionic acid; (3) one or more aromatic organic acid bacteriostats and/or salts thereof with the total amount of 0.1000-10.0000 mmol, wherein the aromatic organic acid bacteriostats are selected from the following groups: benzoic acid, p-hydroxybenzoic acid, p-methoxybenzoic acid, salicylic acid, cinnamic acid; preferably 1.0000-2.5000 mmol of benzoic acid; the vaginal or vulvar composition can be a solution, a spray, a foam, an ointment, a powder, a microcapsule, a membrane, an effervescent tablet, a capsule, a suppository or a tablet.

Preferably, the composition contains 25.00-45.00 mmol of organic acid and/or salt thereof in each hundred grams. Wherein the salt of the organic acid is a sodium salt.

Preferably, the composition also contains one or more aromatic alcohols selected from the following group in a total amount of 0.1000-10.0000 mmol per hundred grams: benzyl alcohol, benzyl dichloride alcohol, phenethyl alcohol, phenoxyethanol and cinnamyl alcohol, and particularly preferably 0.4000-5.0000 mmol of phenethyl alcohol. The composition containing aromatic alcohol has stronger bacteriostatic or antibacterial action, or anti-inflammatory action, or immunoregulation action and the like on candida, escherichia coli, staphylococcus aureus and the like.

Preferably the composition further comprises one or more sugars selected from the group consisting of sugars in a total amount of 0.30 to 20.00% (w/w): glucose, fructose, mannose, sucrose, isomaltulose, kestose, nystose, kestopentaose, maltose, isomaltose, isomaltotriose, isomaltotetraose, isomaltopentaose, trehalose, cellobiose, melibiose, gentiobiose, gentiooligosaccharide, raffinose, panose, maltooligosaccharide, isomaltooligosaccharide, fructooligosaccharides, glucomannan, dextrin, starch, glycogen or mixtures thereof; particularly preferably glucose, fructose, mannose, sucrose, maltose, isomaltulose, isomaltose, trehalose, maltooligosaccharides, isomaltotriose or a mixture thereof in a total content of 1.00 to 6.50% (w/w). The sugar-containing composition for vagina or vulva can inhibit harmful bacteria such as candida, escherichia coli, staphylococcus aureus and the like, has the effect of promoting the growth of lactobacillus in vagina, can adjust vaginal flora, enhance vaginal acidity and maintain beneficial lactobacillus in vagina, and is suitable for preventing or treating vaginal lactobacillus reduction, vaginal flora imbalance, bacterial vaginosis, or for auxiliary treatment of vaginitis, or recovery after vaginal treatment, or for treatment of genital tract infection.

Preferably, the composition further comprises 0.001-1.00% (w/w) of one or more estrogens selected from the group consisting of: diethylstilbestrol, hexestrol, estradiol, estrone, estriol, nilestriol, ethinylestradiol cyclopentyl ether, and ethinylestradiol methyl ether. The vaginal composition containing the estrogen substances can promote the synthesis of glycogen by vaginal mucosa epithelial cells and promote the growth of beneficial lactobacillus, and is particularly suitable for being used in menopause or postmenopause.

Preferably, the composition further comprises 0.001-1.00% (w/w) of one or more phytoestrogens selected from the group consisting of: the vaginal composition containing phytoestrogens can have stronger bacteriostatic action and anti-inflammatory action, can promote the synthesis of glycogen by epithelial cells of vaginal mucosa and promote the growth of beneficial lactobacillus, and is particularly suitable for being used in menopause or postmenopause.

Preferably, the composition also contains one or more amino acids and/or salts thereof selected from the group consisting of 1.0000 to 45.0000mmol in total: l-glutamic acid, glutamine, L-aspartic acid, asparagine, isoleucine, phenylalanine, valine, leucine, proline, threonine; particularly, glutamic acid, aspartic acid and/or salts thereof are preferably contained in a total amount of 5.0000 to 30.0000 mmol. The composition or product for vagina or vulva containing amino acid and/or salt thereof can reduce acid production of lactic acid bacteria and weaken vaginal acidity, and is suitable for regulating vaginal microenvironment and treating or assisting in treating cytolytic vaginosis, lactobacillus vaginosis and colpitis mycotica.

The composition can also optionally contain one or more monoterpene or sesquiterpene compounds in a total amount of 0.1000-10.0000 mmol per hundred grams, including but not limited to: citronellol, linalool, geraniol, nerol, eucalyptol, terpineol, carveol, menthol, and lavender alcohol. The composition containing the monoterpene or sesquiterpene compound has stronger bacteriostatic or antibacterial action, or anti-inflammatory action, or cell regulation action, or immunity promotion action and the like.

The composition may optionally further comprise one or more plant essential oils in a total amount of 0.10-30.00 milligrams% (w/w), including but not limited to: rose essential oil, clove oil, thyme oil, lavender oil, peppermint oil, mugwort leaf oil, eucalyptus oil, sassafras oil, litsea cubeba essential oil, cinnamon essential oil and bay leaf oil. The composition containing the plant aromatic essential oil has stronger bacteriostatic or antibacterial action, or anti-inflammatory action, or cell regulation action, or immunity promotion action and the like.

The composition may optionally further comprise one or more selected from the group consisting of: 0.01-5.0% (w/w) aloe extract, 0.001-1.0% (w/w) vitamin E, 0.001-1.0% (w/w) vitamin A, 0.001-1.0% (w/w) vitamin D, 0.001-1.0% (w/w) vitamin C. The vaginal composition containing the substances can be used for protecting vaginal mucosa and promoting the repair of damaged vaginal mucosa.

The composition may optionally further comprise one or more antibacterial agents, including but not limited to: metronidazole, tinidazole, clotrimazole, fluconazole, miconazole or ketoconazole, preferably metronidazole and clotrimazole. The composition or the product containing metronidazole or clotrimazole is suitable for treating bacterial vaginosis, or bacterial vaginitis, or fungal vaginitis.

Preferably, the composition may further optionally contain one or more bacteriostatic or antibacterial agents, including but not limited to: dehydroacetic acid, sodium dehydroacetate, sorbic acid, potassium sorbate, sodium sorbate, diacetic acid, sodium diacetate, caprylic acid, sodium caprylate, capric acid, sodium decanoate, undecylenic acid, sodium undecylenate, lauric acid, sodium laurate, natamycin, lactoferrin, lactoferricin, lysozyme, bacteriostatic protein, antibacterial peptide, lichenic acid, tigecycline, tropolone, cinnamaldehyde, pseudolaric acid, chlorogenic acid, fibrauretin, propenyloxyethanol, 1, 2-pentanediol, 1, 2-hexanediol, 1, 6-hexanediol, 1, 2-octanediol, 1, 2-decanediol, methylpropanediol, ethylhexylglycerol, benzoyl peroxide. The bacteriostatic or antibacterial agent is used for further enhancing the bacteriostatic or antibacterial effect of the vaginal or vulvar composition or product of the invention on candida, escherichia coli, staphylococcus aureus and other harmful microorganisms including but not limited to viruses such as HIV, HPV and the like.

