WO2015135470A1 - 一种阴道用组合物与该组合物的用途 - Google Patents

一种阴道用组合物与该组合物的用途 Download PDF

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Publication number
WO2015135470A1
WO2015135470A1 PCT/CN2015/073978 CN2015073978W WO2015135470A1 WO 2015135470 A1 WO2015135470 A1 WO 2015135470A1 CN 2015073978 W CN2015073978 W CN 2015073978W WO 2015135470 A1 WO2015135470 A1 WO 2015135470A1
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Prior art keywords
vaginal
composition
sodium
acid
lactobacillus
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PCT/CN2015/073978
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English (en)
French (fr)
Inventor
曾忠铭
周汝云
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曾忠铭
周汝云
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=54070942&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2015135470(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by 曾忠铭, 周汝云 filed Critical 曾忠铭
Priority to CA2942424A priority Critical patent/CA2942424C/en
Priority to SG11201607600TA priority patent/SG11201607600TA/en
Priority to MYPI2016001676A priority patent/MY192494A/en
Priority to CN201580007746.8A priority patent/CN107073019B/zh
Priority to EP15760638.5A priority patent/EP3117827B1/en
Publication of WO2015135470A1 publication Critical patent/WO2015135470A1/zh
Priority to US15/262,529 priority patent/US10869878B2/en
Priority to US17/108,114 priority patent/US11951116B2/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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/886—Aloeaceae (Aloe family), e.g. aloe vera
    • 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
    • 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
    • A61P31/02—Local antiseptics
    • 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 isomaltulose in the preparation of a vaginal composition; the invention also relates to a composition for vaginal, which may be a health product, a health product, a cleansing product, a care product, an odor removal Agent, cosmetic, disinfectant composition, or pharmaceutical composition; the invention also relates in particular to a method of non-therapeutic vaginal health care, and a method of non-therapeutic vaginal hygiene, and a method of enhancing vaginal acidity And a method of promoting growth of Lactobacillus in the vagina, and a method of preventing and treating vaginal flora disorders, particularly bacterial vaginosis.
  • a composition for vaginal which may be a health product, a health product, a cleansing product, a care product, an odor removal Agent, cosmetic, disinfectant composition, or pharmaceutical composition
  • the invention also relates in particular to a method of non-therapeutic vaginal health care, and a method of non-therapeutic va
  • the female vagina is an open system that is susceptible to a variety of microbes and pathogens. Under healthy conditions, the surface of the vaginal mucosa inhabits beneficial lactobacilli. Lactobacillus can metabolize glycogen production in vaginal mucosal epithelial cells, and maintain vaginal acidity in the range of pH 3.5 to 4.5, so that the vagina has a self-purifying effect and is an important component of vaginal anti-infective power. Once the acidity of the vagina is weakened, it will affect the health and health of the vagina, and even the entire reproductive tract, and bring harm to women's lives.
  • Lactobacillus in the vagina There are many types of Lactobacillus in the vagina, and nearly 20 species can be detected [1] . Before 2000, it was considered to be mainly Lactobacillus acidophilus. With the maturity and extensive application of molecular identification technology since 2000, breakthroughs have been made in the study of Lactobacillus species in the vagina. Reports in Zhou in 2004, Linhares in 2010, and Rampersaud R in 2012 [2][3][4] Lactobacilli in the vagina are often dominated by L. crispatus, or Lactobacillus inertia ( L. iners), L. gasseri is the dominant lactobacillus, or L. jensenii is the dominant lactobacillus, and it is also possible to use L.
  • L. crispatus or Lactobacillus inertia ( L. iners)
  • L. gasseri is the dominant lactobacillus
  • L. jensenii is the dominant lactobacillus
  • L. vaginalis is a dominant lactobacillus. They also reported that Lactobacillus is not the dominant bacteria in the vagina of all "healthy" women. Some women have Atopobium as the dominant bacteria, which can also produce lactic acid, which can maintain the weak acidic environment of the vagina.
  • vaginal acidity Menstruation, sexual intercourse, vaginal washing, etc. have a greater impact on vaginal acidity.
  • the vaginal acidity is weakened, the vaginal pH is much higher than 4.5 to 6.6 [6] , and the semen weakens the vaginal acidity [7], etc., so the vaginal washing after menstruation and after the same room becomes a female personal hygiene.
  • Aesthetics, the need for quality of life, and the need to prevent infection about 30% of American women often do vaginal washing. However, improper washing destroys vaginal acidity and flora, which in turn increases the chance of infection [8] .
  • the vaginal acidity is weakened, the pH of the vagina is increased to 4.5 or higher, the number of lactobacilli in the vagina is reduced, and various bacteria such as anaerobic bacteria are grown in large amounts.
  • Fredricks et al [5] used 16S-rDNA technology to analyze the vaginal flora of BV patients, and found that each patient isolated an average of 9-17 anaerobic bacteria, including Megasphaera and Ciliates. (Sneathia).
  • Gardnerella vaginalis can be isolated/detected in almost all BV patients with vaginal secretions, which can be isolated/detected in vaginal secretions of nearly 95% of BV patients.
  • Atopobium vaginae which can be isolated/detected from 50% of vaginal secretions of BV patients, is Mobiluncus spp.
  • Many other anaerobic bacteria, such as Prevot, anaerobic streptococcus, etc. are also important BV bacteria.
  • the cure criteria for BV include that the acidity of the vagina returns to normal, ie the pH of the vagina returns to 3.5 to 4.5.
  • Internationally, BV is the first choice for the antibacterial drug metronidazole with strong anaerobic bacteria, followed by antibiotics such as clindamycin, but the cure rate of the two drugs is only about 60%, and the recurrence rate is as high as 30-40%. And the cure rate is gradually reduced.
  • Livengood CH et al. [10] according to the guidelines issued by the FDA in 1998, if the criteria for clinical cure and microbial cure were met, the cure rate of tinidazole for BV was only 37%. According to the traditional Amsel clinical indicators, 3 of the 4 items are normal, and the cure rate is 57%. Thomas KK et al. reported in 2005 [11] 0.75% metronidazole gel cures BV only 26%.
  • vaginal flora or for the treatment of post-antibiotic restore vaginal beneficial bacteria, or for the prevention or treatment of vaginal flora, or for the prevention or treatment of bacterial vaginosis.
  • isomaltulose can significantly enhance the self-purification and anti-infective power of the vagina, and is particularly suitable for preparing the vagina.
  • the present invention has been completed through further research.
  • the present invention provides the use of isomaltulose in the preparation of a composition for vaginal use, wherein in the preparation, isomaltulose is used in an amount such that 0.05 to 20% (w/w) of isomalt is contained in the composition.
  • the ketose is preferably used in an amount of from 1.5 to 12% (w/w) of isomaltulose in the composition.
  • composition further comprises a total of 0.05 to 2.5% (w/w) of a preservative and/or an antibacterial agent selected from the group consisting of benzoic acid, sodium benzoate, sorbic acid, sorbic acid Potassium, sodium sorbate, acetic acid, sodium acetate, diacetic acid, sodium diacetate, dehydroacetic acid, sodium dehydroacetate, propionic acid, sodium propionate, calcium propionate, caprylic acid, sodium octanoate, citric acid, sodium sulphate, One or a combination of undecylenic acid, sodium undecylenate, lauric acid, sodium laurate, natamycin, lactoferrin, lactoferrin peptide.
  • an antibacterial agent selected from the group consisting of benzoic acid, sodium benzoate, sorbic acid, sorbic acid Potassium, sodium sorbate, acetic acid, sodium acetate, diacetic acid, sodium diacetate, dehydro
  • the preservative and/or antibacterial agent have relatively strong inhibitory effects on pathogens, molds, and candida, and the inhibitory effect on lactobacilli is relatively weak, and is used for preparing the vaginal composition of the present invention. It can delay the growth of pathogenic bacteria, mold, and Candida, and can avoid significant interference and weaken the promotion of isomaltulose on Lactobacillus growth and acid production.
  • vaginal composition product or composition formulation including, but not limited to, non-therapeutic vaginal health products, or vaginal daily necessities, Or vaginal health products, or vaginal care products, or vaginal cosmetics, or vaginal hygiene products, or vaginal cleaning products, or therapeutic vaginal health products, or vaginal medical devices, or vaginal drugs (over-the-counter or prescription drugs) ), or as a cleansing agent, or curing agent for vaginal, or as an odorant, or an antipruritic, or a freshener, or a wetting agent, or a lubricant, or a disinfectant, or an antibacterial agent, or a surface microbicidal Agent, or microecological regulator, or microbial regulator.
  • vaginal composition including, but not limited to, a water-soluble colloid, an aqueous solution, an aerosol, a cream, an ointment , capsules, microcapsules, suppositories, effervescent agents, tablets, preferably water-soluble colloids, creams.
  • a water-soluble colloidal composition for vaginal preparation it can be prepared according to a method known to those skilled in the art such as the following process: isocyanulose, sodium benzoate, sodium propionate, sodium dehydroacetate, water-soluble A colloidal matrix (such as xanthan gum), mixed, quantitatively added with distilled water, stirred to dissolve sugar and preservatives, etc., and the water-soluble colloidal matrix swells into a uniform viscous colloid.
  • the pH of the composition is adjusted to a range of from 3.5 to 6.0, particularly from 4.0 to 5.5, with a pharmaceutically acceptable acid and/or base. Sterilize after sub-packaging, or sterilize and then aseptically dispense.
