WO2018064978A1 - 一种抑菌剂配伍在制备阴道用组合物中的用途与阴道用组合物 - Google Patents

一种抑菌剂配伍在制备阴道用组合物中的用途与阴道用组合物 Download PDF

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WO2018064978A1
WO2018064978A1 PCT/CN2017/105296 CN2017105296W WO2018064978A1 WO 2018064978 A1 WO2018064978 A1 WO 2018064978A1 CN 2017105296 W CN2017105296 W CN 2017105296W WO 2018064978 A1 WO2018064978 A1 WO 2018064978A1
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sodium
acid
vaginal
composition
benzoate
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PCT/CN2017/105296
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English (en)
French (fr)
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曾忠铭
张文勇
武孔媛
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曾忠铭
新加坡善泽国际私人有限公司
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Application filed by 曾忠铭, 新加坡善泽国际私人有限公司 filed Critical 曾忠铭
Priority to EP17857859.7A priority Critical patent/EP3520785A4/en
Priority to MYPI2019001965A priority patent/MY191276A/en
Priority to CA3039556A priority patent/CA3039556C/en
Priority to JP2019540484A priority patent/JP6780123B2/ja
Priority to SG11201903162VA priority patent/SG11201903162VA/en
Publication of WO2018064978A1 publication Critical patent/WO2018064978A1/zh
Priority to US16/379,779 priority patent/US20190231748A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the use of a bacteriostatic agent in the preparation of a vaginal composition for the preparation of a therapeutic or non-therapeutic vaginal composition. It also relates to a vaginal composition for use in vaginal health care, prevention and treatment of vaginal infectious diseases.
  • vaginal normal flora a Gram-positive bacilli
  • These coarse Gram-positive bacilli are mainly Lactobacillus, which can metabolize glycogen and acid in vaginal mucosal epithelial cells.
  • vaginal acidity in the range of pH 3.5 to 4.3, it is extremely important for the female reproductive tract to resist infection.
  • vaginal infections are common, such as bacterial vaginosis, aerobic vaginitis, Candida vaginitis, etc., and more with coagulation in E. coli, gold Staphylococcus aureus, group B streptococci, and increased number of harmful bacteria such as Gardnerella, Prevo, and Candida. Therefore, while inhibiting harmful bacteria and harmful fungi, avoiding inhibition or destruction of beneficial lactobacilli has important clinical significance for preventing and treating genital tract infections.
  • the object of the present invention is to provide a bacteriostatic composition which has a strong inhibitory effect on Escherichia coli, and/or Staphylococcus aureus, and/or Candida, and can be used for promoting beneficial milk in the vagina. Recovery of bacilli and enhancement of vaginal acidity.
  • phenylethyl alcohol and / or phenoxyethanol compatible with benzoic acid and / or its sodium salt and / or p-methoxybenzoic acid and / or its sodium and / or parabens; or phenylethyl alcohol And/or phenoxyethanol, in combination with propionic acid and/or its salt and/or levulinic acid and/or its salt and/or acetic acid and/or its sodium salt, for Escherichia coli, and/or Staphylococcus aureus Synergistic bacteriostatic effect.
  • compatibility of phenylethyl alcohol and/or phenoxyethanol with other bacteriostatic substances such as compatibility with dehydroacetic acid and/or its sodium salt, or with sorbic acid and/or its potassium salt, Not as good as the aforementioned compatibility.
  • the present invention provides a use of a bacteriostatic agent in the preparation of a vaginal composition, wherein the composition comprises the following bacteriostatic agent: (1) a total content of 0.05 to 0.60% (w/v) based on phenylethanol Phenylethanol and/or phenoxyethanol; (2) 0.25-0.70% (w/v) of propionic acid and/or sodium propionate and/or calcium propionate and/or acetyl-propionate in total sodium propionate Acid and / or sodium levulinate and / or acetic acid and / or sodium acetate; and / or a total amount of 0.05 to 0.15% (w / v) of benzoic acid and / or sodium benzoate and / or a pair of sodium benzoate Oxybenzoic acid and/or sodium p-methoxybenzoate and/or benzoate.
  • bacteriostatic agent (1) a total content of 0.05 to 0.60% (w/v) based on pheny
  • the propionic acid-based substance of the present invention is a commonly used short-chain fatty acid bacteriostatic preservative, preferably propionic acid and/or its sodium salt.
  • the benzoate materials include methyl benzoate, ethyl benzoate, propyl benzoate, and butyl benzoate, and the like, and ethyl benzoate is preferred.
  • the content of phenoxyethanol in terms of phenylethanol in the present invention refers to the content of phenoxyethanol converted to the content of phenylethyl alcohol, and the conversion method is: the molecular weight of phenylethyl alcohol is divided by the molecular weight of phenoxyethanol, and multiplied by phenoxy
  • the content of ethanol is the content of phenylethyl alcohol in terms of phenoxyethanol.
  • the phenylethyl alcohol molecular weight 122, the phenoxyethanol molecular weight 138, and the 0.034% (w/v) phenoxyethanol content are 0.030% (w/v) in terms of phenylethyl alcohol.
  • the content of 0.030% (w/v) phenylethyl alcohol The content converted to phenoxyethanol was 0.034% (w/v). I and so on, and vice versa.
  • the content of the benzoic acid, the p-methoxybenzoic acid and/or the sodium salt thereof, the benzoate substance and the like in the sodium benzoate according to the present invention means that the content of the substance such as benzoic acid is converted into sodium benzoate. content.
  • the conversion method is: dividing the molecular weight of sodium benzoate by the molecular weight of a substance such as benzoic acid, and multiplying the content of a substance such as benzoic acid, and the result is a content of a substance such as benzoic acid converted to sodium benzoate.
  • sodium benzoate has a molecular weight of 144
  • benzoic acid has a molecular weight of 122
  • p-methoxybenzoic acid has a molecular weight of 152
  • p-methoxybenzoic acid has a molecular weight of 174
  • ethyl benzoate has a molecular weight of 150.
  • the ethyl benzoate was converted to the content of sodium benzoate, and the result was 0.12% (w/v). I and so on, and vice versa.
  • the content of propionic acid and/or its calcium salt, levulinic acid and/or its sodium salt, acetic acid and/or its sodium salt in the case of sodium propionate according to the present invention means the content of a substance such as propionic acid. , converted to sodium propionate content.
  • the conversion method is: the molecular weight of sodium propionate is divided by the molecular weight of a substance such as propionic acid, and multiplied by the content of a substance such as propionic acid, and the result is a content of a substance such as propionic acid converted into sodium propionate.
  • sodium propionate has a molecular weight of 96
  • propionic acid has a molecular weight of 74
  • levulinic acid has a molecular weight of 116
  • sodium levulinate has a molecular weight of 138
  • acetic acid has a molecular weight of 60
  • sodium acetate has a molecular weight of 82.
  • Sodium acetate (w/v) was converted to sodium propionate as a result of 0.4% (w/v). I and so on, and vice versa.
  • a preferred total amount of phenylethyl alcohol and/or phenoxyethanol in terms of phenylethanol is from 0.10 to 0.40% (w/v); total propionic acid and/or sodium propionate and/or sodium propionate Or the total content of calcium propionate and / or levulinic acid and / or sodium levulinate and / or acetic acid and / or sodium acetate is 0.525 ⁇ 0.575% (w / v); the total amount of benzoic acid and sodium benzoate The total content of sodium benzoate and/or p-methoxybenzoic acid and/or sodium p-methoxybenzoate and/or benzoate is from 0.065 to 0.090% (w/v).
  • the composition contains (1) phenylethyl alcohol and/or phenoxyethanol; (2) propionic acid and/or sodium propionate and/or calcium propionate and/or levulinic acid and/or sodium levulinate and / or acetic acid and / or sodium acetate; (3) benzoic acid and / or sodium benzoate and / or p-methoxybenzoic acid and / or sodium p-methoxybenzoate and / or benzoate substances.
  • Preferred bacteriostatic agents are phenylethyl alcohol, propionic acid and/or sodium propionate, benzoic acid and/or sodium benzoate.
  • the composition further comprises one or more bacteriostatic or antibacterial substances selected from the group consisting of: dehydrogenation Acetic acid, sodium dehydroacetate, sorbic acid, potassium sorbate, sodium sorbate, diacetic acid, sodium diacetate, octanoic acid, sodium octanoate, citric acid, sodium sulphate, undecylenic acid, sodium undecylenate, lauric acid , sodium laurate, natamycin, lactoferrin, lactoferrin peptide, lysozyme, bacteriostatic protein, antimicrobial peptide, lichenic acid, saxifrage, tropone, chlorogenic acid, yellow vine , benzyl alcohol, propylene phenoxyethanol, 1,2-pentanediol, 1,2-hexanediol, 1,6-hexanediol, 1,2-octanediol, 1,2-sodium diol, Methy
  • the bacteriostatic agent or antibacterial agent is used for further enhancing the bacteriostatic composition prepared by the present invention against Staphylococcus aureus, Escherichia coli, and Candida, and against other harmful microorganisms such as HIV, HPV and the like or Antibacterial effect.
  • the composition further comprises from 1.0 to 9.0% (w/v) of one or more sugars selected from the group consisting of glucose, fructose, mannose, sucrose, isomaltulose, Sugar cane trisaccharide, cane fruit tetrasaccharide, cane fruit pentasaccharide, maltose, isomaltose, isomaltose, isomaltose, isomaltose, trehalose, cellobiose, melibiose, gentiobiose , low poly gentian, raffinose, panose, malto-oligosaccharide, oligo-isomaltulose, oligofructose, glucomannan, dextrin, starch and glycogen.
  • sugars selected from the group consisting of glucose, fructose, mannose, sucrose, isomaltulose
  • Sugar cane trisaccharide, cane fruit tetrasaccharide
  • the sugar-containing vaginal composition prepared by the invention has the function of biphasic regulating vaginal flora, that is, selectively inhibiting Escherichia coli, and/or Staphylococcus aureus, and/or Candida, etc. Selectively promote beneficial lactobacilli in the vagina.
  • vaginal flora Compared with the prior art, it has superior effects on regulating vaginal flora, enhancing vaginal acidity, and maintaining vaginal beneficial lactobacilli, and can enhance vaginal anti-infective ability, and is suitable for preventing and/or treating vaginal lactobacillus reduction, or vaginal flora A disorder, or bacterial vaginosis, or a normal flora that restores the vagina after antibacterial treatment of a reproductive tract infection, or an adjuvant treatment for genital tract infections.
  • the present inventors have also found that when the total concentration of sugar is less than 1% (w/v), its effect of promoting growth and acid production of lactobacilli is weak; when the sugar concentration is higher than 9% (w/v), it may be The vaginal mucosa is irritating.
  • the composition further comprises from 0.1 to 10.0% (w/v) of one or more amino acids selected from the group consisting of glutamic acid, glutamine, aspartic acid, and the like. Asparagine, isoleucine, phenylalanine, valine, leucine, valine and threonine.
  • the amino acid-containing vaginal composition prepared by the invention can reduce vaginal flora to produce acid, and can be used for treating or assisting treatment of cytosolic vaginosis, lactobacilli vaginal disease, and fungal vaginitis.
  • the present inventors have also found that when the total concentration of amino acids is less than 0.1% (w/v), the effect of regulating vaginal flora on acid production is weak; when the total concentration is higher than 10% (w/v), vaginal bacteria may be caused. Group abnormal evolution.
  • the composition further comprises from 0.001 to 1.0% (w/v) of one or more substances selected from the group consisting of the following group of estrogens and/or phytoestrogens for use in the present invention: diethylstilbestrol, estradiol Alcohol, estriol, Soybean meal, soybean meal, dye hibiscus, genistein, glycyrrhizin, soy bean flavonoid, chickpea flavin, coumestrol and formononetin.
  • one or more substances selected from the group consisting of the following group of estrogens and/or phytoestrogens for use in the present invention: diethylstilbestrol, estradiol Alcohol, estriol, Soybean meal, soybean meal, dye hibiscus, genistein, glycyrrhizin, soy bean flavonoid, chickpea flavin, coumestrol and formononetin.
  • Diethylstilbestrol, estradiol, and estriol are estrogens, soybean meal, soybean meal, dye hibiscus, genistein, glycyrrhizin, soybean flavin, chicken flavonoids, coumestrol and mango Lutein is a phytoestrogens.
  • the vaginal composition containing the estrogen and/or phytoestrogens prepared by the invention can promote the synthesis of glycogen in the vaginal mucosal epithelial cells, maintain or restore the normality of the vaginal microenvironment, and promote the growth of beneficial lactobacilli and restore micro Ecosystem balance.
  • the composition further comprises one or more materials selected from the group consisting of: 0.01 to 5.0% (w/v) of aloe extract, 0.01 to 5.0% (w/v).
  • Lavender extract 0.001 to 1.0% (w/v) of vitamin E, 0.001 to 1.0% (w/v) of vitamin A, 0.001 to 1.0% (w/v) of vitamin D and 0.001 to 1.0% (w/ v) Vitamin C.
  • the vaginal composition containing the above-prepared substance prepared by the present invention can be used for protecting the vaginal mucosa and promoting the repair of damaged vaginal mucosa.
  • a preferred dosage form of the vaginal composition is a solution, or a water-soluble gel, or an emulsion-type ointment, wherein the composition has a pH of from 3.0 to 4.3.
  • the vaginal composition may be a non-therapeutic vaginal health product, or a vaginal daily necessities, or a vaginal health product, or a vaginal care product, or a vaginal cosmetic, or a vaginal hygiene product, Or vaginal cleaning products; or therapeutic vaginal health products, vaginal medical devices, or vaginal disinfecting devices, or vaginal drug devices, or vaginal drugs; or for vaginal lotions, or cleansers Or curing agent, or deodorant, or antipruritic, or freshener, or wetting agent, or lubricant, or disinfectant, or antibacterial, or bacteriostatic agent, or mucosal surface microbicide, or microecology A regulator, or a microbial regulator.
  • the present invention also provides a composition for a vagina, the composition comprising: (1) a total amount of 0.05 to 0.6% (w/v) of phenylethyl alcohol and/or phenoxyethanol in terms of phenylethanol; a total of 0.25-0.7% (w/v) propionic acid and/or sodium propionate and/or calcium propionate and/or levulinic acid and/or sodium levulinate and/or acetic acid in terms of sodium propionate And/or sodium acetate; and/or a total amount of 0.05 to 0.15% (w/v) of benzoic acid and/or sodium benzoate and/or p-methoxybenzoic acid and/or p-methoxybenzene based on sodium benzoate Sodium formate and/or benzoate.
  • the composition dosage form is a solution, or a water-soluble gel, or an emulsion-type ointment, preferably a water-soluble gel; the composition has a pH of 3.0 to 4.3.