Preferably the composition is an aqueous solution, a water-soluble gel; the pH value of the water solution and the water-soluble gel is 3.0-4.5, and the preferable pH value is 3.5-4.0. Wherein said water-soluble gel comprises a non-flowable, viscous, water-soluble colloidal matrix including, but not limited to, xanthan gum, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carbomer, polycarbophil, preferably xanthan gum.

The water-soluble gels of the present invention may be packaged in a variety of ways, including but not limited to single dose, sterile, sealed packaging, or in a vaginal device, or in a disposable vaginal applicator; preferably in single dose, sterile, sealed packages.

The organic acid composition has an inhibiting effect on candida, escherichia coli and staphylococcus aureus, and has a promoting effect on lactobacillus in a vagina.

The vaginal or vulvar composition or product of the present invention may be a therapeutic composition or product including, but not limited to, pharmaceuticals, medical devices, pharmaceutical devices, disinfecting devices, health products, disinfectants, antibacterial agents, bacteriostatic agents, mucosal surface microbicides, microecological modulators, microenvironment modulators, microbial modulators, flora modulators, single use medical devices. The vaginal or vulvar composition or product of the invention may also be a component of a disinfecting device, or a medical device, or a pharmaceutical device.

The vaginal or vulvar composition or product of the invention may be a non-therapeutic composition or product, including but not limited to health products, hygiene products, care products, cosmetics, hygiene products, disposable hygiene products, cleaning products, daily necessities, as an odor-reducing agent, or a lubricant, or a moisturizer, or a lotion, or a cleanser, or a conditioner, or an antipruritic, or a freshener. The vaginal or vulvar composition or product of the invention may also be used as a component of a sanitary article, or a cleaning and care product, such as a sanitary napkin, or a panty liner, or a tampon.

The invention also provides the application of the organic acid compatibility in preparing the composition for vagina or vulva, wherein the organic acid compatibility contains the following organic acids and/or salts thereof in each hundred grams of the composition: (1) one or more dibasic or polybasic organic acids and/or salts thereof selected from the following group in a total amount of 0.3000 to 60.0000 mmol: malic acid, succinic acid, maleic acid, tartaric acid and citric acid, wherein the total amount of the citric acid and the malic acid is preferably 1.5000-33.0000 mmol; (2) one or more monobasic organic acid bacteriostats and/or salts thereof with the total amount of 0.3000-60.0000 mmol, wherein the monobasic organic acid bacteriostats are selected from the following group: acetic acid, glycolic acid, lactic acid, propionic acid and levulinic acid, preferably 10.4103-33.0000 mmol of propionic acid; (3) one or more aromatic organic acid bacteriostats and/or salts thereof with the total amount of 0.1000-10.0000 mmol, wherein the aromatic organic acid bacteriostats are selected from the following groups: benzoic acid, p-hydroxybenzoic acid, p-methoxybenzoic acid, salicylic acid and cinnamic acid, and 1.0000-2.5000 mmol of benzoic acid is preferred. The vaginal or vulvar composition can be a solution, a spray, a foam, an ointment, a powder, a microcapsule, a membrane, an effervescent tablet, a capsule, a suppository or a tablet, and preferably is an aqueous solution or a water-soluble gel.

The preparation method comprises the step of adding various organic acids and/or salts thereof in an amount of 25.00-45.00 mmol per hundred grams of the composition.

The preparation and use, the preparation process, the method and the selection of auxiliary materials according to the invention are all conceivable by those skilled in the art according to the disclosure of the invention in combination with the background knowledge thereof.

For example, in the preparation of water-soluble colloidal agents, it is desirable to select a non-flowable, viscous, water-soluble colloidal base which allows the composition to act by uniformly contacting the vaginal mucosa and allowing it to remain in contact for an extended period of time. The selection and method of use of the water-soluble colloidal matrix is within the knowledge of one of ordinary skill in the art and, in accordance with the preparative use of the present invention, the matrix is xanthan gum, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carbomer, polycarbophil, preferably xanthan gum.

Can be prepared according to methods known to those skilled in the art, for example, the following process schemes: quantitatively weighing citric acid and/or propionic acid and/or sodium salt thereof, benzoic acid and/or sodium salt thereof, xanthan gum and other components according to a certain proportion, uniformly mixing, quantitatively adding distilled water, stirring, dissolving each component, and swelling the xanthan gum to form uniform colloid; the pH of the composition is adjusted to a predetermined value with an acid and/or a base. The sterilization treatment can be further carried out, and the sterilization can be selected from the following processes: radiation sterilization, high temperature sterilization (for example, sterilization at 112.6 deg.C for 15-20 min; or sterilization at 100 deg.C for 30 min), and intermittent sterilization (for example, treatment at 80 deg.C for 30 min, then treatment at 36 deg.C for 5-10 hr, then treatment at 80 deg.C for 30, then treatment at 36 deg.C for 5-10 hr, and finally treatment at 80 deg.C for 30 min). Or preparing benzoic acid and/or its sodium salt into solution, filtering, sterilizing, and adding into sterilized water soluble colloidal matrix.

For example, when preparing a solution, the above components except xanthan gum can be mixed well, water is added to dissolve the components, and the solution is sterilized and subpackaged; or dissolving the above components, filtering, and packaging. Can be soaked in cotton ball or cotton strip for vaginal administration, or made into vaginal and/or vulvar lotion.

For example, when preparing a negativeFor example, the tablets may be prepared according to methods known to those skilled in the art, for example, as described in "pharmacy" of xi Mian Zhu, looking at the fur coat^【1】Mixing a certain amount of citric acid, sodium propionate, benzoic acid and/or its sodium salt and other components with filling adjuvants, and directly tabletting to obtain tablet; optionally adding adjuvants such as lubricant such as magnesium stearate or disintegrant such as carboxymethyl starch sodium, mixing, and tabletting. The prepared tablet can be subpackaged into a drug administration apparatus, a disinfection apparatus, a medical apparatus or a pharmaceutical apparatus.