  • Sterilization can be selected as follows: radiation sterilization, or high temperature sterilization at 110 ⁇ 115 ° C, 15 ⁇ 20 minutes, or intermittent sterilization, or preservatives, sugar components, etc. can be separately prepared into a solution and then filtered and sterilized. And then added to the sterilized water-soluble gelatinous matrix.
  • the quantitative isomaltulose can be directly mixed with sodium benzoate, sodium propionate and sodium dehydroacetate according to a method known to those skilled in the art, and then the tablet is obtained directly;
  • Excipient ingredients such as a lubricant such as magnesium stearate or a disintegrant such as sodium carboxymethyl starch may be added, uniformly mixed, and tableted.
  • vaginal suppository When preparing a vaginal suppository, it can be prepared according to a method known to those skilled in the art, for example, the following process: quantitatively taking isomaltulose, sodium benzoate, sodium propionate, sodium dehydroacetate, Tween 80, mixing and heating, heating To about 50 ° C, the mixed fatty acid glyceride (also known as solid fat) is heated to 60 ° C to melt, and then a mixture of sugar, preservative and Tween 80 is added to the molten substrate, while stirring, After mixing, pour into the mold at about 40 ° C (before solidification), slightly cool, then mold, cool, demould, and get a vaginal plug.
  • the base of the suppository may be propylene glycol stearate, glycerin gelatin or Tween-61 in addition to the fatty acid glyceride. Mass production can be automated and mechanized.
  • the preparation for use according to the present invention may also optionally further use an effective amount of one or more antibacterial agents and/or preservatives for preparing the composition, including but not limited to: hydrogen peroxide, vitamin B 1 , vitamin K 3 , vitamin K 4 , parabens, defensins, antibacterial peptides.
  • the above substances can further inhibit bacteria, molds, candida, and the like in the composition, further enhancing the microbial stability of the composition.
  • the preparation may also optionally use a total content of 0.001 to 1.0% (w/w) of estrogens and/or phytoestrogens for the preparation of the composition.
  • the estrogen or phytoestrogens include: diethylstilbestrol, estradiol, estriol, Daidzin, Daidzein, Genistin, Genistein, Soybean Glycitin, Glycitein, Biochanin A, Coumestto, Formnonetin, etc.
  • Estrogens and phytoestrogens can promote vaginal mucosal angiogenesis, vaginal mucosal epithelial keratinization and healing of vaginal epithelial damage, and enhance the efficacy of the compositions prepared by the present invention.
  • the selection and use of the above various estrogens and phytoestrogens in the preparation of the present invention are within the knowledge of those skilled in the art.
  • vaginal mucosal cell protective substances and/or antioxidant substances selected from the group consisting of, but not limited to: 0.1 ⁇ 5.0% (w/w) aloe extract, 0.1-5.0 (w/w) lavender 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 to 1.0% (w/w) vitamin C for further nutrition, moisturizing, lubricating, and protecting vaginal mucosal epithelial cells.
  • the preparation may also optionally use an effective amount of one or more saccharide materials selected from the group consisting of, but not limited to, glucose, fructose, mannose , sucrose, maltose, isomaltose, lactose, lactulose, trehalose, cellobiose, melibiose, gentiobiose, pine disaccharide, chitosan, raffinose, gentian, panose, pine Sugar, isomaltotriose, canetriose, isomaltotetraose, cane fruit tetrasaccharide, cane fruit pentasaccharide, malto-oligosaccharide, galacto-oligosaccharide, mannose oligosaccharide, dextran, cyclodextrin, paste Fine, starch and glycogen.
  • saccharide materials selected from the group consisting of, but not limited to, glucose, fructose, mannose , sucrose
  • one or more antibacterial agents effective against bacteria and/or fungi may also be selectively used for the preparation, including but not limited to the following: fluconazole, triconazole, Butoconazole, miconazole, clotrimazole, nystatin, metronidazole, tinidazole, lincomycin, amoxicillin; wherein preferably the bacteriostatic agent and/or bactericide is metronidazole, Tinidazole, clotrimazole, fluconazole.
  • fluconazole triconazole
  • Butoconazole miconazole
  • clotrimazole nystatin
  • metronidazole metronidazole
  • Tinidazole Tinidazole
  • clotrimazole fluconazole
  • the isomaltulose content should be from 0.1 to 20.0% (w/v), and the preferred total content is from 3.0 to 12.0% (w/v).
  • the preparation use of the present invention in the preparation of the water-soluble colloidal agent, it is also required to use a non-flowing, viscous, water-soluble colloidal matrix which allows the sugar to uniformly contact with the vaginal mucosa and stays for a long time, thereby promoting the growth of the lactobacillus.
  • the selection and use of the water-soluble viscous colloid matrix within the knowledge of those skilled in the art, includes, but is not limited to, xanthan gum, carbomer, in accordance with the preparation of the present invention.
  • the pH should be adjusted to a range of from 3.5 to 6.0, particularly from 4.0 to 5.5. Selection of the type and concentration of the acid or base which adjusts the pH of the water-soluble colloidal agent of the present invention is within the knowledge of one of ordinary skill in the art.
  • the water-soluble colloid prepared according to the preparation of the present invention can be used in a sterile, sealed package, preferably a single dose of sterile, sealed package.
  • the sterilized or sterilized composition may be dispensed, sealed in an aseptic package, or the prepared composition may be dispensed, sealed, and dried using aseptic processing techniques familiar to those skilled in the art.
  • the bacteria are treated, or the prepared composition is dispensed into a disposable vaginal applicator, sealed with an outer bag for radiation sterilization, and the like.
  • a lactobacillus live cell can also be selectively used for preparing a capsule, a microcapsule, a tablet, etc. containing a isomaltulose and a lactobacillus live cell, wherein the lactobacillus
  • the living cells are used to directly supplement the lactobacilli lacking in the vagina of the patient, or to replace the original lactobacilli in the vagina of the patient, and the isomaltulose is used to promote the growth of the lactobacillus in the vagina.
  • composition containing isomaltulose and live bacteria of Lactobacillus prepared according to the invention is suitable for regulating vaginal flora, enhancing vaginal acidity, cleaning and vaginal care, preventing or treating vaginal vaginal bacteria, vaginal acidity weakening, and bacteriality Vaginal disease and vaginal flora imbalance.
  • the preparation of Lactobacillus viable cells and methods of use in the preparation of the present invention are within the knowledge of one of ordinary skill in the art.
  • the present invention also provides a composition for vaginal, characterized in that: (1) contains 0.05 to 20% (w/w) isomaltulose; (2) contains a total amount of 0.05 to 2.5% (w/ a preservative and/or antibacterial agent selected from the group consisting of benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, sodium sorbate, acetic acid, sodium acetate, diacetic acid, sodium diacetate, dehydroacetic acid, Sodium hydrogen acetate, propionic acid, sodium propionate, calcium propionate, octanoic acid, sodium octanoate, citric acid, sodium sulphate, undecylenic acid, sodium undecylenate, lauric acid, sodium laurate, natamycin, One or a combination of lactoferrin, lactoferrin peptides; (3) one or more inactive excipient ingredients suitable for use in the human vagina.
  • composition according to the invention wherein the content of isomaltulose in the composition is preferably from 1.5 to 12% (w/w).
  • compositions include, but is not limited to, the following vaginal composition product or composition preparation: non-therapeutic vaginal health product, vaginal daily necessities, or vaginal health care product, or vaginal care product Or vaginal cosmetics, or vaginal hygiene products, or vaginal cleaning products, or therapeutic vaginal health products, or vaginal medical devices, or vaginal drugs (over-the-counter or prescription drugs), or for vaginal cleaning Agent, or curing agent, or deodorant, or antipruritic, or freshener, or wetting agent, or lubricant, or disinfectant, or antibacterial agent, or surface microbicide, or microecological regulator, or Microbial regulators.
  • vaginal composition product or composition preparation non-therapeutic vaginal health product, vaginal daily necessities, or vaginal health care product, or vaginal care product Or vaginal cosmetics, or vaginal hygiene products, or vaginal cleaning products, or therapeutic vaginal health products, or vaginal medical devices, or vaginal drugs (over-
  • the dosage form of the vaginal composition is a dosage form including, but not limited to, a water-soluble colloidal agent, an aqueous solution, an aerosol, a cream, an ointment, a capsule, a microcapsule, a suppository, an effervescent, a tablet, preferably Water-soluble colloidal agent, cream.
  • composition according to the present invention may optionally further comprise an effective amount of a preservative and/or an antibacterial agent selected from the group consisting of hydrogen peroxide, vitamin B, and an antibacterial agent.
  • a preservative and/or an antibacterial agent selected from the group consisting of hydrogen peroxide, vitamin B, and an antibacterial agent.
  • an antibacterial agent selected from the group consisting of hydrogen peroxide, vitamin B, and an antibacterial agent.
  • vitamin K 3 , vitamin K 4 , parabens, defensins, antibacterial peptides.
  • the above substances can further inhibit bacteria, molds, candida, and the like in the composition, further enhancing the microbial stability of the composition.
  • composition according to the present invention wherein the composition further optionally contains a total amount of 0.001 to 1.0% (w/w) of estrogens and/or phytoestrogens, including but not limited to: diethylstilbestrol , estradiol, estriol, daidzin, daidzein, Genistin, Genistein, Glycitin, Glycitein, Biochanin A, Coumestto, Formnonetin.
  • Estrogens and phytoestrogens can promote vaginal mucosal angiogenesis, vaginal mucosal epithelial keratinization, and vaginal epithelial damage healing, thereby further enhancing the effects of the compositions of the present invention.
  • the selection and use of the various estrogens, phytoestrogens, and the like described above in the compositions of the present invention are within the skill of the art and the knowledge of those skilled in the art.