  • the preferred total amount of phenylethyl alcohol and/or phenoxyethanol in terms of phenylethanol is 0.10 to 0.40% (w/v); total propionic acid and/or sodium propionate and/or calcium propionate and/or levulinic acid and/or sodium levulinate and/or acetic acid in terms of sodium propionate And/or the total content of sodium acetate is from 0.525 to 0.575% (w/v); the total amount of sodium benzoate and/or sodium benzoate and/or p-methoxybenzoic acid and/or p-methoxybenzene in terms of sodium benzoate The total content of sodium formate and/or benzoate is from 0.065 to 0.090% (w/v).
  • the composition contains (1) phenylethyl alcohol and/or phenoxyethanol; (2) propionic acid and/or sodium propionate and/or calcium propionate and/or levulinic acid and/or sodium levulinate and / or acetic acid and / or sodium acetate; (3) benzoic acid and / or sodium benzoate and / or p-methoxybenzoic acid and / or sodium p-methoxybenzoate and / or benzoate substances.
  • Preferred bacteriostatic agents are phenylethyl alcohol, propionic acid and/or sodium propionate, benzoic acid and/or sodium benzoate.
  • the composition further comprises one or more bacteriostatic agents or antibacterial agents selected from the group consisting of dehydroacetic acid, sodium dehydroacetate, sorbic acid, potassium sorbate, sodium sorbate, diacetic acid, diacetic acid Sodium, octanoic acid, sodium octanoate, citric acid, sodium sulphate, undecylenic acid, sodium undecylenate, lauric acid, sodium laurate, natamycin, lactoferrin, lactoferrin peptide, lysozyme, inhibition Bacterial protein, antibacterial peptide, lichenic acid, saxifrage, tropone, chlorogenic acid, yellow vine, benzyl alcohol, propylene phenoxyethanol, 1,2-pentanediol, 1,2-hexol Glycol, 1,6-hexanediol, 1,2-octanediol, 1,2-sodium diol, methyl propylene
  • the composition further comprises a total amount of 0.001 to 1.0% (w/v) of one or more substances selected from the group consisting of diethylstilbestrol, estradiol, estriol, soybean meal, soybean meal, Dye hibiscus, genistein, glycyrrhizin, soy flavonoid, chickpea flavin, coumestrol and formononetin.
  • one or more substances selected from the group consisting of diethylstilbestrol, estradiol, estriol, soybean meal, soybean meal, Dye hibiscus, genistein, glycyrrhizin, soy flavonoid, chickpea flavin, coumestrol and formononetin.
  • the composition further comprises a total amount of 1.0 to 9.0% (w/v) of one or more sugars selected from the group consisting of glucose, fructose, mannose, sucrose, isomaltulose, and cane Sugar, sugar cane tetrasaccharide, cane fruit pentasaccharide, maltose, isomaltose, isomaltose, isomaltose, isomaltose, trehalose, cellobiose, melibiose, gentiobiose, oligomeric Gentose, raffinose, panose, malto-oligosaccharide, oligo-isomaltulose, oligofructose, glucomannan, dextrin, starch and glycogen.
  • sugars selected from the group consisting of glucose, fructose, mannose, sucrose, isomaltulose, and cane Sugar, sugar cane tetrasaccharide, cane
  • the sugar is one or more sugars selected from the group consisting of glucose, fructose, mannose, sucrose, maltose, isomaltulose, isomalt, total content of 2.0 to 6.5% (w/v), Trehalose, malt oligosaccharide.
  • the composition further comprises one or more materials selected from the group consisting of 0.01 to 5.0% (w/v) of aloe extract, 0.01 to 5.0% (w/v) of lavender extract, 0.001 to ⁇ 1.0% (w/v) vitamin E, 0.001 to 1.0% (w/v) vitamin A, 0.001 to 1.0% (w/v) vitamin D and 0.001 to 1.0% (w/v) Vitamin C.
  • the composition further comprises 0.1 to 10% (w/v) of one or more amino acids selected from the group consisting of: and glutamic acid, glutamine, aspartic acid, aspartic acid Aminoamide, isoleucine, phenylalanine, valine, leucine, valine and threonine.
  • amino acids selected from the group consisting of: and glutamic acid, glutamine, aspartic acid, aspartic acid Aminoamide, isoleucine, phenylalanine, valine, leucine, valine and threonine.
  • the amino acid is present in an amount of from 1.0 to 5.0% (w/v), wherein the amino acid is glutamic acid and/or aspartic acid.
  • compositions of the present invention may be packaged in a variety of ways including, but not limited to, single dose, sterile, sealed packs, or packaged in vaginal devices, or packaged in disposable vaginal applicators; preferably single dose, no Bacteria, sealed packaging.
  • the preparation process, method and selection of excipients are all contemplated by one of ordinary skill in the art in light of the disclosure of the present invention in conjunction with the background.
  • composition according to the present invention may optionally contain a low dose antibacterial drug metronidazole or tinidazole, wherein the content of metronidazole or tinidazole is such that the dosage per unit or single dose of the composition
  • the total content of metronidazole and/or tinidazole in the package (unit dosage form) such as a tablet, a suppository, or a single-dose packaged ointment is 0.001 to 0.5 mg, preferably 0.01 to 0.25 mg.
  • compositions of the invention containing low doses of metronidazole or tinidazole have the effect of caring for and/or regulating vaginal micro-ecology, against anaerobic bacteria, and maintaining vaginal micro-ecological balance.
  • the present invention also provides a method for producing a composition for a vagina, the method comprising the steps of: adding (1) the total content to the water and/or the water-soluble colloidal matrix and/or the emulsion-type ointment base in terms of phenylethanol 0.05 to 0.60% (w/v) of phenylethyl alcohol and/or phenoxyethanol; (2) 0.25 to 0.70% (w/v) of propionic acid and/or sodium propionate and/or total sodium propionate Or calcium propionate and / or levulinic acid and / or sodium levulinate and / or acetic acid and / or sodium acetate; and / or a total amount of 0.05 to 0.15% (w / v) of benzoic acid and sodium benzoate / or sodium benzoate and / or p-methoxybenzoic acid and / or sodium p-methoxybenzoate and / or benzoate substances.
  • a viscous, non-flowable, water-soluble colloidal matrix such as Caromer, and/or methylcellulose (MC), and/or glucomannan, and / or tragacanth, and / or tragacanth, and / or xanthan gum, etc., preferably xanthan gum
  • MC methylcellulose
  • glucomannan and/ or tragacanth, and / or tragacanth, and / or xanthan gum, etc., preferably xanthan gum
  • preferably xanthan gum can be prepared according to methods known to those skilled in the art, such as the following process: proportionally take (1) benzene Ethanol and / or phenoxyethanol; (2) propionic acid and / or sodium propionate and / or calcium propionate and / or levulinic acid or / or sodium levulinate and / or acetic acid and / or sodium acetate; and / Or benzoic acid and / or sodium benzo
  • sterilization can be selected as follows: radiation sterilization, intermittent sterilization (such as 60 ° C, 15 minutes treatment, then set at 36 ° C, 6 ⁇ 12 hours, then 60 ° C, 15 minutes, then Set at 36 ° C, 6 ⁇ 12 hours, and finally 60 ° C, 15 minutes treatment), or the components such as phenylethyl alcohol, sodium propionate or sodium benzoate can be separately prepared into a solution, filtered and sterilized, and then added to the sterilized In a water-soluble colloidal matrix.
  • materials known to those skilled in the art such as glyceryl monostearate, and/or paraffin, and/or beeswax, and/or white petrolatum, and/or lauryl alcohol may be used.
  • glyceryl monostearate, and/or paraffin, and/or beeswax, and/or white petrolatum, and/or lauryl alcohol may be used.
  • Sodium sulfate, and/or polysorbate, and the like may be used.
  • the above components other than the water-soluble colloidal matrix may be mixed, water is added, the components are dissolved, sterilized, and used; and may be wetted by cotton balls or slivers for vaginal administration. Or make a vaginal lotion.
  • the composition of the present invention can be used to eliminate or reduce discomfort such as vaginal itching, pain, and/or dying pain, and/or improve leucorrhea traits, and/or eliminate leucorrhea odor, and/or Cleans the vagina.
  • the present invention also relates to a method of preventing and/or treating a vaginal infectious disease, wherein the method comprises administering an effective amount of a composition of the present invention to a woman in need thereof.
  • the vaginal infectious diseases include, but are not limited to, fungal vaginitis, cytosolic vaginosis, lactobacilli vaginal diseases, vaginal flora disorders, senile vaginitis, aerobic vaginitis, bacterial vaginosis.
  • the composition is applied to the vagina of a woman in need thereof, such as applying the composition of the water-soluble gel dosage form of the present invention to the vagina with an applicator, or using a cotton sliver or cotton
  • the composition of the invention in a wet solution form of the ball or vaginal plug is placed in the vagina.
  • the raw materials were weighed according to the following ratio, and 100 ml of the composition was prepared in substantially the same manner as in Example 1.
  • the raw materials were weighed according to the following ratio, and 100 ml of the composition was prepared in substantially the same manner as in Example 1.
  • the raw materials were weighed according to the following ratio, and 100 ml of the composition was prepared in substantially the same manner as in Example 1.
  • the raw materials were weighed according to the following ratio, and 100 ml of the composition was prepared in substantially the same manner as in Example 1.
  • the raw materials were weighed according to the following ratio, and 100 ml of the composition was prepared in substantially the same manner as in Example 1.
  • the raw materials were weighed according to the following ratio, and 100 ml of the composition was prepared in substantially the same manner as in Example 1.
  • the raw materials were weighed according to the following ratio, and 100 ml of the composition was prepared in substantially the same manner as in Example 1.
  • the raw materials were weighed according to the following ratio, and 100 ml of the composition was prepared in substantially the same manner as in Example 1.
  • Test strains 1 strain of Lactococcus lactis and Lactobacillus japonicus, all of which are clinical isolates.
  • Base gel Based on the MRS medium, 1.0% xanthan gum, 1.5% isomaltulose, 10% calf serum was added to adjust the pH to 5.0.
  • phenylethyl alcohol has a strong inhibitory effect on the growth of Lactococcus lactis, and has a weak inhibitory effect on the growth of Lactobacillus; however, the pH value is 4.1 to 4.6, which does not decrease to 3.8, suggesting that acid production is inhibited. .
  • Antibacterial liquid a both water and bacteriostatic agent, the specific combination of each bacteriostatic agent is shown in Table 7A, pH value 4.3;
  • Antibacterial solution b both water, bacteriostatic agent, and 6.5% (w/v) maltose, each bacteriostatic agent is the same as group a, see Table 7B, pH 4.3.
  • a specific concentration range of phenylethyl alcohol is compatible with sodium benzoate, and synergistically inhibits against Escherichia coli (ATCC 25922) and Staphylococcus aureus (ATCC 6538).
  • the specific concentration range of phenylethyl alcohol is compatible with sodium propionate, and has synergistic antibacterial activity against Escherichia coli (ATCC 25922) and Staphylococcus aureus (ATCC 6538).
  • phenethyl alcohol is compatible with sodium dehydroacetate, sodium propionate and sodium dehydroacetate, sodium propionate and sodium benzoate, sodium dehydroacetate and sodium benzoate, and Escherichia coli and Staphylococcus aureus.
  • the antibacterial effect is inferior to the compatibility of phenylethyl alcohol with sodium benzoate or with sodium propionate.
  • Example 2 it can be seen that the experimental examples again verify the compatibility of the specific concentration range of phenylethyl alcohol with sodium benzoate, the compatibility of phenylethyl alcohol with sodium propionate, and synergistic effect on Escherichia coli and Staphylococcus aureus.
  • the effect of bacteria; the pH value has a significant effect on the antibacterial effect of the compatibility solution of phenylethyl alcohol and sodium benzoate, and the antibacterial effect of the compatibility solution of phenylethyl alcohol and sodium propionate.
  • the lower the pH value of the solution is in the range of 4.1 to 4.5. The stronger the synergistic antibacterial effect, the higher the pH value of the solution, and the weaker the synergistic antibacterial effect.
  • each bacteriostatic gel group contains water, bacteriostatic agent and xanthan gum, as shown in Table 10;
  • this example observes the antibacterial effect of the bacteriostatic gel, further verifying the compatibility of phenylethyl alcohol with sodium propionate, the compatibility of phenylethyl alcohol with sodium benzoate, against Escherichia coli, and/or Staphylococcus aureus. Has a strong synergistic antibacterial effect.
  • each antibacterial liquid group contains water and bacteriostatic agent, as shown in Table 11;
  • the inhibition rate against Staphylococcus aureus was less than 0.35% (w/v) phenylethyl alcohol and 0.05% (w/v) sodium benzoate, and the pH value of 4.1 solution against Staphylococcus aureus was inhibited. (>99%).
  • phenylethyl alcohol Under low pH (3.5) conditions, 0.35-0.4% (w/v) phenylethyl alcohol is compatible with 0.08-0.1% (w/v) sodium p-methoxybenzoate, which has synergistic antibacterial effect on Escherichia coli; but it has not been observed. To its synergistic antibacterial effect against Staphylococcus aureus.
  • each antibacterial liquid group contains water and bacteriostatic agent, as shown in Table 15;
  • each antibacterial liquid group contains water and bacteriostatic agent, as shown in Table 16;
  • each bacteriostatic gel group contains water, bacteriostatic agent and xanthan gum, as shown in Table 17;
  • each of the gels of the three bacteriostatic agents having a pH of 4.1 in this example "0.4% (w/v) phenylethyl alcohol + 0.55% (w/v) sodium propionate + 0.07% (w/v)
  • the sodium benzoate gel has the strongest antibacterial activity, the inhibition rate against Escherichia coli and Staphylococcus aureus is 99.66% and 91.30%; the sodium phenylacetate, sodium benzoate, dehydroacetic acid without phenylethyl alcohol
  • the gel of the combination of sodium and sodium has the weakest antibacterial activity, and the inhibition rate against Escherichia coli and Staphylococcus aureus is less than 50%.
  • Each antibacterial solution group contains water and bacteriostatic agent, as shown in Table 18, Table 19, Table 20 and Table 21;
  • phenoxyethanol is compatible with 0.06-0.10% (w/v) sodium benzoate, and has synergistic antibacterial activity against Escherichia coli and Staphylococcus aureus.
  • phenoxyethanol is compatible with 0.4-0.55% (w/v) sodium acetate, and has synergistic antibacterial activity against Escherichia coli and Staphylococcus aureus.
  • phenoxyethanol is compatible with 0.015-0.025% (w/v) sodium dehydroacetate, and its antibacterial activity against Escherichia coli and Staphylococcus aureus is about 40-65%, which has a certain synergistic effect. Bacterial action, but its bacteriostatic effect is weaker than the solution of phenoxyethanol and sodium benzoate.