For example, when preparing pessaries, they may be prepared according to methods known to those skilled in the art, such as the following procedures^【2】: quantitatively taking citric acid, propionic acid and/or sodium salt thereof, benzoic acid and/or sodium salt thereof and other components, mixing and grinding with Tween 80, and heating to about 50 ℃; heating mixed fatty glyceride (also called Solid Fat) to 60 deg.C to melt; and then adding the mixed solution of citric acid, sodium propionate, benzoic acid and/or sodium salt thereof and tween 80 into the melted matrix, stirring while adding, pouring into a mold at about 40 ℃ (before solidification) after uniformly mixing, scraping the mold after slight cooling, and demolding to obtain the vaginal suppository. The matrix of the suppository can be mixed fatty glyceride, or propylene glycol stearate, glycerogelatin, tween-61, etc. Mass production may employ automated, mechanized devices. The prepared suppository can also be subpackaged in drug administration instruments, disinfection instruments, medical instruments or pharmaceutical instruments.

For example, when preparing the sanitary napkin, panty liner, or tampon of the present invention, citric acid, sodium propionate, benzoic acid and/or its sodium salt and other components are weighed quantitatively, and added with corresponding adjuvant components to make into powder, film, tablet, microcapsule, or capsule, which is placed inside the sanitary napkin, panty liner, or tampon, etc. by a suitable manner or process; or the components such as citric acid, sodium propionate, benzoic acid and/or sodium salt thereof and auxiliary components are attached to the inner layer material of the sanitary towel, the sanitary pad, the tampon and the like through a proper process.

According to the preparation application of the invention, when preparing dosage forms such as effervescent tablets, capsules, suppositories or tablets, etc., the total dosage of the citric acid is 0.0030 mmol-3.0000 mmol, preferably 0.0150 mmol-1.6500 mmol per unit dosage form; the total dosage of the propionic acid and/or the sodium salt thereof is 0.0030-3.0000 mmol, preferably 0.1041-1.6500 mmol, per unit dosage form; the total amount of benzoic acid and/or its sodium salt is 0.0010-0.5000 mmol, preferably 0.0100-0.1250 mmol per unit dosage form. The preparation process, method and choice of auxiliary materials are all imaginable to those skilled in the art by combining the background knowledge of the invention according to the disclosure of the invention.

The ratio between the various organic acids or their salts, such as propionic acid and sodium propionate, benzoic acid and sodium benzoate, dissolved in water in unionized molecules or ionized ions, for the preparation purposes of the invention depends on the pH of the solution and on the ionization constant PK of the organic acid_aThe value is obtained. It can be seen that both the organic acid and the salt thereof are organic acid molecules or organic acid radical ions after being dissolved in water, and from this viewpoint, the two are not substantially different.

The present invention also provides a method for inhibiting candida, escherichia coli, staphylococcus aureus, and promoting lactobacilli in the vagina, wherein the method comprises intravaginally administering to a woman in need thereof an effective amount of a composition of the present invention.

The method according to the invention, wherein said method is a method for maintaining normal acidity of the vagina, and/or modulating vaginal microecology, and/or modulating vaginal microbiology, and/or selective vaginal decontamination, wherein said method comprises administering an effective amount of a composition of the invention intravaginally to a woman in need thereof.

The method according to the present invention, wherein said method is a method for eliminating or reducing discomfort of vaginal vulvar itching, pain, or dyspareunia, or improving the white-band trait, or eliminating the smell of white-band, or cleansing the vagina, or caring for and/or regulating vaginal microecology, wherein said method comprises intravaginally administering an effective amount of a composition of the present invention to a female in need thereof.

The method according to the present invention, wherein said method is a method for the prevention and/or treatment of a vaginal microbial disease, wherein said vaginal microbial disease is fungal vaginitis, or cytolytic vaginosis, or a dysregulated vaginal flora, or bacterial vaginosis, or senile vaginitis, wherein said method comprises intravaginally administering an effective amount of a composition of the invention to a woman in need thereof.

According to the method, the composition is applied to the female vagina, a composition in a gel dosage form can be applied to the vagina by using an injector, or the composition in a solution dosage form is soaked by a cotton sliver or a cotton ball or a vaginal plug and then placed in the vagina, or the composition in a suppository or tablet dosage form can be applied to the vagina for 1-2 times per day, and each treatment course is 2-7 days, preferably 3-5 days; in the treatment process, the change of the symptoms of the patient is observed, the change of the pH value of the vagina is detected, the symptoms of the patient are obviously improved or disappear, and the medicine can be stopped or reduced when the pH value of the vagina is kept in a range of 3.8-4.3.

The method disclosed by the invention can effectively inhibit candida, escherichia coli, staphylococcus aureus and pathogenic lactobacillus, promote the growth of lactobacillus in the vagina and enhance the microecological physiological function of the vagina, and has important value on female health and wide application prospect.

Detailed Description

Composition examples

Example 1:

uniformly mixing 0.3mmol of citric acid, 0.3mmol of propionic acid, 0.1mmol of benzoic acid and 2.5 g of xanthan gum, adding distilled water to make the total weight be 100 g, and stirring to dissolve the citric acid, the sodium propionate and the sodium benzoate and swell the xanthan gum into uniform viscous jelly; adjusting pH to 3.5 with 1.0mol/L sodium hydroxide solution, sterilizing at 115.6 deg.C for 15 min to obtain the water-soluble colloid composition.

Example 2:

the raw materials were weighed out in the following proportions and 100 g of the gel composition was prepared essentially as in example 1.

Example 3:

Example 4

The raw materials were weighed out in the following proportions and 100 g of the solution composition was prepared essentially as in example 1.

Example 5:

the raw materials were weighed out in the following proportions and a composition of 100 g in gel form was prepared essentially as in example 1.

Example 6:

Example 7:

the raw materials were weighed out in the proportions described below and 100 g of the composition was prepared essentially as in example 1.

Example 8:

the raw materials are weighed according to the following mixture ratio,

example 9:

10.0mmol of malic acid, 1.0mmol of benzoic acid and 10.0mmol of propionic acid;

glutamic acid 1.5mmol, glutamine 1.5mmol, aspartic acid 1.5mmol, asparagine 1.5mmol, isoleucine 1.5mmol, methionine 1.5mmol, phenylalanine 1.5mmol, valine 1.5mmol, leucine 1.5mmol, proline 1.5mmol

Xanthan gum 2.5 g, adding purified water to total weight of 100 g, adjusting pH to 4.5

Example 10:

Example 11

Tablets containing 30 mg of citric acid, 5 mg of sodium benzoate, 30 mg of sodium propionate and 60 mg of sucrose per tablet were prepared essentially according to the method of reference 9.