  • composition according to the present invention wherein the composition further optionally contains an effective amount of a vaginal mucosal cell protective substance and/or an antioxidant substance selected from the group consisting of, but not limited to, 0.1 to 5.0% (w/ w) Aloe extract, 0.1-5.0% (w/w) lavender 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 to 1.0% (w/w) Vitamin C for further nutrition, moisturizing, lubricating, and protecting vaginal mucosal epithelial cells.
  • an antioxidant substance selected from the group consisting of, but not limited to, 0.1 to 5.0% (w/ w) Aloe extract, 0.1-5.0% (w/w) lavender 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, 0.00
  • compositions according to the present invention wherein the composition further optionally contains an effective amount of one or more saccharide materials selected from the group consisting of, but not limited to, glucose, fructose, mannose, sucrose, maltose , isomaltose, lactose, lactulose, trehalose, cellobiose, melibiose, gentiobiose, pine disaccharide, chitosan, raffinose, gentian, panose, pine triose, isomalt Trisaccharide, canetriose, isomaltotetraose, cane sugar, sugar cane, pentasaccharide, malto-oligosaccharide, galactooligosaccharide, mannose oligosaccharide, dextran, cyclodextrin, dextrin, starch and Glycogen.
  • saccharide materials selected from the group consisting of, but not limited to, glucose, fructos
  • composition according to the present invention wherein the composition further optionally contains an effective amount of one or more antibacterial agents selected from the group consisting of, but not limited to, fluconazole, triconazole, butoconazole, Miconazole, clotrimazole, nystatin, metronidazole, tinidazole, lincomycin, amoxicillin, preferably metronidazole, tinidazole, fluconazole, clotrimazole.
  • one or more antibacterial agents selected from the group consisting of, but not limited to, fluconazole, triconazole, butoconazole, Miconazole, clotrimazole, nystatin, metronidazole, tinidazole, lincomycin, amoxicillin, preferably metronidazole, tinidazole, fluconazole, clotrimazole.
  • composition may further optionally contain a live Lactobacillus strain
  • lactobacillus live bacteria include, but are not limited to, Lactobacillus crispus, Lactobacillus johnsonii, Lactobacillus gasseri.
  • the Lactobacillus live bacteria are used to directly supplement the lactobacilli lacking in the vagina of the patient, or to replace the original Lactobacillus in the vagina of the patient, and the isomaltulose is used to promote the growth of the Lactobacillus in the vagina.
  • the composition containing isomaltulose and live Lactobacillus is suitable for regulating vaginal flora, enhancing vaginal acidity, cleaning the vaginal cavity, preventing or treating vaginal vaginal bacteria, vaginal acidity, bacterial vaginosis And vaginal flora imbalance.
  • the preparation of Lactobacillus live cells and methods of use in the compositions of the present invention are within the skill of the art and the knowledge of those skilled in the art.
  • composition according to the present invention wherein the composition is preferably a vaginal water-soluble colloidal composition, characterized in that: (1) the content of isomaltulose in the water-soluble colloidal composition is from 0.1 to 20.0% (w/v), Preferably, it is 3.0 to 12.0% (w/v); (2) further contains a total amount of 0.1 to 2.5% (w/v) of a preservative and/or an antibacterial agent selected from the group consisting of benzoic acid, sodium benzoate, and sorbitol.
  • a preservative and/or an antibacterial agent selected from the group consisting of benzoic acid, sodium benzoate, and sorbitol.
  • Acid potassium sorbate, sodium sorbate, acetic acid, sodium acetate, diacetic acid, sodium diacetate, dehydroacetic acid, sodium dehydroacetate, propionic acid, sodium propionate, calcium propionate, octanoic acid, sodium octanoate, citric acid, One of sodium alginate, undecylenic acid, sodium undecylenate, lauric acid, sodium laurate, natamycin, lactoferrin, lactoferrin peptide, or a combination thereof.
  • the non-reactive excipient component is a non-flowing, viscous, water-soluble colloidal matrix; wherein the colloidal group Preferably, it is xanthan gum, carbomer, particularly preferably xanthan gum; (4) wherein the composition has a pH of 3.5 to 6.0, particularly 4.0 to 5.5; (5) optionally Containing a total amount of 0.0015 to 1.0% (w/v) of estrogens and/or phytoestrogens selected from the group consisting of diethylstilbestrol, estradiol, estriol, soybean meal, soybean aglycone, dye Hibiscus, genistein, glycyrrhizin, soy flavonoid, chickpea flavin, coumestrol, formononetin; (6) optionally also containing vaginal mucosal cell protective material selected from the group consisting of And/or antioxidants, including but not limited to: 0.15 to 5.0% (w/v) aloe extract, 0.15 to
  • the present invention is also particularly directed to a method of supplementing a vaginal substance to a woman, comprising administering to a woman in need thereof an effective amount of an isomaltulose-containing vaginal composition of the present invention, such that isomaltulose
  • the daily dosage is 5 to 2000 mg, preferably 150 to 1200 mg, and the daily dosage can be administered 1 to 2 times, so that the amount of isomaltulose is not more than 1000 mg per dose.
  • the present invention is also particularly directed to a method of non-therapeutic vaginal daily care, or daily maintenance, or daily moisturization, or daily lubrication, or daily cleaning to increase the comfort or freshness of the vaginal vulva, including to women in need thereof.
  • An effective amount of the vaginal composition of the present invention is administered intravaginally, so that the daily dosage of isomaltulose is 5 to 2000 mg, preferably 150 to 1200 mg, and the daily dosage can be administered 1 to 2 times to make the isomalt
  • the amount of ketose used does not exceed 1000 mg per dose.
  • the method of the present invention can increase or maintain the cleansing, comfort, or freshness of the vaginal vulva.
  • the invention particularly relates to a non-therapeutic cleansing, or health care, or maintenance, or moisturization, or lubrication of the vagina after menstruation, or after the same room, or after menopause, or after vaginal washing, or after vaginal administration.
  • a method for enhancing the self-purification of the vagina or enhancing the resistance of the vagina to a pathogenic bacteria wherein the method comprises intravaginally administering to a woman in need thereof an effective amount of the vaginal composition of the present invention to make isomaltulose.
  • the daily dosage is 5 to 2000 mg, preferably 150 to 1200 mg, and the daily dosage can be administered in 1 or 2 times so that the amount of isomaltulose is not more than 1000 mg per dose.
  • This hair The method of Ming can enhance the self-purification of the vagina, or enhance the resistance of the vagina to pathogenic bacteria, and maintain the cleanliness, sanitation, and health of the vagina.
  • the invention particularly relates to a method of enhancing vaginal acidity, or maintaining vaginal acidity in the range of 3.5 to 4.5, comprising administering to a woman in need thereof an effective amount of a composition of the invention to render isomaltulose.
  • the daily dosage is 5 to 2000 mg, preferably 150 to 1200 mg, and the daily dosage can be divided into 1 or 2 times, so that the amount of isomaltulose is not more than 1000 mg per dose.
  • the method of the invention enhances the acidity of the vagina or maintains the vaginal acidity in the range of 3.5 to 4.5, particularly 3.8 to 4.3.
  • the invention also relates in particular to a method for promoting the growth of protective lactobacilli in the vagina, in particular to promote protective growth of Lactobacillus crispi, or Lactobacillus marxianus, or Lactobacillus gasseri, including to a woman's vagina in need thereof
  • An effective amount of the composition of the present invention is administered, and the daily dosage of isomaltulose is 5 to 2000 mg, preferably 150 to 1200 mg, and the daily dosage can be administered 1 to 2 times to make isomaltulose. Do not exceed 1000 mg per dose.
  • the method of the present invention can significantly promote the growth of Lactobacillus in the vagina, particularly the growth of protective Lactobacillus crispii, or Lactobacillus marxianus, or Lactobacillus gasseri.
  • the invention also particularly relates to a method for eliminating or reducing vaginal discharge odor, or eliminating or reducing vaginal genital itching, or eliminating or reducing vaginal genital dryness, or eliminating or reducing vaginal vulvar pain, sexual pain, etc., or improving leucorrhea traits, etc.
  • the method comprises vaginally administering to a woman in need thereof an effective amount of the composition of the present invention such that the daily dosage of isomaltulose is 5 to 2000 mg, preferably 150 to 1200 mg, and the daily dosage is 1 ⁇ 2 times of administration, so that the amount of isomaltulose is not more than 1000 mg per dose.
  • the method of the invention can significantly improve the leucorrhea trait, eliminate or reduce the odor of the leucorrhea, and eliminate or reduce the discomfort of vaginal itching, dryness, pain and the like.
  • the invention also relates in particular to a method for regulating vaginal flora, or recovering a beneficial vaginal flora after antibacterial treatment, or preventing or treating vaginal flora disorders, or preventing or treating bacterial vaginosis, including the vagina of a woman in need thereof
  • An effective amount of the composition of the present invention is administered so that the daily dosage of isomaltulose is 5 to 2000 mg, preferably 150 to 1200 mg, and the daily dosage can be divided into 1 or 2 times to give isomaltone.
  • the amount of sugar should not exceed 1000 mg per dose.
  • the invention may also be used to modulate vaginal flora, or to prevent or treat vaginal flora disorders, or to restore vaginal beneficial flora after antibacterial therapy, or to prevent or treat bacterial vaginosis.