  • Test strains 3 strains of Escherichia coli and 3 strains of Staphylococcus aureus, all of which are vaginal secretion isolates from patients with vaginitis.
  • Enrichment liquid 1% yeast extract powder, 9% sucrose, 0.025% manganese sulfate (MnSO 4 .4H 2 O), 0.058% magnesium sulfate (MgSO 4 .7H 2 O), 0.9% lactic acid, adjust the pH to 4.8, sterilization standby;
  • Test group Prepare the sterile test tube in strict accordance with the aseptic technical requirements:
  • sodium benzoate group 3 ml test tube of 3 ml of bacteria-increasing liquid, adding 0.05% (w/v) sodium benzoate;
  • Phenylethanol group 3 ml test tube of 5 ml of enrichment solution, adding 0.05% (w/v) phenylethyl alcohol;
  • sodium propionate group 3 ml test tube of 3 ml of bacteria-increasing liquid, adding 0.25% (w/v) sodium propionate;
  • Sodium benzoate + sodium propionate + phenylethyl alcohol group: 3 ml test tube of 3 ml of bacteria-increasing liquid, adding 0.05% (w/v) sodium benzoate, 0.25% (w/v) sodium propionate, 0.05% ( w/v) phenylethyl alcohol;
  • Positive control a test tube containing Escherichia coli or Staphylococcus aureus, but no phenylethyl alcohol, sodium benzoate or sodium propionate.
  • Negative control a test tube for the enrichment liquid containing no Escherichia coli or Staphylococcus aureus, phenylethyl alcohol, sodium benzoate or sodium propionate;
  • Each of the above tubes was placed in a 37 ° C biochemical incubator, and the change in turbidity of each tube solution was observed and recorded at 24 hours.
  • each bacteriostatic agent acts alone, and 0.05% (w/v) sodium benzoate, 0.05% (w/v) phenylethyl alcohol, and 0.25% (w/v) sodium propionate cannot inhibit the large intestine. Escherichia coli and Staphylococcus aureus grow.
  • the compatibility of "0.05% (w/v) sodium benzoate + 0.05% (w/v) phenylethyl alcohol” has an inhibitory effect on the growth of 1/3 E. coli strain, against Staphylococcus aureus strain Growth has no inhibition.
  • the combination of "0.25% (w/v) sodium propionate + 0.05% (w/v) phenylethyl alcohol” has an inhibitory effect on the growth of 1/3 of the golden staphylococcus strain, and has a growth effect on 1/3 of the E. coli strain. Inhibition.
  • Test strain 9 strains of Candida albicans, a clinical strain isolated from vaginal secretions of patients with fungal vaginitis, and all capable of growing in an enrichment liquid containing 0.025% (w/v) sodium benzoate.
  • Enrichment liquid 1% yeast extract powder, 9% sucrose, 0.025% manganese sulfate (MnSO 4 .4H 2 O), 0.058% magnesium sulfate (MgSO 4 .7H 2 O), 0.9% lactic acid, adjust the pH to 4.5, sterilization standby;
  • Test group Prepare the sterile test tube in strict accordance with the aseptic technical requirements:
  • sodium benzoate group 5 ml of the test tube for the enrichment solution, adding 0.025% (w/v) sodium benzoate;
  • Phenylethanol group 1 ml of 5 ml enrichment test tube, adding 0.050% (w/v) phenylethyl alcohol;
  • sodium propionate group 5 ml test tube of enrichment liquid, adding 0.125% (w/v) sodium propionate;
  • Sodium benzoate + sodium propionate group 1 tube of 5 ml bacteria-increasing liquid test tube, adding 0.025% (w/v) sodium benzoate, 0.125% (w/v) sodium propionate;
  • Sodium benzoate + sodium propionate + phenylethyl alcohol group: 5 ml test tube of enrichment liquid, adding 0.025% (w/v) sodium benzoate, 0.125% (w/v) sodium propionate, 0.050% ( w/v) phenylethyl alcohol;
  • Positive control test tube containing Candida albicans but no phenylethyl alcohol, sodium benzoate or sodium propionate.
  • Negative control a test tube for the enrichment liquid containing no Candida albicans, phenylethyl alcohol, sodium benzoate or sodium propionate;
  • the bacterial liquid was prepared under strict aseptic technique, and the colonies of Candida albicans were diluted with physiological saline respectively, and the turbidity meter was adjusted to a turbidity of 0.5 M (about 10 8 CFU/ml), and then 1 ml of 0.5 M was respectively taken.
  • the bacterial solution was added to 9 ml of the enrichment liquid, and diluted ten times to make the bacterial liquid contain 10 7 CFU/ml.
  • Each of the above tubes was placed in a 37 ° C biochemical incubator, and the growth of Candida in each tube was observed and recorded at 24 hours.
  • Antibacterial agent compatibility group After the combination of 0.050% (w/v) phenylethyl alcohol + 0.025% (w/v) sodium benzoate + 0.125% (w/v) sodium propionate, none of the nine strains grew. It suggests that the compatibility of three bacteriostatic agents has strong synergistic antibacterial activity against Candida albicans.
  • Experimental preparation According to the preparation method of the present invention, preparation of 9.0% (w/v) maltose, 0.05% (w/v) phenylethyl alcohol, 0.075% (w/v) sodium benzoate, 2.2% (w/v) xanthan gum, gel pH 3.0.
  • the gel of the present invention containing "9.0% (w/v) maltose + 0.05% (w/v) phenylethyl alcohol + 0.075% (w/v) sodium benzoate” can regulate the vaginal flora of the rhesus monkey, and make the vaginal flora Return to normal and reduce the pH of vaginal secretions.
  • Experimental preparation According to the preparation method of the present invention, preparation of 5.5% (w/v) maltose, 1.0% (w/v) isomaltulose, 0.05% (w/v) phenylethyl alcohol, 0.15% (w/ v) sodium benzoate, 2.15% (w/v) xanthan gum, gel pH 3.3.
  • a gel of the invention comprising "5.5% (w/v) maltose + 1.0% (w/v) isomaltulose + 0.05% (w/v) phenylethyl alcohol + 0.15% (w/v) sodium benzoate", It has a certain effect of regulating the vaginal flora, which can restore the vaginal flora of 1/2 rhesus monkeys to normal, and reduce the pH of vaginal secretions of 1/2 rhesus monkeys.
  • Experimental preparation According to the preparation method of the present invention, preparation of 6.5% (w/v) sucrose, 0.10% (w/v) phenylethyl alcohol, 0.05% (w/v) sodium benzoate, 2.15% (w/v). Xanthan gum, gel pH 3.8.
  • the gel of the invention containing "6.5% (w/v) sucrose + 0.10% (w/v) phenylethyl alcohol + 0.05% (w/v) sodium benzoate” can regulate the vaginal flora of rhesus monkeys, and make vaginal bacteria The group returned to normal and reduced the pH of the vaginal secretions.
  • the gel containing "1.0% (w/v) glucose + 0.30% (w/v) phenylethyl alcohol + 0.085% (w/v) sodium benzoate” can effectively regulate the vaginal flora of the rhesus monkey and make the vagina The flora returned to normal and the pH of the vaginal secretions of rhesus monkeys was reduced.
  • the "5.0% (w / v) fructose + 0.4% (w / v) phenylethyl alcohol + 0.09% (w / v) sodium benzoate" gel of the present invention has a certain effect on regulating the vaginal flora of rhesus monkeys, Restores the vaginal flora to normal and reduces the pH of the vaginal secretions.
  • the gel containing "4.0% (w/v) mannose + 0.10% (w/v) phenylethyl alcohol + 0.35% (w/v) sodium propionate” has a certain effect of regulating vaginal flora, and can The vaginal flora of rhesus monkeys returned to normal and reduced the pH of vaginal secretions, but it has not yet fallen to 4.1 and below.
  • the "6.5% (w/v) oligo-isomaltose + 0.10% (w/v) phenylethyl alcohol + 0.475% (w/v) sodium propionate" gel of the present invention can regulate the vaginal flora of rhesus monkeys. Restore normal vaginal flora and reduce the pH of rhesus vaginal secretions.
  • the present invention contains "2.0% (w/v) maltose + 3.5% (w / v) fructose + 0.10% (w / v) phenylethyl alcohol + 0.575% (w / v) sodium propionate” gel can regulate the Ganges
  • the vaginal flora of the monkeys restores the vaginal flora to normal and reduces the pH of the vaginal secretions of rhesus monkeys.
  • the gel of the present invention containing "4.0% (w/v) maltose + 1.0% isomaltulose + 0.10% (w / v) phenoxyethanol + 0.35% (w / v) sodium acetate” has a certain regulation constant
  • the role of the vaginal flora of the river monkey can restore the vaginal flora to normal and reduce the pH of the vaginal secretions of rhesus monkeys, but has not yet fallen to 4.1 and below.
  • the present invention contains "3.5% (w/v) sucrose + 1.0% (w/v) maltose + 0.06% (w / v) phenylethyl alcohol + 0.525% (w / v) sodium propionate + 0.15% (w / v "Sodium benzoate" gel was applied to 2 rhesus monkeys.
  • the pH value of vaginal secretions of one rhesus monkey decreased from 5.4 to 4.1, G- b decreased significantly, G +b increased significantly, and the flora returned to normal. In the other case, although the pH value did not change, the amount of G- b bacteria in the vaginal flora decreased. It is suggested that this combination has a certain regulatory effect on the vaginal flora of rhesus monkeys, which can restore the vaginal flora to normal and the pH of the vaginal secretions to normal.
  • the present invention contains "3.0% (w/v) maltose + 1.0% (w/v) fructose + 0.065% (w/v) phenylethyl alcohol + 0.55% (w/v) sodium propionate + 0.12% (w/v).
  • the sodium benzoate gel was used in 8 rhesus monkeys.
  • the pH of the vaginal secretions of 4 rhesus monkeys decreased from 5.4 to 3.8, and the flora returned to normal. In 2 cases, the bacteria decreased from 5.4 to 4.1. Gram-positive bacilli were dominant; the pH values of the two cases were unchanged, and there was no significant change in the flora before the gel was administered.
  • the gel containing "0.10% (w/v) phenylethyl alcohol + 0.575% (w/v) sodium propionate + 0.09% (w/v) sodium benzoate” is used in 4 cases of rhesus monkeys, one of which is constant
  • the pH of vaginal secretions of rhesus monkeys decreased from 5.4 to 4.1, and the bacteria were mainly Gram-positive bacilli.
  • the pH of the remaining 3 rhesus monkey vaginal secretions did not decrease.
  • Prompt "0.10% (w / v) phenylethyl alcohol + 0.575% (w / v) sodium propionate + 0.09% (w / v) sodium benzoate" gel can regulate the vaginal flora of rhesus monkey, but restore vaginal flora, The effect of lowering the pH of the vagina is less than that of the sugar-containing preparation of the present invention.
  • Experimental preparation According to the preparation method of the present invention, preparation of 0.60% (w/v) phenylethyl alcohol, 0.70% (w/v) sodium propionate, 2.15% (w/v) xanthan gum, gel pH value 4.1.
  • the gel containing "0.60% (w/v) phenylethyl alcohol + 0.70% (w/v) sodium propionate” is used in 2 cases of rhesus monkey, smear microscopy of vaginal secretions, and coagulation Compared with the pre-gel, the number of vaginal bacteria in 2 cases was significantly reduced. One of them occasionally showed coarse Gram-positive bacilli (G +b ), but the pH of vaginal secretions of 2 rhesus monkeys did not decrease.
  • the "0.60% (w/v) phenylethyl alcohol + 0.70% (w/v) sodium propionate" gel of the present invention inhibits bacteria in the vagina of rhesus monkeys, especially Gram-negative bacilli (G- b ). Although one of the rhesus monkeys occasionally saw coarse Gram-positive bacilli, the flora did not return to normal, and the pH of vaginal secretions did not fall to 4.1 or below.
  • the present invention contains "2.0 (w / v)% fructose + 4.0% (w / v) isomaltose + 0.06% (w / v) phenylethyl alcohol + 0.575% (w / v) sodium propionate + 0.12% (w / v) Sodium benzoate gel can regulate the vaginal flora of rhesus monkeys, restore normal vaginal flora and reduce vaginal pH.
  • the present invention contains "5.5% (w/v) maltose + 1.0% isomaltulose + 0.10% (w / v) phenylethyl alcohol + 0.575% (w / v) sodium propionate + 0.065% (w / v) benzene
  • the sodium formate gel modulates the vaginal flora of the rhesus monkey, restores the vaginal flora back to normal, and reduces the pH of the rhesus vaginal secretions.
  • the invention comprises "2.0% (w/v) maltose + 0.20% (w/v) phenylethyl alcohol + 0.575% (w/v) sodium propionate + 0.065% (w/v) sodium benzoate" gel can be adjusted constant
  • the vaginal flora of the monkeys restores the vaginal flora to normal and reduces the pH of the vaginal secretions of rhesus monkeys.