Example 12

Pessaries containing 30 mg of citric acid, 5 mg of sodium benzoate, 30 mg of propionic acid, 60 mg of maltose per granule were prepared essentially according to the method of reference 10.

Experimental examples

Experimental example one

The bacteriostatic action of the candida albicans ATCC10231 on different solutions after the action of the solutions for 20 minutes is experimentally researched according to a method in appendix C of GB15979-2002 hygienic Standard for Disposable sanitary articles, which is specifically shown in Table 1. The results show that:

1. the pH value is 3.6, 2.5% (w/w) propionic acid, 0.25% (w/w) sodium benzoate and 1.5% (w/w) citric acid respectively and independently act, and the candida albicans ATCC10231 is not subjected to bacteriostasis;

2. the pH value is 3.6, 2.00 percent (w/w) propionic acid is compatible with 0.20 percent (w/w) sodium benzoate, and the bacteriostatic action is exerted on candida albicans, but the bacteriostatic rate is less than 50 percent; the concentration of propionic acid is increased to 2.50% (w/w), the concentration of sodium benzoate is increased to 0.25% (w/w), and the bacteriostasis rate to candida albicans is more than 50%. Therefore, the increase of the concentrations of the propionic acid and the sodium benzoate can lead the bacteriostasis rate of the bacteriostasis liquid to the candida albicans, and meet the requirement of GB 15979-.

3. The pH value is 3.6, and the bacteriostatic action of 1.5% (w/w) citric acid on the solution of the propionic acid and the sodium benzoate is not obviously enhanced or weakened.

TABLE 1 bacteriostatic action of different solutions on Candida albicans ATCC10231

Serial number	pH of the solution	Propionic acid (%)	Sodium benzoate (%)	Citric acid (%)	Bacteriostatic ratio (%)
						1	3.60	2.50	--	--	-10.92
2	3.60	--	0.25	--	-6.15
						3	3.6	--	--	1.50	-11.79
4	3.60	2.50	0.25	--	73.80
						5	3.60	2.50	0.25	1.50	70.56
6	3.60	2.00	0.20	--	11.35
						7	3.60	2.00	0.20	1.50	12.23

Experimental example 2

The antibacterial gel effect is experimentally researched for 20 minutes according to a method in appendix C of GB15979-2002 hygienic Standard for Disposable sanitary articles, and the antibacterial effect on Candida albicans ATCC10231 is specifically shown in Table 2. The results show that:

1. the pH value is 3.6, the sodium benzoate with the concentration of 0.18 percent (w/w), the sodium propionate with the concentration of 1.15 percent (w/w) and the phenethyl alcohol with the concentration of 0.45 percent (w/w) are contained, the bacteriostasis rate to the candida albicans is more than 50 percent, and the requirements of GB 15979-. 1.2% (w/w) citric acid has no significant effect on the bacteriostatic action of the gel.

2. As shown in the first experimental example, 0.20% (w/w) sodium benzoate and 2.0% (w/w) propionic acid are compatible, and the bacteriostasis rate of the compound to candida albicans is less than 50%. In the embodiment, the combination of sodium benzoate 0.18% (w/w), sodium propionate 1.15% (w/w) and 0.45% (w/w) phenethyl alcohol has a bacteriostasis rate of more than 50% to candida albicans. Therefore, the phenethyl alcohol, the sodium benzoate and the propionic acid have a synergistic bacteriostatic effect on the candida albicans.

TABLE 2 bacteriostatic action of bacteriostatic gel on Candida albicans

Serial number	Gel pH	Sodium benzoate	Sodium propionate	Phenylethanolic acid	Citric acid	The antibacterial rate is%
							1	3.60	0.18	1.150	0.450	1.200	65.34％
2	3.60	0.18	1.150	0.450	--	69.13％

Experimental example III

The two gel compositions without citric acid were administered intravaginally to rhesus monkeys 1 time a day, 0.5 ml each time, for 5 consecutive days, and vaginal swabs were taken to measure pH and smear staining, and the effect of the gels on the pH of vaginal secretions and vaginal flora of rhesus monkeys was observed, as described in table 3. The results show that:

1. a, B except that the concentration of sodium propionate in the two groups of gels is 0.550% and 0.575%, the other components and contents are completely the same, and no citric acid is contained.

2. Group A gel containing 0.550% sodium propionate was administered for 5 times, and 3 of 4 rhesus monkeys had vaginal acidity reduced to 4.1 or less and recovered vaginal flora, mainly with bacteria in the form of Lactobacillus. Group B gel containing 0.575% sodium propionate was applied 5 times, and only 1 of 4 rhesus monkeys had their vaginal acidity and bacterial flora restored to normal.

From the above results, it can be seen that the bacteriostatic gel without citric acid in this example only increases the content of sodium propionate by less than 5%, and the effect of adjusting vaginal acidity and flora decreases, and most rhesus monkeys have failed to recover vaginal acidity and lactobacilli.

TABLE 3 Effect of citric acid free bacteriostatic gels on rhesus monkey vaginal acidity and flora

Note 1: a contains 3% (w/w) maltose, 0.06% (w/w) phenethyl alcohol, 0.12% (w/w) sodium benzoate, 0.550% (w/w) internal acid steel and xanthan gum, and the pH is adjusted to 3.25

Note 2: b contains 3% (w/w) maltose, 0.06% (w/w) phenethyl alcohol, 0.10% (w/w) sodium benzoate, 0.575% (w/w) sodium propionate and xanthan gum, and the pH is adjusted to 3.25

Note 3: nugent scores are microscopic examination of vaginal secretion smears and gram stains, and scores are carried out according to staining, morphology and quantity of bacteria, and specifically comprise the following steps:

the number of the vaginal bacteria is more than or equal to 7, the vaginal bacteria mainly comprise gram negative bacilli and/or negative cocci and positive cocci, and large positive bacilli are absent or extremely few;

4-6 points, the vaginal bacteria mainly comprise gram negative bacilli and/or negative cocci and/or positive cocci, and the large gram positive bacilli are few;

and 0-3 points, normal vaginal flora, and large gram-positive bacilli as the main bacteria.

Experimental example four

The five gel compositions without citric acid were administered intravaginally to rhesus monkeys 1 time a day, 0.5 ml each time, for 5 consecutive days, and vaginal swabs were taken to measure pH and smear staining, and the effect of the gels on the pH of vaginal secretions and vaginal flora of rhesus monkeys was observed, as described in table 4. The results show that:

1. the gel composition containing 0.40% phenethyl alcohol, 0.050-0.055% sodium benzoate and 0.443% propionic acid, such as 1 group and 2 groups, is administered for 3 times, so that the vaginal acidity of rhesus monkey can be reduced to 3.8 or below, flora recovery is mainly lactobacillus, and Nugent score is 0-3 min.