  • composition was prepared as follows: 9.0 g of isomaltulose, 0.05 g of sodium benzoate, 0.02 g of sodium dehydroacetate, 0.5 g of sodium propionate, 2.7 g of xanthan gum, and added to 100 ml of distilled water, stirred and mixed. , so that isomaltulose, sodium benzoate, sodium dehydroacetate and sodium propionate are dissolved, xanthan gum is swollen into a uniform viscous colloid; pH is adjusted to 5.0; 112.6 ° C, sterilization for 20 minutes, the water solubility of the invention is obtained Colloidal composition. Sterile, sealed and dispensed in a single dose, 5 grams each.
  • Example 2 The raw materials were weighed according to the following ratio, and the composition was prepared in the same manner as in Example 1 : 4.5 g of isomaltulose, 0.02 g of sodium dehydroacetate, 0.5 g of sodium propionate, 2.5 mg of natamycin, and xanthan. 2.6 g of glue, 100 ml of distilled water, pH 5.0, sterilized, single-dose sterile sealed package, 5.0 g each.
  • Example 2 The raw materials were weighed according to the following ratio, and the composition was prepared in the same manner as in Example 1 : 12.0 g of isomaltulose, 0.15 g of sodium benzoate, 0.01 g of sodium dehydroacetate, 0.5 g of sodium propionate, and xanthan gum 2.5. Gram, distilled water 100 ml, pH 4.8.
  • Example 2 The raw materials were weighed according to the following ratio, and a composition was prepared in the same manner as in Example 1 : 20.0 g of isomaltulose, 0.2 g of sodium benzoate, 3.0 g of xanthan gum, 100 ml of distilled water, pH 5.0.
  • Example 2 The raw materials were weighed according to the following ratio, and the composition was prepared in the same manner as in Example 1 : 0.1 g of isomaltulose, 0.2 g of sodium benzoate, 0.1 g of lauric acid, 2.5 g of xanthan gum, 100 ml of distilled water, pH 6. 5.
  • Example 2 The raw materials were weighed according to the following ratio, and the composition was prepared in the same manner as in Example 1 : 8 g of isomaltulose, 0.1 g of sodium alginate, 1.0 g of lactoferrin, 5 g of aloe extract, and xanthan gum 2.5. Gram, distilled water 100 ml, pH 6.5.
  • Example 2 The raw materials were weighed according to the following ratio, and the composition was prepared in the same manner as in Example 1 : 1.5 g of isomaltulose, 0.375 g of sodium propionate, 0.15 g of sodium octanoate, 0.25 g of lactoferrin, 2.5 g of xanthan gum. , distilled water 100 ml, pH 6.5.
  • Example 2 The raw materials were weighed according to the following ratio, and the composition was prepared in the same manner as in Example 1 : 9.0 g of isomaltulose, 0.45 g of sodium propionate, 0.05 g of sodium benzoate, 0.025 g of sodium dehydroacetate, and estriol 0.1. Gram, 3.0 g of xanthan gum, 87.375 g of water, pH 5.0.
  • Example 2 The raw materials were weighed according to the following ratio, and the composition was prepared in the same manner as in Example 1 : 10 g of isomaltulose, 0.15 g of sodium benzoate, 2 mg of natamycin, 3.0 g of xanthan gum, and 100 ml of distilled water. pH 5.0.
  • Example 2 The raw materials were weighed according to the following ratio, and a composition was prepared in substantially the same manner as in Example 1 : 5.0 g of isomaltulose, 0.2 g of sodium benzoate, 2.5 g of xanthan gum, 100 ml of distilled water, pH 5.5.
  • Example 2 The raw materials were weighed according to the following ratio, and a composition was prepared in the same manner as in Example 1 : 2.0 g of isomaltulose, 0.7 g of sodium propionate, 2.5 g of xanthan gum, 94.8 g of distilled water, and pH 6.5.
  • Example 2 The raw materials were weighed according to the following ratio, and the composition was prepared in the same manner as in Example 1 : 6.0 g of isomaltulose, 0.5 g of sodium propionate, 0.02 g of sodium dehydroacetate, 0.05 g of sodium octanoate, lactoferrin 0.5 Gram, natamycin 10 mg, total isoflavone soy 0.02 g, xanthan gum 2.5 g, distilled water 100 ml, pH 6.5.
  • Example 2 The raw materials were weighed according to the following ratio, and a composition was prepared in substantially the same manner as in Example 1 : 1.5 g of isomaltulose, 0.025 g of sodium dehydroacetate, 3.0 g of xanthan gum, 100 ml of distilled water, and pH 6.5.
  • Example 2 The raw materials were weighed according to the following ratio, and the composition was prepared in the same manner as in Example 1 : 8.5 g of isomaltulose, 0.02 g of sodium dehydroacetate, 0.1 g of sodium octanoate, 0.5 g of lactoferrin, and 2.8 of xanthan gum. Gram, distilled water 100 ml, pH 6.5.
  • Example 2 The raw materials were weighed according to the following ratio, and a composition was prepared in substantially the same manner as in Example 1 : 8.0 g of isomaltulose, 0.5 g of sodium propionate, 2.8 g of xanthan gum, 100 ml of distilled water, pH 6.2.
  • Example 2 The raw materials were weighed according to the following ratio, and the composition was prepared in the same manner as in Example 1 : 8.0 g of isomaltulose, 0.5 g of sodium propionate, 0.02 g of sodium dehydroacetate, 0.5 g of lactoferrin, xanthan gum 2.8 g, distilled water 100 ml, pH 6.2.
  • Example 2 The raw materials were weighed according to the following ratio, and the composition was prepared in the same manner as in Example 1 : 9.0 g of isomaltulose, 0.2 g of sodium benzoate, 0.2 g of fluconazole, 3.0 g of xanthan gum, 100 ml of distilled water, pH. 6.5.
  • Example 2 The raw materials were weighed according to the following ratio, and the composition was prepared in the same manner as in Example 1 : 1.5 g of isomaltulose, 0.5 g of sodium propionate, 0.025 g of sodium dehydroacetate, 2.5 g of xanthan gum, and 100 ml of distilled water. , pH 5.4.
  • the raw materials were weighed according to the following ratio: 20.0 g of isomaltulose, 0.5 g of sodium propionate, 0.05 g of sodium benzoate, 0.02 g of sodium dehydroacetate, 0.005 g of metronidazole, 2.5 g of xanthan gum, and 100 ml of distilled water.
  • the raw materials were weighed according to the following ratio: 35 g of isomaltulose, 63 g of isomaltose, 0.5 g of sodium benzoate, 0.01 g of metronidazole, 0.01 g of clotrimazole, 1.48 g of magnesium stearate, uniformly mixed, and compressed.
  • Each tablet contains 0.5 g; each tablet contains 175 mg of isomaltulose, 315 mg of isomaltose, 2.5 mg of sodium benzoate, 0.05 mg of metronidazole, 0.05 mg of clotrimazole, and 7.4 mg of magnesium stearate.
  • Example 2 The raw materials were weighed according to the following ratio, and a composition was prepared in substantially the same manner as in Example 1 : 10 g of isomaltulose, 0.05 g of benzoic acid, 2.0 g of polycarbophil, 100 ml of distilled water, pH 4.0.
  • Example 2 The raw materials were weighed according to the following ratio, and the composition was prepared in the same manner as in Example 1 : 0.15 g of benzoic acid, 3.0 g of isomaltulose, 9.0 g of isomaltose, 0.15 g of fluconazole, 2.5 g of xanthan gum, 100 grams of distilled water, pH 5.4.
  • the aqueous solution composition was prepared according to the following ratio and method: 12 g of isomaltulose and 0.2 g of sodium benzoate were weighed, added to 100 ml of distilled water, stirred, dissolved, adjusted to pH 5.0, and sterilized to obtain an aqueous solution composition.
  • the aqueous solution composition was prepared according to the following ratio and method: 12 g of isomaltulose, 0.5 g of sodium propionate, 0.02 g of sodium dehydroacetate, 0.1 g of sodium octanoate, and added to 100 ml of distilled water, stirred, dissolved, and adjusted. pH 5.0, sterilized.
  • Isomaltulose group 1% (w/v) isomaltulose, sugar-free MRS basic medium, 5% (w/v) calf serum, 0.5% (w/v) xanthan gum, pH 5 .4;
  • Isomalt group containing 1% (w / v) isomaltose, sugar-free MRS basic medium, 5% (w / v) calf serum, 0.5% (w / v) xanthan gum, pH 5.4;
  • sucrose group containing 1% (w / v) sucrose, sugar-free MRS basic medium, 5% (w / v) calf serum, 0.5% (w / v) xanthan gum, pH 5.4;
  • maltose group containing 1% (w / v) maltose, sugar-free MRS basic medium, 5% (w / v) calf serum, 0.5% (w / v) xanthan gum, pH 5.4;
  • each group of gels was carried out in the same manner as in the method of Composition Example 1. After completion, the cells were sterilized, calf serum was added, and 5 g of each tube was dispensed and used.
  • BV secretion specimens vaginal secretions of 5 patients with BV, the inclusion criteria are:
  • BV secretion samples were cultured in 4 kinds of sugar-containing gels.
  • the pH of each experimental tube decreased from the initial 5.4 to 3.8-5.1, respectively, of which isomaltulose gel The pH value is the lowest, the pH of the sucrose gel is the highest, and the pH of the isomaltose gel and the maltose gel is middle.
  • the pH values of the four sugar-containing gels all fell below 4.6, and the pH of the isomaltulose gel was the lowest, and the pH of the sucrose gel was the highest.
  • the pH values of the four sugar-containing gels were the same, both ⁇ 3.8.