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Abstract

一种抑菌剂配伍在制备阴道用组合物中的用途，所述抑菌剂配伍对大肠杆菌、和/或金黄色葡萄球菌、和/或假丝酵母菌的抑制作用较强。还涉及到一种用于阴道的组合物，其对大肠杆菌、和/或金黄色葡萄球菌、和/或假丝酵母菌具有较强抑制作用，用于阴道可促进有益乳杆菌的恢复和增强阴道酸度，适用于调节阴道微生态、调节阴道微生物、和选择性阴道脱污染。

Description

一种抑菌剂配伍在制备阴道用组合物中的用途与阴道用组合物 技术领域
本发明涉及一种抑菌剂配伍在制备阴道用组合物中的用途，可用于制备治疗性或非治疗性的各种阴道用组合物。还涉及一种阴道用组合物，可用于阴道卫生保健、预防和治疗阴道感染性疾病。
背景技术
健康女性阴道黏膜表面栖居着粗大的革兰阳性杆菌，称为“阴道正常菌群”，此类粗大革兰阳性杆菌以乳杆菌为主，能代谢阴道黏膜上皮细胞中的糖原、产酸，使阴道酸度保持在pH值3.5～4.3的范围，对女性生殖道抵御病菌感染极为重要。
很多因素可干扰阴道菌群，导致阴道抗感染力下降，因而阴道感染很常见，如细菌性阴道病、需氧菌阴道炎、假丝酵母菌阴道炎等等，多与阴道中大肠杆菌、金黄色葡萄球菌、B组链球菌，以及阴道加德纳菌、普雷沃氏菌、假丝酵母菌等有害菌的数量增加有关。因而，在抑制有害细菌、有害真菌的同时，避免抑制或破坏有益的乳杆菌，对于预防和治疗生殖道感染具有重要临床意义。
但目前本领域尚缺乏有效的技术或方法，既能选择性地抑制大肠杆菌、金黄色葡萄球菌、及其它有害细菌、有害真菌，又可保护和促进阴道中的有益乳杆菌。
发明内容
本发明的目的是提供一种抑菌剂组合物，该组合物对大肠杆菌、和/或金黄色葡萄球菌、和/或假丝酵母菌具有较强抑制作用，用于阴道可促进有益乳 杆菌的恢复和增强阴道酸度。
如何选择性地抑制有害的细菌、真菌，促进有益的乳杆菌，一直是妇科感染领域关注的前沿课题。本发明人研究发现：苯乙醇、苯甲酸和/或其钠盐、和丙酸和/或其盐分别单独作用，均可选择性地抑制乳酸乳球菌的生长，对乳杆菌生长则无显著抑制作用！其它一些抑菌物质，如乙酸、脱氢乙酸、辛酸等，对乳酸乳球菌和乳杆菌的抑制作用则没有明显选择性。
研究还发现：苯乙醇和/或苯氧乙醇，与苯甲酸和/或其钠盐和/或对甲氧基苯甲酸和/或其钠盐和/或苯甲酸酯类物质配伍；或苯乙醇和/或苯氧乙醇，与丙酸和/或其盐和/或乙酰丙酸和/或其盐和/或乙酸和/或其钠盐配伍，对大肠杆菌、和/或金黄色葡萄球菌具有协同抑菌作用。特别当下述三类物质配伍时，其对大肠杆菌、和/或金黄色葡萄球菌、和/或假丝酵母菌的抑制作用更强：(1)苯乙醇和/或苯氧乙醇；(2)苯甲酸和/或其钠盐和/或对甲氧基苯甲酸和/或其钠盐和/或苯甲酸酯类物质；(3)丙酸和/或其盐和/或乙酰丙酸和/或其盐和/或乙酸和/或其钠盐。
但苯乙醇、和/或苯氧乙醇与其它抑菌物质的配伍，如与脱氢乙酸和/或其钠盐的配伍、或与山梨酸和/或其钾盐的配伍，其抑菌作用则不及前述的配伍。
本发明提供一种抑菌剂配伍在制备阴道用组合物中的用途，其中，所述组合物含有以下抑菌剂：(1)总含量以苯乙醇计的0.05～0.60％(w/v)的苯乙醇和/或苯氧乙醇；(2)总含量以丙酸钠计的0.25～0.70％(w/v)的丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠；和/或总量以苯甲酸钠计的0.05～0.15％(w/v)的苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质。
本发明的丙酸类物质与乙酸类物质同属常用的短链脂肪酸抑菌防腐剂，优选丙酸和/或其钠盐。苯甲酸酯类物质包括苯甲酸甲酯、苯甲酸乙酯、苯甲酸丙酯、以及苯甲酸丁酯等，优选苯甲酸乙酯。
本发明所述以苯乙醇计的苯氧乙醇的含量系指将苯氧乙醇的含量换算为苯乙醇的含量，换算方法为：苯乙醇的分子量除以苯氧乙醇的分子量，再乘以苯氧乙醇的含量，所得结果即为苯氧乙醇换算为苯乙醇的含量。例如，苯乙醇分子量122，苯氧乙醇分子量138，0.034％(w/v)苯氧乙醇的含量，换算为苯乙醇的含量为0.030％(w/v)。反之，0.030％(w/v)苯乙醇的含量， 换算为苯氧乙醇的含量为0.034％(w/v)。余以此类推，反之亦然。
本发明所述以苯甲酸钠计的苯甲酸、对甲氧基苯甲酸和/或其钠盐、苯甲酸酯类物质等物质的含量，系指将苯甲酸等物质的含量，换算为苯甲酸钠的含量。换算方法为：以苯甲酸钠的分子量除以苯甲酸等物质的分子量，再乘以苯甲酸等物质的含量，所得结果即为苯甲酸等物质的含量换算为苯甲酸钠的含量。例如，苯甲酸钠的分子量为144，苯甲酸的分子量为122，对甲氧基苯甲酸的分子量为152，对甲氧基苯甲酸钠的分子量为174，苯甲酸乙酯的分子量为150。分别将0.1％(w/v)苯甲酸、或0.127％(w/v)对甲氧基苯甲酸、或0.145％(w/v)对甲氧基苯甲酸钠、或0.125％(w/v)苯甲酸乙酯，换算为苯甲酸钠的含量，其结果均为0.12％(w/v)。余以此类推，反之亦然。
本发明所述以丙酸钠计的丙酸和/或其钙盐、乙酰丙酸和/或其钠盐、乙酸和/或其钠盐等物质的含量，系指将丙酸等物质的含量，换算为丙酸钠的含量。换算方法为：以丙酸钠的分子量除以丙酸等物质的分子量，再乘以丙酸等物质的含量，所得结果即为丙酸等物质的含量换算为丙酸钠的含量。例如，丙酸钠的分子量为96，丙酸的分子量为74，乙酰丙酸的分子量为116，乙酰丙酸钠的分子量为138，乙酸的分子量为60，乙酸钠的分子量为82。分别将0.31％(w/v)丙酸、或0.48％(w/v)乙酰丙酸、或0.575％(w/v)乙酰丙酸钠、或0.25％乙酸(w/v)、或0.341％乙酸钠(w/v)，换算为丙酸钠的含量结果均为0.4％(w/v)。余以此类推，反之亦然。
优选的总量以苯乙醇计的苯乙醇和/或苯氧乙醇的总含量为0.10～0.40％(w/v)；总量以丙酸钠计的的丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠的总含量为0.525～0.575％(w/v)；总量以苯甲酸钠计的苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质的总含量为0.065～0.090％(w/v)。
优选的所述组合物含有(1)苯乙醇和/或苯氧乙醇；(2)丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠；(3)苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质。
优选的所述抑菌剂为苯乙醇、丙酸和/或丙酸钠、苯甲酸和/或苯甲酸钠。
优选的所述组合物还选用一种或多种选自下组的抑菌或抗菌物质：脱氢 乙酸、脱氢乙酸钠、山梨酸、山梨酸钾、山梨酸钠、双乙酸、双乙酸钠、辛酸、辛酸钠、癸酸、葵酸钠、十一烯酸、十一烯酸钠、月桂酸、月桂酸钠、纳他霉素、乳铁蛋白、乳铁蛋白肽、溶菌酶、抑菌蛋白、抗菌肽、地衣酸、虎耳草素、环庚三烯酚酮、氯原酸、黄藤素、苯甲醇、丙烯苯氧乙醇、1,2-戊二醇、1,2-己二醇、1,6-己二醇、1,2-辛二醇、1,2-葵二醇、甲基丙二醇、乙基己基丙三醇、过氧化苯甲酰。所述抑菌剂或抗菌剂用于进一步增强本发明制备的阴道用组合物对金黄色葡萄球菌、大肠杆菌、及假丝酵母菌，以及对其它有害微生物如HIV、HPV等病毒的抑菌或抗菌作用。
优选的所述组合物还选用1.0～9.0％(w/v)的一种或多种选自下组的糖用于本发明的用途：葡萄糖、果糖、甘露糖、蔗糖、异麦芽酮糖、蔗果三糖、蔗果四糖、蔗果五糖、麦芽糖、异麦芽糖、异麦芽三糖、异麦芽四糖、异麦芽五糖、海藻糖、纤维二糖、蜜二糖、龙胆二糖、低聚龙胆糖、棉子糖、潘糖、麦芽寡糖、低聚异麦芽酮糖、低聚果糖、葡甘聚糖、糊精、淀粉和糖原。本发明制备的含糖的阴道用组合物具有双相调节阴道菌群的作用，亦即既可选择性抑制大肠杆菌、和/或金黄色葡萄球菌、和/或假丝酵母菌等，又可选择性地促进阴道中有益的乳杆菌。与现有技术比较，其调节阴道菌群、增强阴道酸度、维护阴道有益乳杆菌的作用更为优越，可增强阴道抗感染力，适用于预防和/或治疗阴道乳杆菌减少、或阴道菌群失调、或细菌性阴道病，或用于抗菌治疗生殖道感染后恢复阴道的正常菌群，或用于生殖道感染的辅助治疗。本发明人还发现，当糖的总浓度低于1％(w/v)，其促进乳杆菌生长和产酸的作用较弱；当糖浓度高于9％(w/v)，则可能对阴道粘膜产生刺激性。
优选的所述组合物还选用0.1～10.0％(w/v)的一种或多种选自下组的氨基酸用于本发明的用途：谷氨酸、谷氨酰胺、天冬氨酸、天冬氨酰胺、异亮氨酸、苯丙氨酸、颉氨酸、亮氨酸、脯氨酸和苏氨酸。本发明制备的含氨基酸的阴道用组合物可减少阴道菌群产酸，可用于治疗或辅助治疗细胞溶解性阴道病、乳杆菌性阴道病、和真菌性阴道炎。本发明人还发现，当氨基酸总浓度低于0.1％(w/v)，其调节阴道菌群产酸的作用较弱；当总浓度高于10％(w/v)，则可能引起阴道菌群异常演变。
优选的所述组合物还选用0.001～1.0％(w/v)的一种或多种选自下组雌激素类和/或植物雌激素类的物质用于本发明的用途：己烯雌酚、雌二醇、雌三醇、 大豆甙、大豆甙元、染料木甙、染料木素、黄豆黄素、黄豆黄素甙元、鸡豆黄素、香豆雌酚和芒柄花黄素。己烯雌酚、雌二醇、雌三醇为雌激素类物质，大豆甙、大豆甙元、染料木甙、染料木素、黄豆黄素、黄豆黄素甙元、鸡豆黄素、香豆雌酚和芒柄花黄素为植物雌激素类物质。本发明制备的含有雌激素和/或植物雌激素类物质的阴道用组合物，可促进阴道粘膜上皮细胞合成糖原，维护或恢复阴道微环境的正常，以及促进有益的乳杆菌生长，恢复微生态系统平衡。
优选的所述组合物还选用一种或多种选自下组的物质用于本发明的用途：0.01～5.0％(w/v)的芦荟提取物、0.01～5.0％(w/v)的薰衣草提取物、0.001～1.0％(w/v)的维生素E、0.001～1.0％(w/v)的维生素A、0.001～1.0％(w/v)的维生素D和0.001～1.0％(w/v)的维生素C。本发明制备的含上述物质的阴道用组合物可用于保护阴道粘膜，促进损伤的阴道粘膜修复。
优选的所述阴道用组合物的剂型为溶液剂、或水溶性凝胶剂、或乳剂型软膏剂，其中所述组合物pH值为3.0～4.3。
根据本发明的用途，其中所述阴道用组合物可为非治疗性的阴道用健康产品、或阴道用日用品、或阴道保健用品、或阴道护理用品、或阴道用化妆品、或阴道用卫生用品、或阴道用清洁用品；或为治疗性的阴道用健康产品、阴道用医疗器械、或阴道用消毒器械、或阴道用药物器械、或阴道用药品；或为用于阴道的洗剂、或清洁剂、或养护剂、或除异味剂、或止痒剂、或清新剂、或湿润剂、或润滑剂、或消毒剂、或抗菌剂、或抑菌剂、或黏膜表面杀微生物剂、或微生态调节剂、或微生物调节剂。
本发明还提供一种用于阴道的组合物，所述组合物含有：(1)总量以苯乙醇计的0.05～0.6％(w/v)的苯乙醇和/或苯氧乙醇；(2)总量以丙酸钠计的0.25～0.7％(w/v)的丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠；和/或总量以苯甲酸钠计的0.05～0.15％(w/v)的苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质。
其中，所述组合物剂型为溶液剂、或水溶性凝胶剂、或乳剂型软膏剂，优选水溶性凝胶剂；组合物的pH值为3.0～4.3。
优选的总量以苯乙醇计的苯乙醇和/或苯氧乙醇的总含量为 0.10～0.40％(w/v)；总量以丙酸钠计的的丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠的总含量为0.525～0.575％(w/v)；总量以苯甲酸钠计的苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质的总含量为0.065～0.090％(w/v)。