2. In groups 4 and 5, the content of phenethyl alcohol alone increased to 0.45% compared to groups 1 and 2, respectively. The medicine is taken for 3 times, the vaginal acidity of only 1 of 4 rhesus monkeys is reduced to 3.8, and 3 rhesus monkeys are still 5.4; nugent score only decreases from 1 to 0-3 points, and 3 points are still more than 7 points. It is shown that the increase of the content of the phenethyl alcohol from 0.40% to 0.45% leads to the remarkable reduction of the function of the gel for adjusting the vaginal acidity and flora.

3. In group 3, sodium benzoate alone was elevated to 0.060% compared to group 2. The medicine is taken for 3 times, the vaginal acidity of 3 rhesus monkeys is more than 4.4, the vaginal flora is not recovered, the Nugent score of 2 monkeys is 4-6 points, and the Nugent score of 1 monkey is more than 7 points. It shows that the content of sodium benzoate is increased, and the effect of the gel for regulating the acidity and flora of the vagina is reduced.

From the above results, it can be seen that when the concentration of the phenylethyl alcohol is increased from 0.40% to about 10% to 0.45% or the concentration of the sodium benzoate is increased from 0.055% to about 9% to 0.06%, the effect of adjusting the vaginal acidity and flora is reduced, and most rhesus monkeys have failed to recover the vaginal acidity and lactobacilli.

TABLE 4 Effect of citric acid free gels on rhesus monkey vaginal acidity and flora

Note 1: 1 contains 3% (w/w) maltose, 0.40% (w/w) phenethyl alcohol, 0.050% (w/w) sodium benzoate, 0.443% (w/w) propionic acid, xanthan gum, and adjusting pH to 3.5

Note 2: 2 contains 3% (w/w) maltose, 0.40% (w/w) phenethyl alcohol, 0.055% (w/w) sodium benzoate, 0.443% (w/w) propionic acid, xanthan gum, adjusting pH to 3.5

Note 3: 3 contains 3% (w/w) maltose, 0.40% (w/w) phenethyl alcohol, 0.060% (w/w) sodium benzoate, 0.443% (w/w) propionic acid, xanthan gum, and adjusting pH to 3.5

Note 4: 4 contains 3% (w/w) maltose, 0.45% (w/w) phenethyl alcohol, 0.050% (w/w) sodium benzoate, 0.443% (w/w) propionic acid, xanthan gum, and adjusting pH to 3.5

Note 5: 5 contains 3% (w/w) maltose, 0.45% (w/w) phenethyl alcohol, 0.055% (w/w) sodium benzoate, 0.443% (w/w) propionic acid, xanthan gum, and adjusting pH to 3.5

Note 6: the same as note 3 of the third embodiment.

Experimental example five

Experiments and researches are carried out on the bacteriostasis rate of the candida albicans ATCC10231 for 20 minutes according to the method in appendix C of GB15979-2002 sanitary Standard for Disposable sanitary articles, and the specific formula is shown in Table 5. The results show that:

1. the gel containing 0.15% (w/w) sodium benzoate, 0.60% (w/w) sodium propionate, 0.45% (w/w) phenethyl alcohol and 1.2% (w/w) citric acid has an antibacterial rate of less than 50% on Candida albicans ATCC 10231;

2. the gel containing 0.20% (w/w) sodium benzoate, 1.15% (w/w) sodium propionate, 0.45% (w/w) phenethyl alcohol and 1.2% (w/w) citric acid has a bacteriostasis rate of more than 50% on candida albicans ATCC 10231.

TABLE 5 bacteriostatic action of different bacteriostats in combination on Candida albicans

Experimental example six

The three gel compositions without citric acid were administered intravaginally to rhesus monkeys 1 time a day, 0.5 ml each time, for 5 consecutive days, and vaginal swabs were taken daily to measure pH and smear staining, and the effect of the gels on the pH of vaginal secretions and vaginal flora of rhesus monkeys was observed, as described in table 6. The results show that:

1. the E group gel contains 0.06% of phenethyl alcohol and 0.15% of sodium benzoate. The medicine is taken for 3 times, the vaginal pH values of two rhesus monkeys are 4.6 and 5.4 respectively, and Nugent scores are 4-6 and more than 7 respectively; the medicine is taken for 5 times, the vaginal pH value of 1 rhesus monkey is less than 3.8, the Nugent score is 0-3 points, the vaginal pH value of the other 1 rhesus monkey is still 5.4, and the Nugent score is more than 7 points.

2. The G group gel contains 0.06% of phenethyl alcohol, 0.12% of sodium benzoate and 0.55% of sodium propionate. The medicine is taken for 3 times, the vaginal pH value of 2 rhesus monkeys is less than 3.8, the Nugent score is 0-3, the vaginal pH value of 1 rhesus monkey is 4.4, the Nugent score is 4-6, the vaginal pH value of 1 rhesus monkey is still 5.4, and the Nugent score is more than 7; the medicine is taken for 5 times, the vaginal pH value of 3 rhesus monkeys is less than 3.8, the Nugent score is 0-3, the vaginal pH value of 1 rhesus monkey is still 5.4, and the Nugent score is more than 7.

3. The H group gel contains 0.06% of phenethyl alcohol, 0.15% of sodium benzoate and 0.55% of sodium propionate. The medicine is taken for 3 times, the vaginal pH values of two rhesus monkeys are 4.4 and 5.4 respectively, and Nugent scores are 4-6 and more than 7 respectively; the medicine is taken for 5 times, the vaginal pH value of 1 rhesus monkey is 4.1, the Nugent score is 0-3 points, the vaginal pH value of the other 1 rhesus monkey is still 5.4, and the Nugent score is more than 7 points.

In conclusion, the gel without citric acid in group H compared to group G decreased the effect of the gel on the modulation of vaginal acidity and vaginal flora when the concentration of sodium benzoate was increased from 0.12% to 0.15%. Group E, which did not contain sodium propionate, had a sodium benzoate concentration of 0.15%, and was not as good as group G in terms of its ability to regulate vaginal flora and acidity.