  • the sugar-containing gel of this example was inoculated with BV secretion samples and micro-aerobic culture for 14 hours, and the pH of the 4/5 isomaltulose gel was lowered to 4.1 or less, 4/5 isomaltose gel and 4/5 maltose. The pH of the gel dropped below 4.4, while the pH of the 4/5 sucrose gel was still 4.4 or above.
  • the results show that the BV flora metabolizes isomaltulose to produce acid, which is faster than its metabolism of isomaltose and maltose to produce acid, especially faster than its metabolism of sucrose to produce acid.
  • the normal pH of the vagina is generally considered to be in the range of 3.5 to 4.5, and the pH of the vaginal secretions of patients with BV is higher than 4.6.
  • Various bacterial growth has its most suitable pH range.
  • the pH value is 5.4, the growth and acidogenic metabolism of neutrophils are inhibited, while bacteria such as acid-resistant Lactobacilli and Bifidobacteria can still grow and produce acid. Therefore, the pH of the Lactobacillus selective medium is generally 5.4. Lactic acid is also thought to play a major role in maintaining normal vaginal flora, resisting BV flora and other pathogens [12] .
  • the initial pH value of the sugar-containing gel of this example is 5.4. Under such pH conditions, the BV flora, mainly the lactic acid bacteria therein, metabolizes carbohydrates to produce acid. The faster the gel pH drops, the faster the inhibition of BV harmful bacteria, and the faster the regulation of BV flora.
  • isomaltulose is more susceptible to acid production by BV bacteria under microaerobic conditions, so it is superior to isomaltose and maltose, especially significantly better than sucrose, so isomaltulose is more suitable.
  • vaginal composition of the present invention For preparing the vaginal composition of the present invention.
  • 1 glucose group containing 1.5% (w / v) glucose, sugar-free MRS basal medium, 5% (w / v) calf serum, 0.45% (w / v) agar, pH 5.4;
  • fructose group containing 1.5% (w / v) fructose, sugar-free MRS basal medium, 5% (w / v) calf serum, 0.45% (w / v) agar, pH 5.4;
  • 3 mannose group containing 1.5% (w / v) mannose, sugar-free MRS basic medium, 5% (w / v) calf serum, 0.45% (w / v) agar, pH 5.4;
  • sucrose group containing 1.5% (w / v) sucrose, sugar-free MRS basal medium, 5% (w / v) calf serum, 0.45% (w / v) agar, pH 5.4;
  • maltose group containing 1.5% (w / v) maltose, sugar-free MRS basic medium, 5% (w / v) calf serum, 0.45% (w / v) agar, pH 5.4;
  • Isomalt group 1.5% (w/v) isomaltose, sugar-free MRS basic medium, 5% (w/v) calf serum, 0.45% (w/v) agar, pH 5.4;
  • Isomaltulose group 1.5% (w/v) isomaltulose, sugar-free MRS basic medium, 5% (w/v) calf serum, 0.45% (w/v) agar, pH 5.4 ;
  • each group of semi-solid agar was carried out according to the method of Composition Example 1. After completion, it was sterilized, calf serum was added, and 5 g of each tube was dispensed and used.
  • BV secretion specimens vaginal secretions of 5 patients with BV, the inclusion criteria are:
  • the seven semi-solid agars of this example were inoculated with 5 samples of BV secretions and anaerobic culture for 24 hours.
  • the pH value of each culture tube decreased, and the decrease range reflected the metabolism of various sugars and acid by BV bacteria under anaerobic conditions. s efficiency.
  • the pH of the disaccharide semi-solid agar decreased by more than the pH of the monosaccharide semi-solid agar.
  • the pH of the isomaltulose and maltose semi-solid agar decreased by more than the pH of the sucrose or isomaltose semi-solid agar.
  • the BV flora metabolizes disaccharides, especially metabolized isomaltulose and maltose to produce acid, which is faster than its metabolism of sucrose and isomaltose to produce acid, which is faster than the metabolism of monosaccharides to produce acid.
  • the normal pH of the vagina is generally considered to be in the range of 3.5 to 4.5, and the pH of the vaginal secretions of patients with BV is higher than 4.6.
  • Various bacterial growth has its most suitable pH range.
  • the pH value is 5.4, the growth and acidogenic metabolism of neutrophils are inhibited, while bacteria such as acid-resistant Lactobacilli and Bifidobacteria can still grow and produce acid. Therefore, the pH of the Lactobacillus selective medium is generally 5.4. Lactic acid is also thought to play a major role in maintaining normal vaginal flora, resisting BV flora and other pathogens [12] .
  • the initial pH of the sugar-containing gel of this example was 5.4.
  • the BV flora mainly the lactic acid bacteria therein, metabolized the carbohydrate to produce acid.
  • sucrose preservative group containing 1.5% (w / v) sucrose, 0.5% (w / v) sodium propionate, 0.025% (w / v) sodium dehydroacetate, sugar-free MRS basic medium, 5% (w /v) calf serum, 0.45% (w/v) agar, pH 5.4;
  • Isomalt preservative group 1.5% (w/v) isomaltose, 0.5% (w/v) sodium propionate, 0.025% (w/v) sodium dehydroacetate, sugar-free MRS basic medium, 5% (w/v) calf serum, 0.45% (w/v) agar, pH 5.4;
  • 3 isomaltulose preservative group containing 1.5% (w / v) isomaltulose, 0.5% (w / v) sodium propionate, 0.025% (w / v) sodium dehydroacetate, sugar-free MRS basic culture Liquid, 5% (w/v) calf serum, 0.45% (w/v) agar, pH 5.4;
  • sucrose control group containing 1.5% (w / v) sucrose, sugar-free MRS basal medium, 5% (w / v) calf serum, 0.45% (w / v) agar, pH 5.4;
  • Isomalt control group 1.5% (w / v) isomaltose, sugar-free MRS basic medium, 5% (w / v) calf serum, 0.45% (w / v) agar, pH 5.4;
  • Isomaltulose control group 1.5% (w / v) isomaltulose, sugar-free MRS basic medium, 5% (w / v) calf serum, 0.45% (w / v) agar, pH 5. 4
  • each group of semi-solid agar was carried out according to the method of Composition Example 1. After completion, it was sterilized, calf serum was added, and 5 g of each tube was dispensed and used.
  • BV secretion specimens vaginal secretions of 2 patients with BV, the inclusion criteria are:
  • BV specimens were inoculated with three sugar-containing semi-solid agars containing the same preservative for 30 to 48 hours.
  • the pH of the isomaltulose agar matrix was the lowest, dropping to 3.8, 3.8 to 4.1 in 40 to 48 hours, significantly lower than that of sucrose.
  • the three control groups contained 3 sugars, respectively, and contained no preservatives.
  • the pH of the agar matrix drops rapidly.
  • the pH of 5/6 is reduced to 3.8 at 30-32 hours, and the pH of 1/6 drops to 3.8-4.1, which is significantly lower than
  • the preservative-containing agar matrix showed that the preservative had a significant effect on the acid production of vaginal bacteria.
  • the effect of vaginal bacteria on the production of sucrose and isomaltose was the most prominent.
  • the acid production decreased and the pH of the matrix decreased slowly to 40 to 48 hours.
  • the 3/4 agar matrix pH was still 4.4 or above and 1/4 was 4.1. Isomaltulose is also affected by preservatives, but to a lesser extent.
  • the pH of the agar matrix can be reduced to 3.8 or 3.8 to 4.1 at 40 to 48 hours, while avoiding excessive acid production and pH drop. Too low.
  • the results of this example show that isomaltulose is significantly superior to sucrose and isomaltose, and is more suitable for use in combination with a preservative for the preparation of a vaginal composition containing a preservative and/or antibacterial agent of the present invention.
  • Isomaltulose group 1% (w/v) isomaltulose, sugar-free MRS basic medium, 5% (w/v) calf serum, 0.5% (w/v) xanthan gum, pH 5 .4;
  • Isomalt group containing 1% (w / v) isomaltose, sugar-free MRS basic medium, 5% (w / v) calf serum, 0.5% (w / v) xanthan gum, pH 5.4;
  • sucrose group containing 1% (w / v) sucrose, sugar-free MRS basic medium, 5% (w / v) calf serum, 0.5% (w / v) xanthan gum, pH 5.4;
  • maltose group containing 1% (w / v) maltose, sugar-free MRS basic medium, 5% (w / v) calf serum, 0.5% (w / v) xanthan gum, pH 5.4;
  • each group of gels was carried out in the same manner as in the method of Composition Example 1. After completion, the cells were sterilized, calf serum was added, and 5 g of each tube was dispensed and used.
  • BV secretion samples vaginal secretions of 20 patients with BV, the inclusion criteria are:
  • BV vaginal secretions were cultured with four kinds of sugar-containing gels respectively, and isomaltulose gel, isomaltose gel, and sucrose gel were all cultured from 9 BV secretions.
  • Maltose gel Lactobacillus was cultured from 8 BV secretions, and no Lactobacillus inertia was cultured.
  • Nine cases of BV were cultured, including 4 cases of Lactobacillus japonicus, 2 cases of Lactobacillus berghei, 1 case of Lactobacillus crispus, Lactobacillus brevis and Lactobacillus aeruginosa.
  • the number “4” refers to the total number of positive samples of Lactobacillus cinnafa culture, and Tables 2 and 3 are the same;
  • BV vaginal secretions were cultured with four kinds of sugar-containing gels respectively, and only two maltose gels were cultured from one BV secretion, and the other three gels were not cultured.
  • Bifidobacterium breve, Bifidobacterium longum and Bifidobacterium longum showed that the three sugar-containing gels of isomaltulose, isomaltose and sucrose had weak growth promoting effects on Bifidobacteria in the BV flora.