优选的所述组合物含有(1)苯乙醇和/或苯氧乙醇；(2)丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠；(3)苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质。
优选的所述抑菌剂为苯乙醇、丙酸和/或丙酸钠、苯甲酸和/或苯甲酸钠。
优选的所述组合物还含有一种或多种选自下组的抑菌剂或抗菌剂：脱氢乙酸、脱氢乙酸钠、山梨酸、山梨酸钾、山梨酸钠、双乙酸、双乙酸钠、辛酸、辛酸钠、癸酸、葵酸钠、十一烯酸、十一烯酸钠、月桂酸、月桂酸钠、纳他霉素、乳铁蛋白、乳铁蛋白肽、溶菌酶、抑菌蛋白、抗菌肽、地衣酸、虎耳草素、环庚三烯酚酮、氯原酸、黄藤素、苯甲醇、丙烯苯氧乙醇、1,2-戊二醇、1,2-己二醇、1,6-己二醇、1,2-辛二醇、1,2-葵二醇、甲基丙二醇、乙基己基丙三醇、过氧化苯甲酰。
优选的所述组合物还含有总量为0.001～1.0％(w/v)的一种或多种选自下组的物质：己烯雌酚、雌二醇、雌三醇、大豆甙、大豆甙元、染料木甙、染料木素、黄豆黄素、黄豆黄素甙元、鸡豆黄素、香豆雌酚和芒柄花黄素。
优选的所述组合物还含有总量为1.0～9.0％(w/v)的一种或多种选自下组的糖：葡萄糖、果糖、甘露糖、蔗糖、异麦芽酮糖、蔗果三糖、蔗果四糖、蔗果五糖、麦芽糖、异麦芽糖、异麦芽三糖、异麦芽四糖、异麦芽五糖、海藻糖、纤维二糖、蜜二糖、龙胆二糖、低聚龙胆糖、棉子糖、潘糖、麦芽寡糖、低聚异麦芽酮糖、低聚果糖、葡甘聚糖、糊精、淀粉和糖原。
优选的所述糖为总含量为2.0～6.5％(w/v)的一种或多种选自下组的糖：葡萄糖、果糖、甘露糖、蔗糖、麦芽糖、异麦芽酮糖、异麦芽糖、海藻糖、麦芽寡糖。
优选的所述组合物还含有一种或多种选自下组的物质：0.01～5.0％(w/v)的芦荟提取物、0.01～5.0％(w/v)的薰衣草提取物、0.001～1.0％(w/v)的维生素E、0.001～1.0％(w/v)的维生素A、0.001～1.0％(w/v)的维生素D和0.001～1.0％(w/v) 的维生素C。
优选的所述组合物还含有0.1～10％(w/v)的一种或多种选自下组的氨基酸和/或其盐：谷氨酸、谷氨酰胺、天冬氨酸、天冬氨酰胺、异亮氨酸、苯丙氨酸、颉氨酸、亮氨酸、脯氨酸和苏氨酸。
优选的所述氨基酸的含量为1.0～5.0％(w/v)，其中所述氨基酸为谷氨酸和/或天冬氨酸。
本发明的组合物可采用多种方式包装，包括但不限于单次剂量、无菌、密封包装，或包装于阴道用器械中，或包装于一次性阴道施用器中；优选单次剂量、无菌、密封包装。其制备工艺、方法和辅料的选择，都是本领域普通技术人员可以根据本发明的公开内容结合其背景知识可以想见的。
根据本发明的组合物，可选择性地含有低剂量抗菌药物甲硝唑或替硝唑，其中所述甲硝唑或替硝唑的含量为使组合物的每单位施用剂量或每单次剂量包装(单位剂型)如一粒片剂、一粒栓剂、或一支单次剂量包装的软膏等的甲硝唑和/或替硝唑总含量为0.001～0.5毫克，优选0.01～0.25毫克。含低剂量甲硝唑或替硝唑的本发明组合物具有护理和/或调节阴道微生态、抗厌氧细菌、和维护阴道微生态平衡的作用。
本发明还提供一种用于阴道的组合物的制造方法，该方法包括以下步骤：向水和/或水溶性胶体基质和/或乳剂型软膏基质中加入(1)总含量以苯乙醇计的0.05～0.60％(w/v)的苯乙醇和/或苯氧乙醇；(2)总含量以丙酸钠计的0.25～0.70％(w/v)的丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠；和/或总量以苯甲酸钠计的0.05～0.15％(w/v)的苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质。
例如，在制备胶体组合物时,采用粘性、非流动性、水溶性胶状基质，如卡波姆(Caromer)、和/或甲基纤维素(MC)、和/或葡甘聚糖、和/或黄芪胶、和/或西黄芪胶、和/或黄原胶等，优选黄原胶,可按本领域技术人员已知的方法例如下述工艺流程制备：按比例定量取(1)苯乙醇和/或苯氧乙醇；(2)丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸或/或乙酰丙酸钠和/或乙酸和/或乙酸钠；和/或苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质；(3)其它组分，以及(4)黄原胶。将以上各组分混匀， 定量加蒸馏水，搅拌，各组分溶解、黄原胶溶胀呈均匀胶体；用酸和/或碱调组合物pH值至3.0～4.3的范围。可进一步做灭菌处理，灭菌可选择如下工艺：辐射灭菌，间歇灭菌(如先60℃、15分钟处理，然后置36℃、6～12小时，再60℃、15分钟处理，再置36℃、6～12小时，最后再60℃、15分钟处理)，或将苯乙醇、丙酸钠或苯甲酸钠等组分单独配制成溶液后滤过除菌，再添加到经灭菌的水溶性胶状基质中。
例如，当制备乳剂型软膏剂时，可选用本领域技术人员已知的物质，如单硬脂酸甘油酯、和/或石蜡、和/或蜂蜡、和/或白凡士林、和/或月桂醇硫酸钠、和/或聚山梨酯，等等。
例如，当制备溶液剂时，可将除水溶性胶状基质以外的上述各组分混匀，加水，溶解各组分，灭菌，备用；可用棉球或棉条浸湿用于阴道施用，或做成阴道洗剂。
根据本发明的技术方案，本发明的组合物可以用于消除或减轻阴道外阴瘙痒、疼痛、和/或性交痛等不适，和/或改善白带性状，和/或消除白带嗅味，和/或清洁护理阴道。
因而，本发明还涉及一种预防和/或治疗阴道感染性疾病的方法，其中所述方法为包括向有此需要的女性的阴道内给予有效量的本发明的组合物。其中所述阴道感染性疾病包括但不限于真菌性阴道炎、细胞溶解性阴道病、乳杆菌性阴道病、阴道菌群失调、老年性阴道炎、需氧菌性阴道炎、细菌性阴道病。根据本发明的技术方案，将所述组合物施用于有此需要的女性阴道内，如用给药器将本发明的水溶性凝胶剂型的组合物施用于阴道内，或用棉条或棉球或阴道塞浸湿溶液剂型的本发明的组合物后放置于阴道内。
具体实施方式
组合物实施例
实施例1：
将苯甲酸钠0.05克、丙酸钠0.25克、黄原胶1.0克混匀，加入蒸馏水100毫升，搅拌，使苯甲酸钠与丙酸钠溶解、黄原胶溶胀呈均匀粘性胶状，加苯乙醇0.05克，调溶液的pH至3.0，再60℃、15分钟加热，即得本发明的水溶性胶体组合物。
实施例2：
按下述配比称取原料，基本按实施例1的方法制备了100毫升组合物。
Figure PCTCN2017105296-appb-000001
实施例3：
按下述配比称取原料，基本按实施例1的方法制备了100毫升组合物。
Figure PCTCN2017105296-appb-000002
实施例4
按下述配比称取原料，基本按实施例1的方法制备了100毫升组合物。
Figure PCTCN2017105296-appb-000003
实施例5：
按下述配比称取原料，基本按实施例1的方法制备了100毫升组合物。
Figure PCTCN2017105296-appb-000004
实施例6：
按下述配比称取原料，基本按实施例1的方法制备了100毫升组合物。
Figure PCTCN2017105296-appb-000005
实施例7：
按下述配比称取原料，基本按实施例1的方法制备了100毫升组合物。
Figure PCTCN2017105296-appb-000006
实施例8：
按下述配比称取原料，基本按实施例1的方法制备了100毫升组合物。
苯乙醇0.3克，丙酸钠0.5克，苯甲酸钠0.06克，乳铁蛋白0.5克；
谷氨酸0.5克，谷氨酰胺0.25克，天冬氨酸0.5克，天冬酰胺0.25克，异亮氨酸0.25克，蛋氨酸0.25克，苯丙氨酸0.25克，颉氨酸0.25克，亮氨酸0.25克，脯氨酸0.25克
黄原胶1.5克，蒸馏水100毫升，pH调至3.5
实施例9
按下述配比称取原料，基本按实施例1的方法制备了100毫升组合物。
Figure PCTCN2017105296-appb-000007
Figure PCTCN2017105296-appb-000008
实施例10
按本领域常规的方法，制备如下溶液剂：
Figure PCTCN2017105296-appb-000009
实验实施例
实验实施例一
1、目的：观察特定浓度范围的苯乙醇、丙酸和/或其盐、苯甲酸和/或其钠盐、乙酸和/或其盐、脱氢乙酸和/或其盐、辛酸和/或其盐对乳酸乳球菌、乳杆菌的抑制作用。
2、实验方法：
2.1试验菌株：乳酸乳球菌、詹氏乳杆菌各1株，均为临床分离株。
2.2基础凝胶：以MRS培养液为基础，添加1.0％黄原胶、1.5％异麦芽酮糖、10％小牛血清，调pH值至5.0。
2.3以基础凝胶为基质，配制如表1～6所示含不同浓度抑菌剂的凝胶实验管，再加10％小牛血清，分装每管5毫升，备用。
2.4实验方法：如表1～6所示的含不同浓度抗菌剂的各凝胶实验管，同时接种浊度为0.5麦氏单位的乳酸乳球菌菌悬液、詹氏乳杆菌菌悬液各100微升，37℃、5％CO2培养，32小时，观察凝胶pH值变化，涂片、革兰染色，观察细菌种类和数量。
3、实验结果：
3.1如表1所示，0.35～0.45％苯乙醇对乳酸乳球菌生长的抑制作用强，对乳杆菌生长的抑制作用弱；但pH值为4.1～4.6，未降至3.8，提示产酸受抑制。
表1.苯乙醇对乳酸乳球菌、詹氏乳杆菌生长的抑制作用
Figure PCTCN2017105296-appb-000010
Figure PCTCN2017105296-appb-000011
3.2如表2所示，0.4～0.6％丙酸钠对乳酸乳球菌生长的抑制作用强、对乳杆菌生长的抑制作用弱，具有选择性抑菌作用；但pH值为4.4～4.6，未降至3.8，提示产酸受抑制。
表2.丙酸钠对乳酸乳球菌、詹氏乳杆菌生长的抑制作用
Figure PCTCN2017105296-appb-000012
3.3如表3所示，0.065～0.1％苯甲酸钠对乳酸乳球菌生长的抑制作用强、对乳杆菌生长的抑制作用弱，具有选择性抑菌作用；但pH值为4.1～4.6，未降至3.8，提示产酸受抑制。
表3.苯甲酸钠对乳酸乳球菌、詹氏乳杆菌生长的抑制作用
Figure PCTCN2017105296-appb-000013
3.4如表4所示，未观察到0.1～0.8％乙酸钠对乳酸乳球菌生长的抑制作用，乳酸乳球菌生长多，乳杆菌生长少。
表4.乙酸钠对乳酸乳球菌、詹氏乳杆菌生长的抑制作用
Figure PCTCN2017105296-appb-000014
Figure PCTCN2017105296-appb-000015
3.5如表5所示，未观察到0.005～0.035％脱氢乙酸钠对乳酸乳球菌生长的抑制作用，乳酸乳球菌生长多、乳杆菌生长少。
表5.脱氢乙酸钠对乳酸乳球菌、詹氏乳杆菌生长的抑制作用
Figure PCTCN2017105296-appb-000016
3.6如表6所示，未观察到0.010～0.020％辛酸钠对乳酸乳球菌生长的抑制作用，乳酸乳球菌生长多、乳杆菌生长少。而0.05％辛酸钠对乳酸乳球菌、乳杆菌的抑制作用较强。
表6.辛酸钠对乳酸乳球菌、詹氏乳杆菌生长的抑制作用
Figure PCTCN2017105296-appb-000017
4、结论：特定浓度范围的苯乙醇、丙酸和/或其盐、苯甲酸和/或其钠盐对乳酸乳球菌的抑制作用强，对詹氏乳杆菌的抑制作用弱，抑菌作用具有一定选择性；尚未观察到特定浓度范围的乙酸和/或其盐、脱氢乙酸和/或其盐、辛酸和/或其盐对乳酸乳球菌、乳杆菌的抑制作用具有类似的选择性。
实验实施例二
1、目的：观察苯乙醇、苯甲酸钠、丙酸钠、脱氢乙酸钠两两配伍溶液组合物的抑菌作用。
2、实验方法：
A.实验菌株：大肠杆菌(ATCC25922)、金黄色葡萄球菌(ATCC6538).