TABLE 6 Effect of citric acid-free bacteriostatic gels on rhesus monkey vaginal acidity and flora

Note 1: e contains 3.5% (w/w) maltose, 0.06% (w/w) phenethyl alcohol, 0.15% (w/w) benzoic acid steel, xanthan gum, and adjusting pH to 3.3

Note 2: g contains 3.5% (w/w) maltose, 0.06% (w/w) phenethyl alcohol, 0.12% (w/w) sodium benzoate, 0.55% (w/w) sodium propionate and xanthan gum, and the pH is adjusted to 3.3

Note 3: h contains 3.5% (w/w) maltose, 0.06% (w/w) phenethyl alcohol, 0.15% (w/w) sodium benzoate, 0.55% (w/w) sodium propionate and xanthan gum, and the pH is adjusted to 3.3

Note 4: the same as note 3 of the third embodiment.

Experimental example seven

The two gel compositions containing citric acid were administered intravaginally to rhesus monkeys 1 time a day and 0.5 ml each time for 5 consecutive days, and vaginal swabs were taken daily to measure pH and smear staining, and the effect of the gels on the pH of vaginal secretions and vaginal flora of rhesus monkeys was observed, as described in table 7. The results show that:

1. the gel of group 1 contained a higher concentration of bacteriostatic agent, with 0.45% of phenethyl alcohol, 0.15% of sodium benzoate, 0.46% of propionic acid, and 1.0% of citric acid. The application is carried out for 3 times, the vaginal pH value of 4 rhesus monkeys is reduced to 4.1 or below, and the Nugent score is 0-3.

2. Group 2 gels still contained 0.45% phenylethyl alcohol, but 0.20% sodium benzoate, 0.86% propionic acid, and 1.2% citric acid. Referring to the results of the second experimental example, the group 2 gel has a candida albicans inhibition rate of > 50%. The gel of this group was administered 3 times, the vaginal pH of 3 rhesus monkeys was reduced to 4.1 or less, and the Nugent score was 0-3 points.

3. In this example, the concentrations of phenethyl alcohol in group 1 and group 2 containing 1.0% and 1.2% of citric acid were 0.45% as compared with those in group 4 and group 5 containing no citric acid in the fourth example. As described in example four, the rise in the phenethyl alcohol concentration from 0.40% to 0.45% was the main cause of the deterioration of the effects of groups 4 and 5 in example four. In this example, the concentration of the sodium benzoate and the propionic acid is higher than that of the 1 st group and the 2 nd group, wherein the concentration of the sodium benzoate is 0.20% and that of the propionic acid is 0.86%! The concentration of the sodium benzoate is far higher than that of the sodium benzoate of the 4 th group and the 5 th group and that of the propionic acid is 0.050-0.055% and 0.443% in the fourth group. However, as the gel contains 1.0-1.2% citric acid, the adjustment effect of the gel of the 1 st group and the 2 nd group in the embodiment on the vaginal acidity and vaginal flora is obviously better than that of the gel of the 4 th group and the 5 th group in the embodiment.

4. In this example, the content of sodium benzoate in group 1 is 0.15% compared with that in group E and group H in example six, the content of propionic acid or sodium propionate in group 1 and group H in this example is close, and the content of 0.45% in group 1 phenethyl alcohol in this example is significantly higher than that in group E and group H by 0.06%. Since the gel of group 1 of this example contains 1.0% citric acid, the results showed that the effects of adjusting vaginal acidity and vaginal flora were significantly better than those of groups E and H of example six.

In summary, the gel containing citric acid can not only improve the regulation effect of the gel containing lower-concentration propionic acid and sodium benzoate on the acidity of the vagina and the vaginal flora, but also improve the regulation effect of the gel containing higher-concentration propionic acid, sodium benzoate and phenethyl alcohol on the acidity of the vagina and the vaginal flora, so that the gel has a bacteriostatic rate of more than 50 percent on candida albicans, and has good regulation effect on the acidity of the vagina and the vaginal flora.

TABLE 7 Effect of citric acid containing bacteriostatic gels on rhesus monkey vaginal acidity and flora

Note 1: 1 contains 3% (w/w) maltose, 0.45% (w/w) phenethyl alcohol, 0.15% (w/w) sodium benzoate, 0.46% (w/w) internal acid, 1.0% (w/w) citric acid, xanthan gum, and adjusting pH to 3.5

Note 2: 2 contains 3% (w/w) palatinose, 0.45% (w/w) phenethyl alcohol, 0.20% (w/w) sodium benzoate, 0.86% (w/w) propionic acid, 1.2% (w/w) citric acid and xanthan gum, and the pH is adjusted to 3.6

Note 3: the same as note 3 of the third embodiment.

Experimental example eight

The bacteriostasis rate of the Candida albicans ATCC10231 on the solution with the compatibility of the dibasic acid and the sodium benzoate is studied for 20 minutes according to the method in appendix C of GB15979-2002 hygienic Standard for Disposable sanitary articles, and is specifically shown in Table 7. The results show that:

1. the pH value is 3.6, 30mmol percent of succinic acid, malic acid, tartaric acid and maleic acid respectively and independently act, and the bacteriostasis rate to candida albicans is lower and is not more than 10 percent;

2. the pH value is 3.6, 30mmol percent of succinic acid, malic acid, tartaric acid and maleic acid are respectively matched with 0.25 percent (w/v) of sodium benzoate, the bacteriostasis rate to the candida albicans is still low and still does not exceed 10 percent.

3. In conclusion, it can be seen that succinic acid, malic acid, tartaric acid and maleic acid are respectively combined with sodium benzoate, and have no synergistic bacteriostatic effect on candida albicans.

TABLE 8 bacteriostatic action of the dibasic acid in combination with sodium benzoate on Candida albicans ATCC10231

Serial number	pH of the solution	Sodium benzoate (%)	Dibasic organic acid (%)	The antibacterial rate is%
					1	3.60	0.000	30mmol of succinic acid 3.54g	9.74％
2	3.60	0.250	30mmol of succinic acid 3.54g	9.23％
					3	3.60	0.000	30mmol of malic acid 4.02g	4.10％
4	3.60	0.250	30mmol of malic acid 4.02g	3.08％
					5	3.60	0.000	30mmol of tartaric acid 4.50g	3.59％
6	3.60	0.250	30mmol of tartaric acid 4.50g	6.67％
					7	3.60	0.000	30mmol of maleic acid 3.48g	6.15％
8	3.60	0.250	30mmol of maleic acid 3.48g	-5.64％

Experimental example nine

The bacteriostasis rate of the Candida albicans ATCC10231 is researched by the action of a solution prepared by mixing binary or ternary organic acid and phenethyl alcohol for 20 minutes according to a method in appendix C of GB15979-2002 hygienic Standard for Disposable sanitary articles, and is specifically shown in Table 8. The results show that:

1. the pH value is 3.6, 30mmol percent of succinic acid, malic acid, tartaric acid, maleic acid and citric acid respectively and independently act, and the bacteriostasis rate to candida albicans is not more than 20 percent;

2. the pH value is 3.6, the 30mm0 l% succinic acid, malic acid, tartaric acid, maleic acid and citric acid are respectively matched with 0.45% (w/v) phenethyl alcohol, the bacteriostasis rate to candida albicans is still low, and the bacteriostasis rate is still not more than 20%.