  • BV vaginal secretions were cultured with 4 kinds of sugar-containing gels respectively, in which maltose gel was cultured from 6 cases of BV secretions, Gardnerella vaginalis, sucrose gel from 3 cases of BV secretions The Gardnerella vaginalis, isomaltulose gel and isomaltose gel were cultured from 2 cases of BV secretion to form Gardnerella vaginalis, indicating that the maltose gel is beneficial to the growth of Gardnerella vaginalis.
  • BV flora is complex, with Gardnerella vaginalis, Prevo, Megacocci, C. mobilis, Streptococcus mutans, Micromonas, Anaerobacter, Cilia The dominant bacteria, the copy number of the 16S rRNA gene sequence of Gardnerella vaginalis accounted for 29.1% of the number of copies of the 16S rRNA gene sequence of the vaginal flora of BV patients, ranking first and second.
  • the Prevotella is more than twice as large as 13.2% and is three times as large as the third Megasphaera (9.8%).
  • Gardnerella vaginalis In intermediate BV, the number of copies of the 16S rRNA gene sequence of Gardnerella vaginalis accounted for 30.5% of the number of copies of the 16S rRNA gene sequence of the vaginal flora of intermediate BV patients, ranking second after the inert Lactobacillus. It can be seen that Gardnerella vaginalis is one of the most representative dominant bacteria of vaginal flora in BV patients.
  • Lactobacillus in the BV flora decreased, and the number of copies of the 16S rRNA gene sequence of L. iners was ranked sixth in the number of copies of the 16S rRNA gene sequence of the BV total bacterial population, and the Lactobacillus crispus only It is 0.3%, while Lactobacillus johnsonii and Lactobacillus licheniformis are less, and together with other types of Lactobacillus, the total is 0.2%.
  • the number of copies of the 16S rRNA gene sequence of Lactobacillus inertia accounted for the number of copies of the 16S rRNA gene sequence of the total vaginal flora. 43.9%, ranking first, Lactobacillus crispus accounted for 1.2%, and the total number of Lactobacillus johnsonii, Lactobacillus licheniformis and other lactobacilli was 6.1%.
  • Lactobacillus inertia The most abundant Lactobacillus in the BV flora was not cultivated. It is suggested that the four gels containing isomaltulose, isomaltose, sucrose and maltose are selective for Lactobacillus in BV secretion, and promote the growth of Lactobacillus johnsonii, Lactobacillus bulgaricus, Lactobacillus crispi, etc. The promotion of Lactobacillus inertia is weak.
  • the vaginal Gardnerella is the most common in the BV flora.
  • maltose gel was cultured from 6 cases of BV secretions of Gardnerella vaginalis
  • sucrose gel was cultured from 3 cases of BV secretions of Gardnerella vaginalis
  • isomaltulose gel isomaltose gel
  • the Gardnerella vaginalis was cultured from 2 cases of BV secretion, suggesting that the maltose gel is more suitable for the growth of Gardnerella vaginalis, while the isomaltulose gel and the isomaltose gel are relatively unsuitable for the growth of Gardnerella vaginalis.
  • the Bifidobacteria in the BV flora are mostly Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium bifidum and Bifidobacterium longum.
  • Bifidobacterium bifidum Bifidobacterium breve
  • Bifidobacterium bifidum Bifidobacterium longum.
  • maltose gel cultured Bifidobacterium bifidum from a BV secretion and the isomaltulose gel, the isomaltose gel, and the sucrose gel did not culture Bifidobacteria, suggesting that the malt is different.
  • Ketosaccharide, isomaltose, and sucrose have no significant growth promoting effect on Bifidobacteria in BV secretions.
  • Isomaltulose gel, isomaltose gel, and sucrose gel have no significant growth promoting effect on Bifidobacteria in BV secretion.
  • Maltose gel may promote the growth of Gardnerella vaginalis in BV vaginal secretions, while isomaltulose gel and isomaltose gel have no obvious effect on the growth of Gardnerella vaginalis.
  • Isomaltulose group 1.5% (w/v) isomaltulose, sugar-free MRS basic medium, 5% (w/v) calf serum, pH 7.0;
  • Isomaltose group 1.5% (w/v) isomaltose, sugar-free MRS basic medium, 5% (w/v) calf serum, pH 7.0;
  • Sucrose group 1.5% (w/v) sucrose, sugar-free MRS basal medium, 5% (w/v) calf serum, pH 7.0;
  • Maltose group 1.5% (w/v) maltose, sugar-free MRS basic medium, 5% (w/v) calf serum, pH 7.0;
  • Candida albicans was cultured with isomaltulose broth, isomaltose broth, sucrose broth, and maltose broth at a concentration of 1.5% (w/v) for 72 hours. The concentration decreased to varying degrees, followed by maltose, isomaltulose, isomaltose, and sucrose. The maltose concentration was reduced from 1.5% (w/v) to less than 0.05% (w/v).
  • the detection limit is 0.05% (w/v).
  • Candida albicans more than 85% of the pathogens of Candida vaginal vulvitis are Candida albicans.
  • Two strains of Candida albicans were cultured in four sugar-containing medium for 72 hours.
  • the residual concentration of maltose was less than 0.05% (w/v), and the residual concentration of isomaltulose was 0.11%.
  • w/v one strain was 0.12% (w/v)
  • the residual concentration of isomaltose was 0.74% (w/v)
  • the other strain was 0.76% (w/v).
  • the residual concentration of sucrose was the highest.
  • One strain was 1.04% (w/v) and one strain was 0.95% (w/v).
  • sucrose, isomaltose, isomaltulose, which is superior to maltose is more suitable for the preparation of the vaginal composition of the present invention.
  • Isomaltulose agar 1.5% (w/v) isomaltulose, 0.05% (w/v) sodium benzoate, 0.5% (w/v) sodium propionate, 0.025% (w/v) Sodium hydroacetate, sugar-free MRS basal medium, 5% (w/v) calf serum, 0.45% (w/v) agar, pH 5.4.
  • BV secretion specimen vaginal secretion of 1 patient with BV, the inclusion criteria are:
  • vaginal secretion specimens meeting the inclusion criteria.
  • the vaginal swabs were sampled at the bedside and eluted in the sugar-free MRS basal medium. Immediately inoculated with isomaltulose agar, anaerobic culture for 40 hours at 37 ° C, agar was taken. Substrate and secretion sample solution, sent to Sangon Biotech (Shanghai) Co., Ltd., Shanghai for 16s rDNA macrogene analysis, and qPCR for detection of Lactobacillus, Lactobacillus crispus, Lactobacillus inertarum, Lactobacillus japonicus, format Lactobacillus, Gardnerella vaginalis, and Prevoella.
  • the following culture medium [containing 0.5% (w/v) isomaltulose, sugar-free MRS medium, 5% (w/v) calf serum] was prepared with the following culture solutions containing different concentrations of preservatives:
  • the pH of each group was adjusted to 5.4, and the tubes were sterilized and packed into 2 ml tubes.
  • test tube was inoculated with (1 ⁇ 5) ⁇ 10 5 cfu/ml suspension of Candida glabrata isolates, (1 ⁇ 5) ⁇ 10 5 cfu/ml Jane's milk Bacillus isolate strain suspension.
  • Candida glabrata was cultured at 37 ° C for 72 hours in aerobic culture, and slightly aerobically cultured for 22 hours.
  • Sodium dehydroacetate and sodium propionate have a synergistic inhibitory effect on Candida glabrata, and 0.02% (w/v) sodium dehydroacetate combined with 0.5% (w/v) sodium propionate can completely inhibit smooth leave in 72 hours.
  • S. cerevisiae grows with no change in turbidity.
  • the inhibition of L. jensei was relatively weak, and its turbidity increased at 22 hours.
  • vaginal bacteria Two female rhesus monkeys were screened, and their vaginal secretions were 5.1 and 4.8, respectively.
  • the vaginal bacteria were mainly negative bacilli and positive cocci, and there were no large positive bacilli and few white blood cells.
  • the isomaltulose gel of the composition of Example 1 was administered 0.5 g once a day for 5 consecutive days, and the vaginal pH was 3.8 and 4.1, respectively, and the vaginal bacteria were mainly crude positive bacteria.
  • vaginal swabs Female, 28 years old, healthy, no discomfort. Regular menstrual cycle, vaginal swabs were taken three days after menstruation clean, pH value was measured 4.8, smear Gram stain microscopy, see more crude positive bacilli, multiple positive cocci, and a few negative bacilli, white blood cells are rare. Volunteer composition of the composition of Example 2 for vaginal cleansing care, 3 grams each time, for two consecutive days, then take a vaginal swab, measure pH 4.1, smear Gram stain microscopic examination, check more coarse and positive Bacillus, positive cocci, and negative bacilli were reduced. Consciously the genitals are cleaner, more comfortable and refreshing.
  • vaginal swab measure the pH value of 5.1, smear Gram stain microscopy, less bacteria, mostly positive cocci, occasionally positive bacilli, white blood cells are rare. Volunteer composition of the composition of Example 13 for vaginal cleansing care, 5 grams each time, for 5 consecutive days, then take a vaginal swab, measuring pH 4.1, smear staining microscopy, large positive bacilli, other types Less bacteria, conscious genital comfort, no dryness or stinging.
  • vaginal swab measure the pH value of 5.4, smear Gram stain microscopic examination, bacteria are rare, no white blood cells are found.
  • Volunteer composition of the composition of Example 6 for vaginal cleansing care once a day, 5 grams each time, for 3 consecutive days, then take a vaginal swab, measuring pH 3.8, smear Gram stain microscopic examination, see More large positive bacilli. Consciously comfortable and comfortable.