B.实验分组：抑菌液分a、b两大组
抑菌液a：均含水和抑菌剂，各抑菌剂配伍具体见表7A，pH值4.3；
抑菌液b：均含水、抑菌剂、和6.5％(w/v)麦芽糖，各抑菌剂配伍与a组相同，具体见表7B，pH值4.3。
C.实验方法：基本参照GB15979-2002附录C的方法，完成实验。
3、实验结果：如表7A、7B所示，pH值为4.3的各抑菌液的抑菌率：
表7A.两种抑菌剂配伍的溶液对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000018
表7B.两种抑菌剂配伍的溶液对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000019
4、结论：
4.1抑菌剂配伍相同、pH值均为4.3的、含6.5％(w/v)麦芽糖的各抑菌 液与不含麦芽糖的各抑菌液两两比较，其抑菌率无显著差异。
4.2当溶液pH值为4.3时，0.35％(w/v)苯乙醇与0.06％(w/v)苯甲酸钠配伍的溶液，对大肠杆菌、金黄色葡萄球菌具有协同抑菌作用，抑菌率超过50％；0.35％(w/v)苯乙醇与0.5％(w/v)丙酸钠配伍，对大肠杆菌、金黄色葡萄球菌具有协同抑菌作用，抑菌率均超过50％。
4.3当溶液pH值为4.3时，0.35％(w/v)苯乙醇与0.02％(w/v)脱氢乙酸钠配伍，或0.06％(w/v)苯甲酸钠与0.02％(w/v)脱氢乙酸钠配伍，或0.5％(w/v)丙酸钠与0.02％(w/v)脱氢乙酸钠配伍，或0.06％(w/v)苯甲酸钠与0.5％(w/v)丙酸钠配伍，其抑菌作用均较弱。
4.4综上所述，在pH值4.3，特定浓度范围的苯乙醇与苯甲酸钠配伍，对大肠杆菌(ATCC 25922)、金黄色葡萄球菌(ATCC 6538)存在协同抑菌作用。特定浓度范围的苯乙醇与丙酸钠配伍，对大肠杆菌(ATCC 25922)、金黄色葡萄球菌(ATCC 6538)存在协同抑菌作用。
但苯乙醇与脱氢乙酸钠配伍，丙酸钠与脱氢乙酸钠的配伍，丙酸钠与苯甲酸钠的配伍，脱氢乙酸钠与苯甲酸钠的配伍，其对大肠杆菌、金黄色葡萄球菌的抑菌作用，均不及苯乙醇与苯甲酸钠或与丙酸钠的配伍。
实验实施例三
1、目的：观察pH值对两两配伍的抑菌剂的抑菌作用的影响。
2、实验方法：
A.实验菌株：大肠杆菌(ATCC25922)、金黄色葡萄球菌(ATCC 6538)
B.实验分组：各抑菌液组均含水和抑菌剂，具体见表8、表9；
C.实验方法：基本参照GB15979-2002附录C的方法，完成实验。
3、实验结果：如表8、表9所示，pH值4.1和pH值4.5的抑菌溶液的抑菌率：
表8.pH 4.1的抑菌剂配伍溶液对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000020
Figure PCTCN2017105296-appb-000021
表9.pH 4.5的抑菌剂配伍溶液对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000022
4、结论：
本实验实施例与前述实验实施例2比较，各抑菌剂浓度未改变，但pH值分别调为4.1和4.5，观察pH值对抑菌作用的影响。
当溶液pH值为4.1时，0.35％(w/v)苯乙醇分别与0.5％(w/v)丙酸钠、0.06％(w/v)苯甲酸钠配伍的溶液，其对大肠杆菌(ATCC 25922)、金黄色葡萄球菌(ATCC 6538)存在较强抑菌作用，抑菌率高于pH值为4.3的对应的溶液。但当溶液pH值为4.5时，0.35％(w/v)苯乙醇与0.5％(w/v)丙酸钠配伍、或其与0.06％(w/v)苯甲酸钠配伍的溶液对大肠杆菌、金黄色葡萄球菌的抑菌作用较弱。
但即便溶液pH值为4.1，苯乙醇与脱氢乙酸钠的配伍，或苯甲酸钠与脱氢乙酸钠的配伍，或丙酸钠与脱氢乙酸钠的配伍，或苯甲酸钠与丙酸钠的配伍，其抑菌作用仍较弱，其抑菌率均低于50％。
综上所述并结合实施例2可见：本实验实施例再次验证了特定浓度范围的苯乙醇与苯甲酸钠的配伍、苯乙醇与丙酸钠的配伍，对大肠杆菌、金黄色葡萄球菌具有协同抑菌作用；pH值对苯乙醇与苯甲酸钠配伍溶液的抑菌作用、和苯乙醇与丙酸钠配伍溶液的抑菌作用均具有显著影响，在4.1～4.5的范围内，溶液pH值越低，协同抑菌作用越强，溶液pH值越高，协同抑菌作用越弱。
实验实施例四
1、目的：观察两两配伍的抑菌剂凝胶的抑菌作用
2、实验方法：
A.实验菌株：大肠杆菌(ATCC25922)、金黄色葡萄球菌(ATCC 6538)
B.实验分组：各抑菌凝胶组均含水、抑菌剂和黄原胶，具体见表10；
C.实验方法：基本参照GB15979-2002附录C的方法，完成实验。
3、实验结果：如表10所示，不同配伍的pH值4.3的各抑菌凝胶的抑菌率：
表10 两种抑菌剂配伍的凝胶对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000023
4、结论：
4.1当抑菌凝胶的pH值为4.3时，0.375％(w/v)苯乙醇与0.06％(w/v)苯甲酸钠配伍，对大肠杆菌、金黄色葡萄球菌具有协同抑菌作用，其中对金黄色葡萄球菌的抑菌率超过50％；0.375％(w/v)苯乙醇与0.55％(w/v)丙酸钠配伍，对大肠杆菌、金黄色葡萄球菌均具有协同抑菌作用，且抑菌率均超过50％。
4.2当抑菌凝胶pH值为4.3时，0.375％(w/v)苯乙醇与0.02％(w/v)脱氢乙酸钠配伍，或0.06％(w/v)苯甲酸钠与0.02％(w/v)脱氢乙酸钠配伍，或0.55％(w/v)丙酸钠与0.02％(w/v)脱氢乙酸钠配伍，或0.06％(w/v)苯甲酸钠与0.55％(w/v)丙酸钠配伍，其抑菌作用均不及前述苯乙醇与苯甲酸钠或丙酸钠的配伍。
综上所述，本实施例观察抑菌剂凝胶的抑菌作用，进一步验证了苯乙醇与丙酸钠的配伍、苯乙醇与苯甲酸钠的配伍，对大肠杆菌、和/或金黄色葡萄球菌具有较强的协同抑菌作用。
实验实施例五
1、目的：观察苯乙醇分别与乙酸钠、山梨酸钾、苯甲酸乙酯、对甲氧基苯甲酸钠配伍，对大肠杆菌、金黄色葡萄球菌的抑菌作用。
2、实验方法：
A.实验菌株：大肠杆菌(ATCC25922)、金黄色葡萄球菌(ATCC 6538)
B.实验分组：各抑菌液组均含水、抑菌剂，具体见表11；
C.实验方法：基本参照GB15979-2002附录C的方法，完成实验。
3、实验结果：苯乙醇与乙酸钠配伍溶液的抑菌作用如表11所示；苯乙醇与山梨酸钾配伍溶液的抑菌作用如表12所示；苯乙醇与苯甲酸乙酯配伍溶液的抑菌作用如表13所示；苯乙醇与对甲氧基苯甲酸钠配伍溶液的抑菌作用如表14所示：
表11 苯乙醇与乙酸钠配伍对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000024
表12 苯乙醇与山梨酸钾配伍对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000025
表13 苯乙醇与苯甲酸乙酯配伍对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000026
表14 苯乙醇与对甲氧基苯甲酸钠配伍对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000027
4、结论：
低pH值条件下(pH值3.5)，观察到0.35～0.4％(w/v)的苯乙醇与0.6～0.8％(w/v)的乙酸钠配伍的溶液，对大肠杆菌具有协同抑菌作用；未观察到其对金黄色葡萄球菌具有协同抑菌作用。
低pH值(3.5)条件下，0.35～0.4％(w/v)苯乙醇与0.09％山梨酸钾(w/v)配伍的溶液，对大肠杆菌、金黄色葡萄球菌均具有协同抑菌作用，但其对金黄色葡萄球菌的抑菌率显著低于0.35％(w/v)苯乙醇与0.05％(w/v)苯甲酸钠配伍的、pH值为4.1的溶液对金黄色葡萄球菌的抑菌率(>99％)。
低pH值(3.5)条件下，0.3％(w/v)苯乙醇与0.025％(w/v)苯甲酸乙酯配伍的溶液，对大肠杆菌和金黄色葡萄球菌均具有协同抑菌作用；0.2～0.3％(w/v)苯乙醇与0.050％(w/v)苯甲酸乙酯配伍，对大肠杆菌和金黄色葡萄 球菌均具有协同抑菌作用。但对金黄色葡萄球菌的抑菌率，低于0.35％(w/v)苯乙醇与0.05％(w/v)苯甲酸钠配伍的、pH值为4.1的溶液对金黄色葡萄球菌的抑菌率(>99％)。
低pH值(3.5)条件下，0.35～0.4％(w/v)苯乙醇与0.08～0.1％(w/v)对甲氧基苯甲酸钠配伍，对大肠杆菌具有协同抑菌作用；但未观察到其对金黄色葡萄球菌的协同抑菌作用。
实验实施例六
1、目的：观察三种抑菌剂配伍溶液的抑菌作用。
2、实验方法：
A.实验菌株：大肠杆菌(ATCC25922)、金黄色葡萄球菌(ATCC6538)
B.实验分组：各抑菌液组均含水和抑菌剂，具体见表15；
C.实验方法：基本参照GB15979-2002附录C的方法，完成实验。
3、实验结果：如表15所示，pH值4.3抑菌溶液的杀菌效果。
表15 三种抑菌剂配伍溶液对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000028
4、结论：
本实施例的pH值为4.3的三种抑菌剂配伍溶液中，“0.35％(w/v)苯乙醇+0.5％(w/v)丙酸钠+0.05％(w/v)苯甲酸钠”的配伍溶液的抑菌作用最强，对大肠杆菌、金黄色葡萄球菌的抑菌率达100％，显著优于相同pH值条件下(pH值4.3)、相同抑菌剂浓度的“0.35％(w/v)苯乙醇+0.5％(w/v)丙酸钠”、“0.35％(w/v)苯乙醇+0.05％(w/v)苯甲酸钠”的两种抑菌剂配伍溶液的抑菌作用，而与“0.35％(w/v)苯乙醇+0.5％(w/v)丙酸钠+0.05％(w/v)苯甲酸钠+0.02％脱氢乙酸钠”四种抑菌剂配伍溶液的抑菌率一致。
实验实施例七
1、目的：观察较低pH值时苯乙醇、丙酸钠、苯甲酸钠三者配伍溶液的抑菌作用。
2、实验方法：
A.实验菌株：大肠杆菌(ATCC25922)、金黄色葡萄球菌(ATCC6538)
B.实验分组：各抑菌液组均含水和抑菌剂，具体见表16；
C.实验方法：基本参照GB15979-2002附录C的方法，完成实验。
3、实验结果：如表16所示，不同配伍的pH值4.1的各抑菌溶液的杀菌效果。
表16 三种抑菌剂配伍对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000029
4、结论
pH值为4.1的三种抑菌剂配伍溶液对金黄色葡萄球菌的抑菌作用强于pH值为4.3的相同抑菌剂配伍的溶液，其中仍以“0.35％(w/v)苯乙醇+0.5％(w/v)丙酸钠+0.05％(w/v)苯甲酸钠”配伍的溶液抑菌作用最强，对大肠杆菌、金黄色葡萄球菌的抑菌率达100％；亦强于相同pH值、相同抑菌剂浓度的“0.35％(w/v)苯乙醇+0.5％(w/v)丙酸钠”和“0.35％苯乙醇+0.05％苯甲酸钠”的两种抑菌剂配伍的溶液；与“0.35％(w/v)苯乙醇+0.5％(w/v)丙酸钠+0.05％(w/v)苯甲酸钠+0.02％(w/v)脱氢乙酸钠”四种抑菌剂配伍溶液的抑菌率一致。
不含苯乙醇的“0.5％(w/v)丙酸钠+0.05％(w/v)苯甲酸钠+0.02％(w/v)脱氢乙酸钠”的配伍溶液抑菌作用最弱。其对大肠杆菌无抑菌作用，对金葡菌的抑菌率为59.62％。
实验实施例八
1、目的：观察三种抑菌剂配伍凝胶的抑菌作用。
2、实验方法：
A.实验菌株：大肠杆菌(ATCC25922)、金黄色葡萄球菌(ATCC 6538)
B.实验分组：各抑菌凝胶组均含水、抑菌剂和黄原胶，具体见表17；
C.实验方法：基本参照GB15979-2002附录C的方法，完成实验。
3、实验结果：如表17所示，不同配伍的pH值4.1的各抑菌凝胶的杀菌效果。
表17.三种抑菌剂配伍对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000030
4、结论
本实施例的pH值为4.1的三种抑菌剂配伍的各组凝胶中，“0.4％(w/v)苯乙醇+0.55％(w/v)丙酸钠+0.07％(w/v)苯甲酸钠”配伍的凝胶其抑菌作用最强，对大肠杆菌、金黄色葡萄球菌的抑菌率为99.66％和91.30％；不含苯乙醇的由丙酸钠、苯甲酸钠、脱氢乙酸钠三者配伍的凝胶其抑菌作用最弱，对大肠杆菌和金黄色葡萄球菌的抑菌率均低于50％。
实验实施例九
1、目的：观察苯氧乙醇与苯甲酸钠、丙酸钠、乙酸钠、脱氢乙酸钠配伍溶液的抑菌作用。
2、方法：
A.实验菌株：大肠杆菌(ATCC25922)、金黄色葡萄球菌(ATCC 6538)
B.实验分组：各抑菌液组均含水和抑菌剂，具体见表18、表19、表20和表21；
C.实验方法：基本参照GB15979-2002附录C的方法，完成实验。
3、结果：苯氧乙醇与苯甲酸钠配伍溶液的抑菌作用如表18所示；苯氧乙醇与丙酸钠配伍溶液的抑菌作用如表19所示；苯氧乙醇与乙酸钠配伍溶液 的抑菌作用如表20所示；苯氧乙醇与脱氢乙酸钠配伍溶液的抑菌作用如表21所示：
表18 苯氧乙醇与苯甲酸钠配伍对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000031
表19 苯氧乙醇与丙酸钠配伍对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000032
表20 苯氧乙醇与乙酸钠配伍对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000033
Figure PCTCN2017105296-appb-000034
表21 苯氧乙醇与脱氢乙酸钠配伍对大肠杆菌和金黄色葡萄球菌的抑菌作用
Figure PCTCN2017105296-appb-000035
4、结论：
0.3～0.4％(w/v)苯氧乙醇与0.06～0.10％(w/v)苯甲酸钠配伍，对大肠杆菌、金黄色葡萄球菌具有协同抑菌作用。
0.4％(w/v)苯氧乙醇与0.4～0.55％(w/v)丙酸钠配伍的溶液，其对大肠杆菌和金黄色葡萄球菌的抑菌率约为40～60％，具有一定协同抑菌作用，但其抑菌作用较前述苯氧乙醇与苯甲酸钠配伍的溶液弱。
0.4％(w/v)苯氧乙醇与0.4～0.55％(w/v)乙酸钠配伍，对大肠杆菌、金黄色葡萄球菌具有协同抑菌作用。
0.4％(w/v)苯氧乙醇与0.015～0.025％(w/v)脱氢乙酸钠配伍，其对大肠杆菌、金黄色葡萄球菌的抑菌率约为40～65％，具有一定协同抑菌作用，但其抑菌作用较前述苯氧乙醇与苯甲酸钠配伍的溶液弱。
实验实施例十
1、实验目的：观察本发明的抑菌剂配伍溶液对大肠杆菌和金黄色葡萄球菌的生长抑制作用。
2、实验方法：
(1)试验材料
a、试验菌株：大肠埃希氏菌3株，金黄色葡萄球菌3株，均为自阴道炎患者的阴道分泌物分离株。
b.增菌液：1％酵母浸出粉，9％蔗糖，0.025％硫酸锰(MnSO4.4H2O)，0.058％硫酸镁(MgSO4.7H2O)，0.9％乳酸，调pH值至4.8，灭菌备用；
(2)试验分组：严格按无菌技术要求，配制无菌试验管：
a.苯甲酸钠组：5毫升增菌液试验管3支，添加0.05％(w/v)苯甲酸钠；
b.苯乙醇组：5毫升增菌液试验管3支，添加0.05％(w/v)苯乙醇；
c.丙酸钠组：5毫升增菌液试验管3支，添加0.25％(w/v)丙酸钠；
d.“苯甲酸钠+丙酸钠组”：5毫升增菌液试验管3支，添加0.05％(w/v)苯甲酸钠、0.25％(w/v)丙酸钠；
e.“苯甲酸钠+苯乙醇组”：5毫升增菌液试验管3支，添加0.05％(w/v)苯甲酸钠、0.05％(w/v)苯乙醇；
f.“丙酸钠+苯乙醇”组：5毫升增菌液试验管3支，添加0.25％(w/v)丙酸钠、0.05％(w/v)苯乙醇；
g.“苯甲酸钠+丙酸钠+苯乙醇”组：5毫升增菌液试验管3支，添加0.05％(w/v)苯甲酸钠、0.25％(w/v)丙酸钠、0.05％(w/v)苯乙醇；
h.阳性对照：含大肠埃希菌或金黄色葡萄球菌，但不含苯乙醇、苯甲酸钠、丙酸钠的增菌液试验管。
i.阴性对照：为不含大肠埃希菌或金黄色葡萄球菌、苯乙醇、苯甲酸钠、丙酸钠的增菌液试验管；