3. In conclusion, it can be seen that succinic acid, malic acid, tartaric acid, maleic acid and citric acid are respectively compatible with phenethyl alcohol, and have no significant synergistic bacteriostatic action on candida albicans.

TABLE 9 bacteriostatic action of the binary or ternary organic acids in combination with phenethyl alcohol on Candida albicans ATCC10231

Experimental example ten

The bacteriostasis rate of the Candida albicans ATCC10231 is researched by the action of a solution prepared by combining a binary or ternary organic acid and propionic acid for 20 minutes according to a method in appendix C of GB15979-2002 hygienic Standard for Disposable sanitary articles, and is specifically shown in Table 9. The results show that:

1. the pH value is 3.6, 30mmol percent of succinic acid, malic acid, tartaric acid, maleic acid and citric acid respectively and independently act, and the bacteriostasis rate to candida albicans is not more than 10 percent;

2. the pH value is 3.6, 30mmol percent of succinic acid, malic acid, tartaric acid, maleic acid and citric acid are respectively matched with 1.00 percent (w/v) of propionic acid, the bacteriostasis rate to candida albicans is still low and is not more than 10 percent.

3. In conclusion, it can be seen that succinic acid, malic acid, tartaric acid, maleic acid and citric acid are respectively combined with propionic acid, and have no significant synergistic bacteriostatic effect on candida albicans.

TABLE 10 bacteriostatic action of the solution of binary or ternary organic acid in combination with propionic acid on Candida albicans ATCC10231

Experimental example eleven

The bacteriostasis rates of solutions with different bacteriostat combinations are studied for 20 minutes according to the method in appendix C of GB15979-2002 hygienic Standard for Disposable sanitary articles, and are specifically shown in Table 8 for the bacteriostasis rates of Staphylococcus aureus and Candida albicans ATCC 10231. The results show that:

1. the pH value is 3.5-3.8, the bacteriostatic rate of the solution containing 0.06% (w/w) of sodium benzoate, 0.50% (w/w) of sodium propionate and 0.40% (w/w) of phenethyl alcohol to staphylococcus aureus is more than 50%; but when the pH value is 4.0, the bacteriostasis rate of the solution to staphylococcus aureus is less than 50 percent.

2. The pH value is 3.5-4.0, the solution containing 0.06% (w/w) of sodium benzoate, 0.50% (w/w) of sodium propionate and 0.40% (w/w) of phenethyl alcohol has the bacteriostasis rate of less than 50% on candida albicans.

TABLE 11 bacteriostatic action of different bacteriostatic solutions on Staphylococcus aureus and Candida albicans

Reference documents:

1. xi to think of Zhu, consider learning the fur coat to compile: pharmacy, second edition 1990, pp 292 + 349, Min health Press;

2. xi to think of Zhu, consider learning the fur coat to compile: pharmacy, second edition 1990, pp 377-386.

Claims

1. An organic acid composition for vaginal or vulvar use, characterized in that it comprises, per hundred grams of composition, the following organic acids and/or salts thereof:

(1) one or more dibasic or polybasic organic acids and/or salts thereof selected from the following group in a total amount of 0.3000 to 60.0000 mmol: citric acid, malic acid, succinic acid, tartaric acid, maleic acid; preferably 1.5000-33.0000 mmol of citric acid and malic acid;

(2) one or more monobasic organic acid bacteriostats and/or salts thereof with the total amount of 0.3000-60.0000 mmol, wherein the monobasic organic acid bacteriostats are selected from the following group: acetic acid, glycolic acid, lactic acid, propionic acid, levulinic acid; preferably 10.4103-33.0000 mmol of propionic acid;

(3) one or more aromatic organic acid bacteriostats and/or salts thereof with the total amount of 0.1000-10.0000 mmol, wherein the aromatic organic acid bacteriostats are selected from the following groups: benzoic acid, p-hydroxybenzoic acid, p-methoxybenzoic acid, salicylic acid, cinnamic acid; preferably 1.0000-2.5000 mmol of benzoic acid;

the vaginal or vulvar composition can be a solution, a spray, a foam, an ointment, a powder, a microcapsule, a membrane, an effervescent tablet, a capsule, a suppository or a tablet.

2. A composition according to claim 1, wherein the total content of organic acid and/or salt thereof per hundred grams of the composition is from 25.00 to 45.00 mmol.

3. The composition according to claim 1, wherein the salt of the organic acid is a sodium salt.

4. A composition according to claim 1, wherein said composition further comprises, per hundred grams of composition, a total amount of 0.1000 to 10.0000mmol of one or more aromatic alcohols selected from the group consisting of: benzyl alcohol, benzyl dichloride alcohol, phenethyl alcohol, phenoxyethanol and cinnamyl alcohol, and preferably 0.4000-5.0000 mmol of phenethyl alcohol.

5. The composition according to claim 1, wherein the composition further comprises one or more sugars selected from the group consisting of sugars in a total amount of 0.30-20.00% (w/w): glucose, fructose, mannose, sucrose, isomaltulose, kestose, nystose, kestopentaose, maltose, isomaltose, isomaltotriose, isomaltotetraose, isomaltopentaose, trehalose, cellobiose, melibiose, gentiobiose, gentiooligosaccharide, raffinose, panose, maltooligosaccharide, isomaltooligosaccharide, fructooligosaccharides, glucomannan, dextrin, starch, glycogen or mixtures thereof; preferably, the total content of glucose, fructose, mannose, sucrose, maltose, isomaltulose, isomaltose, trehalose, maltooligosaccharides, or a mixture thereof is 1.00 to 6.50% (w/w).

6. The composition according to claim 1, wherein the composition further comprises 0.001-1.00% (w/w) of one or more estrogens selected from the group consisting of: diethylstilbestrol, hexestrol, estradiol, estrone, estriol, nilestriol, ethinylestradiol cyclopentyl ether, and ethinylestradiol methyl ether.

7. The composition according to claim 1, wherein the composition further comprises 0.001-1.00% (w/w) of one or more phytoestrogens selected from the group consisting of: daidzin, daidzein, glycitein, coumestrol, genistein, equol, apigenin, genistin, genistein, biochanin, coumestrol, formononetin, resveratrol, secoisolariciresinol diglucoside, and lignans.