  • vaginal flora imbalance was suspected, but there was no obvious discomfort.
  • vaginal swab measure the pH value of 4.6, smear staining microscopy, less large positive bacilli, more positive cocci, visible staining of small bacilli, Nugent score of 5 points, less white blood cells, in line with intermediate BV performance.
  • Volunteer composition of the composition of Example 17 for vaginal cleansing care once a day, 5 grams each time, for 5 consecutive days, review, vaginal secretions pH 3.8, vaginal bacteria dominated by crude positive bacteria, positive cocci, negative The small bacilli were significantly reduced. Consciously the leucorrhea is clean and refreshing.

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Abstract

一种异麦芽酮糖在制备阴道用组合物中的用途，其中异麦芽酮糖的用量为0.05-20%（w/w）。一种用于阴道的组合物，其中含有0.05-20%（w/w）的异麦芽酮糖，所述组合物可为健康产品、保健品、清洁品、护理品、除异味剂、化妆品、消毒剂组合物、或药物组合物；一种通过向女性阴道给予所述组合物的非治疗性阴道保健护理的方法，和一种非治疗性阴道清洁卫生的方法，和一种增强阴道酸度的方法，和一种促进阴道内乳杆菌生长的方法，以及一种预防和治疗阴道菌群失调、特别是细菌性阴道疾病的方法。

Description

一种阴道用组合物与该组合物的用途 技术领域
本发明涉及异麦芽酮糖在制备阴道用组合物中的用途；本发明还涉及一种用于阴道的组合物，所述组合物可为健康产品、保健品、清洁品、护理品、除异味剂、化妆品、消毒剂组合物、或药物组合物；本发明还特别涉及一种非治疗性阴道保健护理的方法，和一种非治疗性阴道清洁卫生的方法，和一种增强阴道酸度的方法，和一种促进阴道内保护性乳杆菌生长的方法，以及一种预防和治疗阴道菌群失调、特别是细菌性阴道病的方法。
背景技术
女性阴道是一个开放系统，易受各种微生物和病原体的侵袭。健康状态下，阴道黏膜表面栖居着有益的乳杆菌。乳杆菌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3.5～4.5的范围，从而使阴道具有自净作用，是阴道抗感染力的重要组成部分。阴道的酸度一旦减弱，就会影响到阴道、乃至整个生殖道的卫生和健康，给女性生活带来危害。
阴道内的乳杆菌种类较多，可检测到近二十来种[1]，在2000年以前认为主要是嗜酸性乳杆菌。2000年以后随着分子鉴定技术的成熟和广泛运用，对阴道内乳杆菌种类的研究取得了突破性进展。2004年Zhou、2010年Linhares、以及2012年Rampersaud R等报告[2][3][4]阴道内的乳杆菌常以卷曲乳杆菌(L.crispatus)为优势乳杆菌，或以惰性乳杆菌(L.iners)、格氏乳杆菌(L.gasseri)为优势乳杆菌，或以詹氏乳杆菌(L.jensenii)为优势乳杆菌，还可能以沙门氏乳杆菌(L.gallinarum)与阴道乳杆菌(L.vaginalis)为优势乳杆菌。他们还报告乳杆菌不是所有“健康”女性阴道内的优势菌，一些女性以小阿托波氏菌(Atopobium)为优势菌，该菌也可产乳酸，可维持阴道的弱酸性环境。
除了乳杆菌外，健康女性阴道内还栖居着很多其它种类的细菌。2005年Fredricks等报告[5]自健康女性阴道内检测出以下细菌：大肠杆菌(Escherichia coli)，消化链球菌(Peptostreptococcus)，微单胞菌属(Finegoldia)，普雷沃 氏菌(Prevotella)，厌氧球菌属(Anaerococcus)，布氏乳杆菌(Lactobacillus reuteri)，链球菌(Streptococcus)，亚利氏菌(Allisonella)，毛螺旋菌(Lachnospiraceae)，假丁酸弧菌属(Moryella)，气球菌(Aerococcus)，加德纳菌属(Gardnerella)，动弯杆菌(Mobiluncus)，纤毛菌属(Sneathia)，消化链球菌(Peptoniphilus)，等等。
尤其当阴道酸度减弱时，有益的乳杆菌减少，种类复杂的厌氧菌以及需氧/兼性需氧的葡萄球菌、大肠杆菌等生长增多，可引起一系列不良后果，危害女性健康和生活质量，严重时可导致疾病如细菌性阴道病(Bacterial vaginosis，BV)。
月经、性交、阴道冲洗等对阴道酸度有较大影响。如月经后第一周时阴道酸度减弱，阴道pH值远高于4.5达6.6[6]，以及精液减弱阴道酸度[7]等等，因而月经后、同房后阴道的冲洗，成为女性个人卫生、审美、和高品质生活质量的需要，以及预防感染的需要，美国女性约30％经常做阴道冲洗。然而不恰当的冲洗破坏阴道酸度和菌群，反而增加感染机会[8]。
如BV病人的阴道酸度减弱，阴道pH值升高至4.5以上，阴道中的乳杆菌减少，各种厌氧菌等杂菌大量生长。2005年Fredricks等报告[5]利用16S-rDNA技术对BV患者的阴道菌群分析后，发现每例患者平均分离出9-17种厌氧菌，其中包括巨型球菌属(Megasphaera)与纤毛菌属(Sneathia)。2009年Livengood[9]等报告，几乎所有的BV患者阴道分泌物中均可分离/检测到阴道加德纳菌(Gardnerella vaginalis)，可在近95％的BV患者阴道分泌物中分离/检测到阿托波菌群(Atopobium vaginae)，可自50％的BV患者阴道分泌物中分离/检测到动弯杆菌属(Mobiluncus spp)。许多其他厌氧菌，如普雷沃菌属、厌氧型的链球菌等等，也是重要的BV菌。
BV的治愈标准包含阴道的酸度恢复正常，亦即阴道的pH值恢复至3.5～4.5。国际上治疗BV首选对厌氧菌作用强的抗菌药物甲硝唑，其次为氯林可霉素等抗菌药物，但两种药物的治愈率仅约60％，复发率则高达30～40％，且治愈率逐渐降低。2007年Livengood CH等报告[10]，按照1998年FDA发布的指南，若同时满足临床治愈与微生物治愈的标准，则替硝唑治疗BV的治愈率仅为37％。按照传统的Amsel临床指标4项中3项正常即为治愈，则治愈率为57％。Thomas KK等更于2005年报告[11]0.75％甲硝唑凝胶对BV的治愈率仅为26％。
鉴于女性阴道的开放性、脆弱性、易感性，以及传统的阴道冲洗、以及抗菌药物、抗菌产品，难以满足女性阴道日常卫生、护理、保健的需要，尤其难以满足月经后、同房后、绝经后、以及阴道感染等特殊生理、病理情况时阴道卫生、护理、保健的需要，因而研究开发有效的阴道用健康产品、保健品、卫生用品、药品等，成为维护女性健康、保障女性高品质生活质量的迫切需求。
发明内容
本发明的目的是提供阴道用组合物，以及使用该组合物非治疗性地对阴道进行日常保健、或日常养护、或日常湿润、或日常润滑、或日常清洁，用于增加阴道外阴的舒适感、或清新感；特别是非治疗性地用于月经后、或同房后、或绝经后、或阴道冲洗后、或阴道用药治疗后、或阴道感染后对阴道进行保健、或养护、或润滑、或湿润、或清洁，用于增强阴道的自净作用、或增强阴道对病原菌的抵抗力；还可用于增强阴道酸度、或维护阴道酸度在3.5～4.5的范围内，或促进阴道内的保护性乳杆菌生长、特别是促进保护性的卷曲乳杆菌(L.crispatus)、或詹氏乳杆菌(L.jensenii)、或格氏乳杆菌(L.gasseri)的生长；还特别用于消除或减轻阴道分泌物异味、或消除或减轻阴道外阴瘙痒、或消除或减轻阴道外阴干涩、或消除或减轻阴道外阴疼痛、性交痛等不适感，或改善白带性状；以及用于调节阴道菌群、或用于抗菌治疗后恢复阴道有益菌群、或用于预防或治疗阴道菌群失调、或用于预防或治疗细菌性阴道病。