(3)试验方法：
严格无菌操作技术下制备菌液，将大肠埃希菌和金黄色葡萄球菌菌落分别用生理盐水稀释，浊度仪调浊度至0.5M(约108CFU/ml)，然后分别吸取1ml 0.5M的菌液加入到增菌液9ml中，稀释十倍，使菌液含菌107CFU/ml。
严格无菌操作技术下吸取上述配备好的菌液100μl，分别加入到前述a～h实验管和阳性对照管中，阴性对照管i中不加菌液。
将上述各试管放置37℃生化培养箱中培养，于24小时观察、记录各试管溶液的浊度变化。
3、实验结果：
如表22A所示：
表22A.抑菌剂溶液对大肠埃希菌和金黄色葡萄球菌生长的影响
Figure PCTCN2017105296-appb-000036
注：“+”：有菌生长；“-”：无菌生长。
4、结论：
(1)本实施例中，各抑菌剂单独作用，0.05％(w/v)苯甲酸钠、0.05％(w/v)苯乙醇、0.25％(w/v)丙酸钠，均不能抑制大肠埃希菌和金黄色葡萄球菌生长。
(2)本实施例中，未观察到“0.05％(w/v)苯甲酸钠+0.25％(w/v)丙酸钠”的配伍对大肠杆菌、金黄色葡萄球菌生长具有抑制作用。
(3)本实施例中，“0.05％(w/v)苯甲酸钠+0.05％(w/v)苯乙醇”的配伍，对1/3大肠杆菌株生长具有抑制作用，对金黄色葡萄球菌株生长无抑制作用。“0.25％(w/v)丙酸钠+0.05％(w/v)苯乙醇”的配伍，对1/3金黄色葡萄球菌株的生长具有抑制作用，对1/3大肠杆菌株的生长具有抑制作用。
(4)本实施例中，“0.05％(w/v)苯乙醇+0.05％(w/v)苯甲酸钠+0.25％(w/v)丙酸钠”的配伍，对2/3大肠杆菌株和2/3金黄色葡萄球菌株生长具有抑制作用。提示三种抑菌剂的配伍对大肠杆菌和金黄色葡萄球菌具有协同抑菌作用。
实验实施例十一
1、实验目的：观察本发明的抑菌剂配伍溶液对白假丝酵母菌的生长抑制作用。
2、实验方法：
(1)试验材料：
a.试验菌株：白假丝酵母菌9株，为自真菌性阴道炎患者的阴道分泌物分离的临床菌株，且均能在含0.025％(w/v)苯甲酸钠的增菌液中生长。
b.增菌液：1％酵母浸出粉，9％蔗糖，0.025％硫酸锰(MnSO4.4H2O)，0.058％硫酸镁(MgSO4.7H2O)，0.9％乳酸，调pH值至4.5，灭菌备用；
(2)试验分组：严格按无菌技术要求，配制无菌试验管：
a.苯甲酸钠组：5毫升增菌液试验管1支，添加0.025％(w/v)苯甲酸钠；
b.苯乙醇组：5毫升增菌液试验管1支，添加0.050％(w/v)苯乙醇；
c.丙酸钠组：5毫升增菌液试验管1支，添加0.125％(w/v)丙酸钠；
d.“苯甲酸钠+丙酸钠组”：5毫升增菌液试验管1支，添加0.025％(w/v)苯甲酸钠、0.125％(w/v)丙酸钠；
e.“苯甲酸钠+苯乙醇组”：5毫升增菌液试验管1支，添加0.025％(w/v)苯甲酸钠、0.050％(w/v)苯乙醇；
f.“丙酸钠+苯乙醇”组：5毫升增菌液试验管1支，添加0.125％(w/v)丙酸钠、0.050％(w/v)苯乙醇；
g.“苯甲酸钠+丙酸钠+苯乙醇”组：5毫升增菌液试验管1支，添加0.025％(w/v)苯甲酸钠、0.125％(w/v)丙酸钠、0.050％(w/v)苯乙醇；
h.阳性对照：含白假丝酵母菌，但不含苯乙醇、苯甲酸钠、丙酸钠的增菌液试验管。
i.阴性对照：为不含白假丝酵母菌、苯乙醇、苯甲酸钠、丙酸钠的增菌液试验管；
(3)试验方法：
严格无菌操作技术下制备菌液，将各株白假丝酵母菌菌落分别用生理盐水稀释，浊度仪调浊度至0.5M(约108CFU/ml)，然后分别吸取1ml 0.5M的菌液加入到增菌液9ml中，稀释十倍，使菌液含菌107CFU/ml。
严格无菌操作技术下吸取上述配备好的菌液100μl，分别加入到前述a～i实验管和阳性对照管中，阴性对照管f中不加菌液。
将上述各试管放置37℃生化培养箱中培养，于24小时观察、记录各试管假丝酵母菌生长情况。
3、实验结果：
如表22B所示：
表22B.苯甲酸钠与有机酸防腐剂配伍对白假丝酵母菌的抑制作用
Figure PCTCN2017105296-appb-000037
注：“+”：有菌生长；“-”：无菌生长。
4、结论：
(1)0.025％(w/v)苯甲酸钠单独作用，9株白假丝酵母菌均生长；0.050％(w/v)苯乙醇单独作用，9株白假丝酵母菌中7株生长；0.125％(w/v)丙酸钠单独作用，9株白假丝酵母菌中6株生长。提示各浓度的抑菌剂单独作用，不能抑制全部9株白假丝酵母菌生长。
(2)“0.025％(w/v)苯甲酸钠+0.125％(w/v)丙酸钠”的配伍，9株假丝酵母菌中3株生长；“0.025％(w/v)苯甲酸钠+0.050％(w/v)苯乙醇”的配伍，9株假丝酵母菌中4株生长；“0.125％(w/v)丙酸钠+0.050％(w/v)苯乙醇”的配伍，9株中4株生长。提示三种抑菌剂两两配伍，对假丝酵母菌具有一定协同抑菌作用。
(3)抑菌剂配伍组：0.050％(w/v)苯乙醇+0.025％(w/v)苯甲酸钠+0.125％(w/v)丙酸钠配伍后，9株菌均无生长。提示三种抑菌剂的配伍对白假丝酵母菌具有较强的协同抑菌作用。
实验实施例十二
1、目的：观察含“9.0％(w/v)麦芽糖+0.05％(w/v)苯乙醇+0.075％(w/v)苯甲酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含9.0％(w/v)麦芽糖，0.05％ (w/v)苯乙醇，0.075％(w/v)苯甲酸钠，2.2％(w/v)黄原胶,凝胶pH值3.0。
B.实验动物：1只。成年雌性恒河猴，阴道分泌物pH值>5.4，阴道拭子涂片染色以革兰阴性菌(G-b)为主，及较多革兰阴性球菌(G-c)、革兰阳性球菌(G+c)，粗大革兰阳性杆菌(G+b)极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表23A所示：
表23A 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000038
4.结论
本发明的含“9.0％(w/v)麦芽糖+0.05％(w/v)苯乙醇+0.075％(w/v)苯甲酸钠”的凝胶可调节恒河猴阴道菌群、使阴道菌群恢复正常，并降低阴道分泌物pH值。
实验实施例十三
1、目的：观察含“5.5％(w/v)麦芽糖+1.0％(w/v)异麦芽酮糖+0.05％(w/v)苯乙醇+0.15％(w/v)苯甲酸钠”配伍的凝胶对恒河猴阴道BV样菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含5.5％(w/v)麦芽糖，1.0％(w/v)异麦芽酮糖，0.05％(w/v)苯乙醇，0.15％(w/v)苯甲酸钠，2.15％(w/v)黄原胶,凝胶pH值3.3。
B.实验动物：2只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌 种类和数量，并与给药前比较。
3、实验结果
如表23B所示：
表23B 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000039
4.结论
本发明的含“5.5％(w/v)麦芽糖+1.0％(w/v)异麦芽酮糖+0.05％(w/v)苯乙醇+0.15％(w/v)苯甲酸钠”的凝胶，具有一定的调节阴道菌群的作用，可使1/2恒河猴的阴道菌群恢复正常，和使1/2恒河猴的阴道分泌物的pH值降低。
实验实施例十四
1、目的：观察含“6.5％(w/v)蔗糖+0.10％(w/v)苯乙醇+0.05％(w/v)苯甲酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含6.5％(w/v)蔗糖，0.10％(w/v)苯乙醇，0.05％(w/v)苯甲酸钠，2.15％(w/v)黄原胶,凝胶pH值3.8。
B.实验动物：2只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表24所示：
表24 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000040
Figure PCTCN2017105296-appb-000041
4.结论
本发明的含“6.5％(w/v)蔗糖+0.10％(w/v)苯乙醇+0.05％(w/v)苯甲酸钠”的凝胶可调节恒河猴的阴道菌群、使阴道菌群恢复正常，并降低阴道分泌物pH值。
实验实施例十五
1、目的：观察含“1.0％(w/v)葡萄糖+0.30％(w/v)苯乙醇+0.085％(w/v)苯甲酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含1.0％(w/v)葡萄糖，0.30％(w/v)苯乙醇，0.085％(w/v)苯甲酸钠，2.15％(w/v)黄原胶,凝胶pH值3.8。
B.实验动物：1只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表25所示：
表25 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000042
4.结论
本发明的含“1.0％(w/v)葡萄糖+0.30％(w/v)苯乙醇+0.085％(w/v)苯甲酸钠”的凝胶可有效调节恒河猴的阴道菌群、使阴道菌群恢复正常，降低恒河猴阴道分泌物的pH值。
实验实施例十六
1、目的：观察含“5.0％(w/v)果糖+0.40％(w/v)苯乙醇+0.09％(w/v)苯甲酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含5.0％(w/v)果糖，0.4％(w/v)苯乙醇，0.09％(w/v)苯甲酸钠，2.15％(w/v)黄原胶,凝胶pH值4.1。
B.实验动物：2只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表26所示：
表26 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000043
4.结论
本发明的含“5.0％(w/v)果糖+0.4％(w/v)苯乙醇+0.09％(w/v)苯甲酸钠”凝胶具有一定的调节恒河猴阴道菌群的作用，可使阴道菌群恢复正常，并降低阴道分泌物pH值。
实验实施例十七
1、目的：观察含“4.0％(w/v)甘露糖+0.10％(w/v)苯乙醇+0.35％(w/v) 丙酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含4.0％(w/v)甘露糖，0.10％(w/v)苯乙醇，0.35％(w/v)丙酸钠，2.15％(w/v)黄原胶,凝胶pH值3.5。
B.实验动物：1只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表27所示：
表27 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000044
4.结论
本发明的含“4.0％(w/v)甘露糖+0.10％(w/v)苯乙醇+0.35％(w/v)丙酸钠”凝胶具有一定的调节阴道菌群的作用，可使恒河猴的阴道菌群部分恢复正常，并可降低阴道分泌物pH值，但尚未降至4.1及以下。
实验实施例十八
1、目的：观察含“6.5％(w/v)低聚异麦芽糖+0.10％(w/v)苯乙醇+0.475％(w/v)丙酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含6.5％(w/v)低聚异麦芽糖，0.10％(w/v)苯乙醇，0.475％(w/v)丙酸钠，2.15％(w/v)黄原胶,凝胶pH值3.3。
B.实验动物：2只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表28所示：
表28 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000045
4.结论
本发明的含“6.5％(w/v)低聚异麦芽糖+0.10％(w/v)苯乙醇+0.475％(w/v)丙酸钠”凝胶可调节恒河猴的阴道菌群，恢复阴道菌群正常，并降低恒河猴阴道分泌物的pH值。
实验实施例十九
1、目的：观察含“2.0％(w/v)麦芽糖+3.5％(w/v)果糖+0.10％(w/v)苯乙醇+0.575％(w/v)丙酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含2.0％(w/v)麦芽糖，3.5％(w/v)果糖，0.10％(w/v)苯乙醇，0.575％(w/v)丙酸钠，2.15％(w/v)黄原胶,凝胶pH值3.3。
B.实验动物：1只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表29所示：
表29 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000046
4.结论
本发明的含“2.0％(w/v)麦芽糖+3.5％(w/v)果糖+0.10％(w/v)苯乙醇+0.575％(w/v)丙酸钠”凝胶可调节恒河猴的阴道菌群、使阴道菌群恢复正常，并降低恒河猴阴道分泌物的pH值。
实验实施例二十
1、目的：观察含“4.0％(w/v)麦芽糖+1.0％异麦芽酮糖+0.10％(w/v)苯氧乙醇+0.35％(w/v)乙酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含4.0％(w/v)麦芽糖+1.0％异麦芽酮糖+0.10％(w/v)苯氧乙醇+0.35％(w/v)乙酸钠，2.15％(w/v)黄原胶,凝胶pH值3.3。
B.实验动物：1只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表30所示：
表30 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000047
4.结论
本发明的含“4.0％(w/v)麦芽糖+1.0％异麦芽酮糖+0.10％(w/v)苯氧乙醇+0.35％(w/v)乙酸钠”的凝胶具有一定的调节恒河猴阴道菌群的作用，可使阴道菌群部分恢复正常，并可降低恒河猴阴道分泌物的pH值，但尚未降至4.1及以下。
实验实施例二十一
1、目的：观察含“3.5％(w/v)蔗糖+1.0％(w/v)麦芽糖+0.06％(w/v)苯乙醇+0.525％(w/v)丙酸钠+0.15％(w/v)苯甲酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含3.5％(w/v)蔗糖，1.0％(w/v)麦芽糖，0.06％(w/v)苯乙醇，0.525％(w/v)丙酸钠，0.15％(w/v)苯甲酸钠，2.15％(w/v)黄原胶,凝胶pH值3.3。
B.实验动物：2只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表31所示：
表31 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000048
Figure PCTCN2017105296-appb-000049
4.结论
本发明的含“3.5％(w/v)蔗糖+1.0％(w/v)麦芽糖+0.06％(w/v)苯乙醇+0.525％(w/v)丙酸钠+0.15％(w/v)苯甲酸钠”凝胶作用于2例恒河猴，其中1例恒河猴的阴道分泌物pH值从5.4降到4.1，G-b显著减少、G+b显著增加，菌群基本恢复正常；另1例pH值虽然没有变化，但阴道菌群中G-b菌量变少。提示本组合对恒河猴阴道菌群有一定的调节作用，可使阴道菌群部分恢复正常、阴道分泌物pH值部分恢复正常。
实验实施例二十二
1、目的：观察含“3.0％(w/v)麦芽糖+1.0％(w/v)果糖+0.065％(w/v)苯乙醇+0.55％(w/v)丙酸钠+0.12％(w/v)苯甲酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含3.0％(w/v)麦芽糖，1.0％(w/v)果糖，0.065％(w/v)苯乙醇，0.55％(w/v)丙酸钠，0.12％(w/v)苯甲酸钠，2.15％(w/v)黄原胶,凝胶pH值3.3。