8. The composition according to claim 1, wherein said composition further comprises one or more amino acids and/or salts thereof selected from the group consisting of 1.0000 to 45.0000mmol in total per hectogram: l-glutamic acid, glutamine, L-aspartic acid, asparagine, isoleucine, phenylalanine, valine, leucine, proline, threonine; preferably the total amount of the glutamic acid, the aspartic acid and/or the salt thereof is 5.0000-30.0000 mmol.

9. The method according to claim 1, wherein said composition optionally further comprises one or more monoterpene or sesquiterpene compounds in a total amount of 0.1000-10.0000 mmol per hundred gram of composition, including but not limited to: citronellol, linalool, geraniol, nerol, eucalyptol, terpineol, carveol, menthol, and lavender alcohol.

10. The composition according to claim 1, wherein the composition may further comprise a total amount of 0.10-30.00 milligrams% (w/w) of one or more plant essential oils, including but not limited to: rose essential oil, clove oil, thyme oil, lavender oil, peppermint oil, mugwort leaf oil, eucalyptus oil, sassafras oil, litsea cubeba essential oil, cinnamon essential oil and bay leaf oil.

11. The composition according to claim 1, wherein the composition further comprises one or more selected from the group consisting of: 0.01-5.0% (w/w) aloe extract, 0.001-1.0% (w/w) vitamin E, 0.001-1.0% (w/w) vitamin A, 0.001-1.0% (w/w) vitamin D, 0.001-1.0% (w/w) vitamin C.

12. The composition according to claim 1, wherein said composition further comprises one or more antibacterial agents including but not limited to: metronidazole, tinidazole, clotrimazole, fluconazole, miconazole or ketoconazole, preferably metronidazole and clotrimazole.

13. The composition of claim 1, wherein said composition further comprises one or more bacteriostatic or antibacterial agents, including but not limited to: dehydroacetic acid, sodium dehydroacetate, sorbic acid, potassium sorbate, sodium sorbate, diacetic acid, sodium diacetate, caprylic acid, sodium caprylate, capric acid, sodium decanoate, undecylenic acid, sodium undecylenate, lauric acid, sodium laurate, natamycin, lactoferrin, lactoferricin, lysozyme, bacteriostatic protein, antibacterial peptide, lichenic acid, tigecycline, tropolone, cinnamaldehyde, pseudolaric acid, chlorogenic acid, fibrauretin, propenyloxyethanol, 1, 2-pentanediol, 1, 2-hexanediol, 1, 6-hexanediol, 1, 2-octanediol, 1, 2-decanediol, methylpropanediol, ethylhexylglycerol, benzoyl peroxide.

14. The composition according to claim 1, which is a water-soluble gel, characterized by further comprising a non-flowing, viscous, water-soluble colloidal matrix including, but not limited to xanthan gum, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carbomer, polycarbophil, preferably xanthan gum; the pH value of the composition is 3.0-4.5.

15. The composition according to claim 1, wherein the composition is a micro-ecological regulator, or a micro-environment regulator, or a micro-organism regulator, or a pharmaceutical product, or a disinfectant, or an antibacterial agent, or a bacteriostatic agent, or a mucosal skin surface microbicide, or a disposable medical product; or a disinfection apparatus, or a medical apparatus, or a pharmaceutical apparatus; or as a component of a sterile device, or a medical device, or a pharmaceutical device.

16. The composition according to claim 1, wherein the composition is a hygiene product, or a cosmetic product, or a micro-ecological care product, or a cleaning care product, or an odor eliminating agent, or a lubricant, or a moisturizer, or a lotion; or be a component of a hygiene product, or a cleaning care product.

17. The composition according to claim 16, wherein said composition is a component of a sanitary napkin, or a panty liner, or a tampon.

18. The composition according to claim 14, wherein said composition is packaged in a variety of ways, including but not limited to single dose, sterile, sealed package, or packaged in a vaginal device, or packaged in a disposable vaginal applicator; preferably in single dose, sterile, sealed packages.

19. Use of a formulation of organic acids comprising per hundred grams of said composition the following types of organic acids and/or salts thereof for the preparation of a composition for vaginal or vulval use:

(1) one or more dibasic or polybasic organic acids and/or salts thereof selected from the following group in a total amount of 0.3000 to 60.0000 mmol: citric acid, malic acid, succinic acid, tartaric acid and maleic acid, wherein the total amount of the citric acid and the malic acid is preferably 1.5000-33.0000 mmol;

(2) one or more monobasic organic acids and/or salts thereof selected from the group consisting of 0.3000 to 60.0000mmol in total: acetic acid, glycolic acid, lactic acid, propionic acid and levulinic acid, preferably 10.4103-33.0000 mmol of propionic acid;

(3) one or more aromatic organic acids and/or salts thereof in a total amount of 0.1000 to 10.0000 mmol: benzoic acid, p-hydroxybenzoic acid, p-methoxybenzoic acid, salicylic acid and cinnamic acid, wherein 1.0000-2.5000 mmol of benzoic acid is preferred;

20. Use according to claim 19, wherein the total content of the respective organic acids and/or salts thereof per hundred grams of the composition is from 25.00 to 45.00 mmol.

21. A method for inhibiting candida, escherichia coli, staphylococcus aureus, and promoting lactobacilli in the vagina, wherein the method comprises intravaginally administering to a woman in need thereof an effective amount of a composition according to any one of claims 1-18.

22. The method according to claim 21, wherein the method is a method of maintaining normal acidity of the vagina, and/or modulating vaginal microecology, and/or modulating vaginal microbiota, and/or selective vaginal decontamination, wherein the method comprises intravaginally administering to a woman in need thereof an effective amount of a composition according to any one of claims 1 to 18.

23. A method according to claim 21, wherein the method is a method of eliminating or reducing discomfort such as vaginal vulvar itching, pain, or dyspareunia, or improving the white-band trait, or eliminating the smell of white-band, or cleansing the vagina, or caring for and/or regulating vaginal microecology, wherein the method comprises intravaginally administering to a female in need thereof an effective amount of a composition according to any one of claims 1 to 18.

24. The method according to claim 21, wherein the method is a method for the prevention and/or treatment of a vaginal microbial disease, wherein the vaginal microbial disease is fungal vaginitis, or cytolytic vaginosis, or a dysregulated vaginal flora, or bacterial vaginosis, or senile vaginitis, wherein the method comprises intravaginally administering an effective amount of a composition according to any one of claims 1 to 18 to a woman in need thereof.