B.实验动物：8只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表32所示：
表32 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000050
Figure PCTCN2017105296-appb-000051
4.结论
本发明的含“3.0％(w/v)麦芽糖+1.0％(w/v)果糖+0.065％(w/v)苯乙醇+0.55％(w/v)丙酸钠+0.12％(w/v)苯甲酸钠”凝胶用于8例恒河猴，其中4例恒河猴的阴道分泌物pH值从5.4降到3.8以下，菌群恢复正常；2例从5.4降到4.1，细菌以粗大的革兰阳性杆菌为主；2例pH值未变化，菌群与给予凝胶前比较无显著变化。显示本发明的含“3.0％(w/v)麦芽糖+1.0％(w/v)果糖+0.065％(w/v)苯乙醇+0.55％(w/v)丙酸钠+0.12％(w/v)苯甲酸钠”的凝胶具有较好的调节恒河猴阴道菌群的作用，可使多数恒河猴阴道菌群恢复正常，和使多数恒河猴阴道分泌物pH值降至4.1或以下。
实验实施例二十三
1、目的：观察含“0.10％(w/v)苯乙醇+0.575％(w/v)丙酸钠+0.09％(w/v)苯甲酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含0.10％(w/v)苯乙醇，0.575％(w/v)丙酸钠，0.09％(w/v)苯甲酸钠，2.15％(w/v)黄原胶,凝胶pH值3.3。
B.实验动物：4只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表33所示：
表33 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000052
4.结论
本发明的含“0.10％(w/v)苯乙醇+0.575％(w/v)丙酸钠+0.09％(w/v)苯甲酸钠”凝胶用于4例恒河猴，其中1例恒河猴的阴道分泌物pH值从5.4降到4.1，细菌以粗大革兰阳性杆菌为主。其余3例恒河猴阴道分泌物pH值未降低。提示“0.10％(w/v)苯乙醇+0.575％(w/v)丙酸钠+0.09％(w/v)苯甲酸钠”凝胶可调节恒河猴阴道菌群，但恢复阴道菌群、降低阴道pH值的作用不及本发明的含糖的制剂。
实验实施例二十四
1、目的：观察含“0.60％(w/v)苯乙醇+0.70％(w/v)丙酸钠”配伍的凝胶对恒河猴阴道菌群的影响。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含0.60％(w/v)苯乙醇，0.70％(w/v)丙酸钠，2.15％(w/v)黄原胶,凝胶pH值4.1。
B.实验动物：2只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少见。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表34所示：
表34 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000053
4.结论
本发明的含“0.60％(w/v)苯乙醇+0.70％(w/v)丙酸钠”的凝胶用于2例恒河猴，阴道分泌物涂片染色镜检、并与给予凝胶前比较，2例的阴道细菌数量均显著减少，其中1例偶见粗大革兰阳性杆菌(G+b)，但2例恒河猴的阴道分泌物pH值均未降低。提示本发明的“0.60％(w/v)苯乙醇+0.70％(w/v)丙酸钠”的凝胶可抑制恒河猴阴道中的细菌、尤其是革兰阴性杆菌(G-b)，尽管其中1例恒河猴偶见粗大革兰阳性杆菌，但菌群未恢复正常，阴道分泌物的pH值亦未降至4.1或以下。
实验实施例二十五
1、目的：观察含“2.0％(w/v)果糖+4.0％(w/v)异麦芽糖+0.06％(w/v)苯乙醇+0.575％(w/v)丙酸钠+0.12％(w/v)苯甲酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含2.0％(w/v)果糖，4.0％(w/v) 异麦芽糖，0.06％(w/v)苯乙醇，0.575％(w/v)丙酸钠，0.12％(w/v)苯甲酸钠，2.15％(w/v)黄原胶,凝胶pH值3.3。
B.实验动物：3只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表35所示：
表35 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000054
4.结论
本发明的含“2.0(w/v)％果糖+4.0％(w/v)异麦芽糖+0.06％(w/v)苯乙醇+0.575％(w/v)丙酸钠+0.12％(w/v)苯甲酸钠”的凝胶可调节恒河猴阴道菌群，恢复阴道菌群正常，降低阴道pH值。
实验实施例二十六
1、目的：观察含“5.5％(w/v)麦芽糖+1.0％异麦芽酮糖+0.10％(w/v)苯乙醇+0.575％(w/v)丙酸钠+0.065％(w/v)苯甲酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：含5.5％(w/v)麦芽糖，1.0％异麦芽酮糖，0.10％(w/v)苯乙醇，0.575％(w/v)丙酸钠，0.065％(w/v)苯甲酸钠，2.15％(w/v)黄 原胶,凝胶pH值4.3。
B.实验动物：2只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表36所示：
表36 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000055
4.结论
本发明的含“5.5％(w/v)麦芽糖+1.0％异麦芽酮糖+0.10％(w/v)苯乙醇+0.575％(w/v)丙酸钠+0.065％(w/v)苯甲酸钠”的凝胶可调节恒河猴阴道菌群，使阴道菌群恢复正常，并降低恒河猴阴道分泌物的pH值。
实验实施例二十七
1、目的：观察含“2.0％(w/v)麦芽糖+0.20％(w/v)苯乙醇+0.575％(w/v)丙酸钠+0.065％(w/v)苯甲酸钠”配伍的凝胶对恒河猴阴道菌群的调节作用。
2、实验方法：
A.实验制剂：按本发明的制备方法，制备含2.0％(w/v)麦芽糖，0.20％(w/v)苯乙醇，0.575％(w/v)丙酸钠，0.065％(w/v)苯甲酸钠，2.15％(w/v)黄原胶,凝胶pH值3.3。
B.实验动物：5只。成年雌性恒河猴，阴道分泌物pH值5.4，阴道拭子涂片染色以革兰阴性菌为主，粗大革兰阳性杆菌极少。
C.动物处理：阴道局部给予A的凝胶0.5毫升，每天1次、连续5天，第6天采阴道拭子，测阴道分泌物pH值，涂片染色，显微镜下观察阴道细菌种类和数量，并与给药前比较。
3、实验结果
如表37所示：
表37 复方抑菌凝胶对恒河猴阴道菌群的影响
Figure PCTCN2017105296-appb-000056
4.结论
本发明的含“2.0％(w/v)麦芽糖+0.20％(w/v)苯乙醇+0.575％(w/v)丙酸钠+0.065％(w/v)苯甲酸钠”凝胶可调节恒河猴阴道菌群，使阴道菌群恢复正常，并降低恒河猴阴道分泌物的pH值。

Claims (22)

  1. 一种抑菌剂配伍在制备阴道用组合物中的用途，其中，所述组合物含有以下抑菌剂：(1)总含量以苯乙醇计的0.05～0.60％(w/v)的苯乙醇和/或苯氧乙醇；(2)总含量以丙酸钠计的0.25～0.70％(w/v)的丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠；和/或总含量以苯甲酸钠计的0.05～0.15％(w/v)的苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质。
  2. 根据权利要求1所述的用途，其特征在于，总量以苯乙醇计的苯乙醇和/或苯氧乙醇的总含量为0.10～0.40％(w/v)；总量以丙酸钠计的的丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠的总含量为0.525～0.575％(w/v)；总量以苯甲酸钠计的苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质的总含量为0.065～0.090％(w/v)。
  3. 根据权利要求1的组合物，其特征在于，所述组合物含有(1)苯乙醇和/或苯氧乙醇；(2)丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠；(3)苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质。
  4. 根据权利要求1的组合物，其特征在于，所述抑菌剂为苯乙醇、丙酸和/或丙酸钠、苯甲酸和/或苯甲酸钠。
  5. 根据权利要求1的用途，其特征在于，所述组合物还选用一种或多种选自下组的抑菌或抗菌物质：脱氢乙酸、脱氢乙酸钠、山梨酸、山梨酸钾、山梨酸钠、双乙酸、双乙酸钠、辛酸、辛酸钠、癸酸、葵酸钠、十一烯酸、十一烯酸钠、月桂酸、月桂酸钠、纳他霉素、乳 铁蛋白、乳铁蛋白肽、溶菌酶、抑菌蛋白、抗菌肽、地衣酸、虎耳草素、环庚三烯酚酮、氯原酸、黄藤素、苯甲醇、丙烯苯氧乙醇、1,2-戊二醇、1,2-己二醇、1,6-己二醇、1,2-辛二醇、1,2-葵二醇、甲基丙二醇、乙基己基丙三醇、过氧化苯甲酰。
  6. 根据权利要求1的用途，其特征在于，所述组合物还选用1.0～9.0％(w/v)的一种或多种选自下组的糖用于本发明的用途：葡萄糖、果糖、甘露糖、蔗糖、异麦芽酮糖、蔗果三糖、蔗果四糖、蔗果五糖、麦芽糖、异麦芽糖、异麦芽三糖、异麦芽四糖、异麦芽五糖、海藻糖、纤维二糖、蜜二糖、龙胆二糖、低聚龙胆糖、棉子糖、潘糖、麦芽寡糖、低聚异麦芽酮糖、低聚果糖、葡甘聚糖、糊精、淀粉和糖原。
  7. 根据权利要求1的用途，其特征在于，所述组合物还选用0.1～10.0％(w/v)的一种或多种选自下组的氨基酸用于本发明的用途：谷氨酸、谷氨酰胺、天冬氨酸、天冬氨酰胺、异亮氨酸、苯丙氨酸、颉氨酸、亮氨酸、脯氨酸和苏氨酸。
  8. 根据权利要求1的用途，其特征在于，所述组合物还选用0.001～1.0％(w/v)的一种或多种选自下组的物质用于本发明的用途：己烯雌酚、雌二醇、雌三醇、大豆甙、大豆甙元、染料木甙、染料木素、黄豆黄素、黄豆黄素甙元、鸡豆黄素、香豆雌酚和芒柄花黄素。
  9. 根据权利要求1的用途，其特征在于，所述组合物还选用一种或多种选自下组的物质用于本发明的用途：0.01～5.0％(w/v)的芦荟提取物、0.01～5.0％(w/v)的薰衣草提取物、0.001～1.0％(w/v)的维生素E、0.001～1.0％(w/v)的维生素A、0.001～1.0％(w/v)的维生素D、0.001～1.0％(w/v)的维生素C。
  10. 根据权利要求1的用途，其特征在于，所述阴道用组合物的 剂型为溶液剂、或水溶性凝胶剂、或乳剂型软膏剂，其中所述组合物pH值为3.0～4.3。
  11. 一种用于阴道的组合物，其特征在于，所述组合物含有：(1)总量以苯乙醇计的0.05～0.6％(w/v)的苯乙醇和/或苯氧乙醇；(2)总量以丙酸钠计的0.25～0.7％(w/v)的丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠；和/或总量以苯甲酸钠计的0.05～0.15％(w/v)的苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质；
    其中，所述组合物剂型为溶液剂、或水溶性凝胶剂、或乳剂型软膏剂；组合物的pH值为3.0～4.3。
  12. 根据权利要求11的组合物，其特征在于，总量以苯乙醇计的苯乙醇和/或苯氧乙醇的总含量为0.10～0.40％(w/v)；总量以丙酸钠计的的丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠的总含量为0.525～0.575％(w/v)；总量以苯甲酸钠计的苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质的总含量为0.065～0.090％(w/v)。
  13. 根据权利要求11的组合物，其特征在于，所述组合物含有(1)苯乙醇和/或苯氧乙醇；(2)丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠；(3)苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质。
  14. 根据权利要求11的组合物，其特征在于，所述抑菌剂为苯乙醇、丙酸和/或丙酸钠、苯甲酸和/或苯甲酸钠。
  15. 根据权利要求11的组合物，其特征在于，所述组合物还含 有一种或多种选自下组的抑菌剂或抗菌剂：脱氢乙酸、脱氢乙酸钠、山梨酸、山梨酸钾、山梨酸钠、双乙酸、双乙酸钠、辛酸、辛酸钠、癸酸、葵酸钠、十一烯酸、十一烯酸钠、月桂酸、月桂酸钠、纳他霉素、乳铁蛋白、乳铁蛋白肽、溶菌酶、抑菌蛋白、抗菌肽、地衣酸、虎耳草素、环庚三烯酚酮、氯原酸、黄藤素、苯甲醇、丙烯苯氧乙醇、1,2-戊二醇、1,2-己二醇、1,6-己二醇、1,2-辛二醇、1,2-葵二醇、甲基丙二醇、乙基己基丙三醇、过氧化苯甲酰。
  16. 根据权利要求11的组合物，其特征在于，所述组合物还含有总量为0.001～1.0％(w/v)的一种或多种选自下组的物质：己烯雌酚、雌二醇、雌三醇、大豆甙、大豆甙元、染料木甙、染料木素、黄豆黄素、黄豆黄素甙元、鸡豆黄素、香豆雌酚和芒柄花黄素。
  17. 根据权利要求11的组合物，其特征在于，所述组合物还含有总量为1.0～9.0％(w/v)的一种或多种选自下组的糖：葡萄糖、果糖、甘露糖、蔗糖、异麦芽酮糖、蔗果三糖、蔗果四糖、蔗果五糖、麦芽糖、异麦芽糖、异麦芽三糖、异麦芽四糖、异麦芽五糖、海藻糖、纤维二糖、蜜二糖、龙胆二糖、低聚龙胆糖、棉子糖、潘糖、麦芽寡糖、低聚异麦芽酮糖、低聚果糖、葡甘聚糖、糊精、淀粉和糖原。
  18. 根据权利要求17的组合物，其特征在于，其中所述糖为总含量为2.0～6.5％(w/v)的一种或多种选自下组的糖：葡萄糖、果糖、甘露糖、蔗糖、麦芽糖、异麦芽酮糖、异麦芽糖、海藻糖、麦芽寡糖。
  19. 根据权利要11的组合物，其特征在于，所述组合物还含有一种或多种选自下组的物质：0.01～5.0％(w/v)的芦荟提取物、0.01～5.0％(w/v)的薰衣草提取物、0.001～1.0％(w/v)的维生素E、0.001～1.0％(w/v)的维生素A、0.001～1.0％(w/v)的维生素D和0.001～1.0％(w/v)的维生素C。
  20. 根据权利要求11的组合物，其特征在于，所述组合物还含有0.1～10％(w/v)的一种或多种选自下组的氨基酸和/或其盐：谷氨酸、谷氨酰胺、天冬氨酸、天冬氨酰胺、异亮氨酸、苯丙氨酸、颉氨酸、亮氨酸、脯氨酸和苏氨酸。
  21. 根据权利要求20的组合物，其特征在于，所述氨基酸的含量为1.0～5.0％(w/v)，其中所述氨基酸为谷氨酸和/或天冬氨酸。
  22. 一种用于阴道的组合物的制造方法，其特征在于，包括向水和/或水溶性胶体基质和/或乳剂型软膏基质中加入(1)总含量以苯乙醇计的0.05～0.60％(w/v)的苯乙醇和/或苯氧乙醇；(2)总含量以丙酸钠计的0.25～0.70％(w/v)的丙酸和/或丙酸钠和/或丙酸钙和/或乙酰丙酸和/或乙酰丙酸钠和/或乙酸和/或乙酸钠；和/或总量以苯甲酸钠计的0.05～0.15％(w/v)的苯甲酸和/或苯甲酸钠和/或对甲氧基苯甲酸和/或对甲氧基苯甲酸钠和/或苯甲酸酯类物质。
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