研究显示卷曲乳杆菌、詹氏乳杆菌、格氏乳杆菌和惰性乳杆菌这四种最常见乳杆菌在维护阴道菌群的正常生理和稳定方面，具有不同作用。2012年Ma[12]等报告了关于阴道菌群稳定性方面的研究结果，相比以其它三种乳杆菌为优势菌的阴道菌群，以惰性乳杆菌为优势菌的阴道菌群不稳定、易变化。这可能与惰性乳杆菌产H2O2的能力弱有关，Antonio等[13]发现，分离自女性阴道的乳杆菌中，仅9％的惰性乳杆菌菌株能产H2O2，而95％的卷曲乳杆菌菌株、94％的詹氏乳杆菌菌株、和71％的格氏乳杆菌菌株产H2O2。可见，只有当卷曲乳杆菌、或詹氏乳杆菌、或格氏乳杆菌恢复成为了阴道内的优势菌时，才最有利于阴道菌群保持正常和稳定，因而这三种乳杆菌又被称为阴道的“保护性乳杆菌”。
鉴于女性阴道的开放性、脆弱性、易感性，以及传统阴道冲洗、抗菌药物、抗菌产品等难以满足女性对月经后、同房后、绝经后、以及阴道感染等等特 殊生理或病理情况时阴道清洁卫生、养护、保健的需要，为此本发明人进行了大量研究、试验，发现异麦芽酮糖具有很强的增强阴道酸度的作用，且同时对卷曲乳杆菌、詹氏乳杆菌、格氏乳杆菌这三种保护性乳杆菌的生长亦具有较强的促进作用，因而，异麦芽酮糖能显著增强阴道的自净作用和抗感染力，特别适合用于制备阴道用非治疗性的健康产品、或日用品、或保健用品、或化妆品、或卫生用品、或清洁品、或护理品，或用于制备阴道用治疗性的健康产品、或药品、或医疗器械。在此基础上，通过进一步研究完成了本发明。
本发明提供一种异麦芽酮糖在制备阴道用组合物中的用途，其中在所述制备中，异麦芽酮糖的用量为使组合物中含有0.05～20％(w/w)的异麦芽酮糖，优选的用量为使组合物中含有1.5～12％(w/w)的异麦芽酮糖。
根据本发明的制备用途，其中所述组合物还含有总量为0.05～2.5％(w/w)选自下组的防腐剂和/或抗菌剂：苯甲酸、苯甲酸钠、山梨酸、山梨酸钾、山梨酸钠、乙酸、乙酸钠、双乙酸、双乙酸钠、脱氢乙酸、脱氢乙酸钠、丙酸、丙酸钠、丙酸钙、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、乳铁蛋白肽中的一种或其组合。
其中所述防腐剂和/或抗菌剂对病菌、霉菌、及假丝酵母菌等的抑制作用相对较强，而对乳杆菌的抑制作用相对较弱，用于制备本发明的阴道用组合物既可迟滞病菌、霉菌、及假丝酵母菌等的生长，又可避免显著干扰、减弱异麦芽酮糖对乳杆菌生长和产酸的促进作用。
根据本发明的制备用途，其中在所述制备中还使用非活性的辅料/基质成分用于制备组合物。制备工艺、方法和辅料的选择，均为本领域专业技术人员根据本发明的公开内容并结合其专业技能和背景知识可以想见的。
根据本发明的制备用途，其中所述用途为将异麦芽酮糖用于制备包括但不限于下列的阴道用组合物产品或组合物制剂：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，或治疗性的阴道用健康产品、或阴道用医疗器械、或阴道用药品(非处方药或处方药)，或为用于阴道的清洁剂、或养护剂、或除异味剂、或止痒剂、或清新剂、或润湿剂、或润滑剂、或消毒剂、或抗菌剂、或表面杀微生物剂、或微生态调节剂、或微生物调节剂。
根据本发明的制备用途，其中所述用途为将异麦芽酮糖用于制备包括但不限于下列的阴道用组合物的剂型：水溶性胶体剂、水溶液剂、气雾剂、霜剂、软膏剂、胶囊剂、微囊剂、栓剂、泡腾剂、片剂，优选水溶性胶体剂、霜剂。
例如，在制备阴道用水溶性胶体组合物时，可按本领域技术人员已知的方法例如下述工艺流程制备：按定量取异麦芽酮糖，苯甲酸钠、丙酸钠、脱氢乙酸钠、水溶性胶体基质(例如黄原胶)，混匀，定量加蒸馏水，搅拌使糖和防腐剂等溶解，水溶性胶体基质溶胀呈均匀粘性胶体。用可药用的酸和/或碱调组合物pH值至3.5～6.0的范围、特别是4.0～5.5的范围。分装后灭菌，或灭菌后再无菌分装。灭菌可选择如下工艺：辐射灭菌，或采用110～115℃、15～20分钟高温灭菌，或采用间歇灭菌，或将防腐剂、糖组分等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。
如制备阴道片时，可按本领域技术人员已知的方法，将定量的异麦芽酮糖，与苯甲酸钠、丙酸钠、脱氢乙酸钠混合均匀后直接压片，即得片剂；亦可加入辅料成分，如硬脂酸镁等润滑剂或羧甲基淀粉钠等崩解剂，混合均匀，压片。
制备阴道栓剂时，可按本领域技术人员已知的方法例如下述工艺流程制备：定量取异麦芽酮糖，苯甲酸钠、丙酸钠、脱氢乙酸钠、吐温80，混合研匀，加热至50℃左右，另将混合脂肪酸甘油酯(亦称固体脂肪Solid Fat)加热至60℃熔化，然后将糖、防腐剂与吐温80的混合液加入熔化的基质中，边加入、边搅拌，待混匀后，于40℃左右(即凝固前)倾入模具中，稍冷后刮模，冷却，脱模，即得阴道栓。栓剂的基质除了混合脂肪酸甘油酯，亦可选用硬脂酸丙二醇酯、甘油明胶、吐温-61等。大量生产可采用自动化、机械化装置。
根据本发明的制备用途，其中所述制备还可选择性地进一步使用有效量的一种或多种抗菌剂和/或防腐剂用于制备组合物，包括但不限于：过氧化氢、维生素B1、维生素K3、维生素K4、对羟基苯甲酸酯类、防御素、抗菌肽。上述物质可进一步抑制组合物中的细菌、霉菌、假丝酵母菌等，进一步增强组合物的微生物稳定性。
根据本发明的制备用途，其中所述制备还可选择性地使用总含量为0.001～1.0％(w/w)的雌激素类物质和/或植物雌激素(Phytoestrogen)类物质用于制备组合物，其中所述雌激素或植物雌激素包括：己烯雌酚、雌二醇、雌三醇、大豆甙(Daidzin)、大豆甙元(Daidzein)、染料木甙(Genistin)、染料木素(Genistein)、黄豆黄素(Glycitin)、黄豆黄素甙元(Glycitein)、鸡豆黄素(Biochanin A)、香豆雌酚(Coumestto)、芒柄花黄素(Formnonetin)等。雌激素类物质、植物雌激素类物质可促进阴道黏膜血管新生、阴道黏膜上皮角化和阴道上皮损伤愈合，可增强本发明制备的组合物的功效。上述各种雌激素类物质、植物雌激素类物质在本发明制备用途中的选择和使用方法，在本领域专业技术人员的知识范围以内。
根据本发明的制备用途，其中所述制备还可选择性地使用一种或多种选自下组的阴道黏膜细胞保护物质和/或抗氧化物质用于制备组合物，包括但不限于：0.1～5.0％(w/w)芦荟提取物、0.1～5.0(w/w)薰衣草提取物、0.001～1.0％(w/w)维生素E、0.001～1.0％(w/w)维生素A、0.001～1.0％(w/w)维生素D、0.001～1.0％(w/w)维生素C，用于进一步营养、湿润、润滑、保护阴道黏膜上皮细胞。
根据本发明的制备用途，其中所述制备还可选择性地使用有效量的一种或多种选自下组的糖类物质用于制备组合物，包括但不限于：葡萄糖、果糖、甘露糖、蔗糖、麦芽糖、异麦芽糖、乳糖、乳果糖、海藻糖、纤维二糖、蜜二糖、龙胆二糖、松二糖、壳二糖、棉子糖、龙胆糖、潘糖、松三糖、异麦芽三糖、蔗果三糖、异麦芽四糖、蔗果四糖、蔗果五糖、麦芽寡糖、低聚半乳糖、甘露低聚糖、葡聚糖、环糊精、糊精、淀粉和糖原。
根据本发明的制备用途，还可选择性地使用一种或多种对细菌和/或真菌有效的抗菌药物于所述的制备用途，包括但不限于下列物质：氟康唑、曲康唑、布康唑、咪康唑、克霉唑、制霉菌素、甲硝唑、替硝唑、林可霉素、阿莫西林；其中优选所述抑菌剂和/或杀菌剂为甲硝唑、替硝唑、克霉唑、氟康唑。上述各种抑菌剂和/或杀菌剂在本发明制备用途中的选择和使用方法，在本领域普通专业人员的知识范围以内。
根据本发明的制备用途，其中制备水溶性胶体剂时，异麦芽酮糖的含量应为0.1～20.0％(w/v)，优选的总含量为3.0～12.0％(w/v)。
根据本发明的制备用途，其中制备水溶性胶体剂时，还需选用非流动性、粘性、水溶性胶体基质，该基质使糖与阴道粘膜均匀接触并停留较长时间，从而发挥促进乳杆菌生长的作用。该水溶性粘性胶体基质的选择和使用方法，在本领域专业技术人员的知识范围之内，根据本发明的制备用途，该基质包括但不限于黄原胶、卡波姆。
根据本发明的制备用途，其中制备水溶性胶体剂时，应将其pH值调至3.5～6.0的范围，特别是4.0～5.5的范围。调节本发明中所述水溶性胶体剂pH值的酸或碱的种类和浓度的选择，在本领域普通技术人员的知识范围以内。
根据本发明制备用途制备的水溶性胶体剂，可采用无菌、密封包装，优选单次剂量的无菌、密封包装。可采用本领域技术人员熟悉的无菌工艺技术，将经过灭菌或无菌化处理的组合物分装、密封于无菌包装中，或将制备好的组合物分装、密封好后进行灭菌处理，或将制备好的组合物分装于一次性阴道给药器中，用外包装袋密封后进行辐射灭菌，等等。
根据本发明优选的实施方案，还可选择性地使用乳杆菌活菌体用于制备同时含异麦芽酮糖和乳杆菌活菌体的胶囊剂、微囊剂、片剂等，其中的乳杆菌活菌体用于直接补充患者阴道缺少的乳杆菌、或用于替代患者阴道内原有的乳杆菌，异麦芽酮糖用于促进该乳杆菌在阴道内生长。根据本发明制备用途的含异麦芽酮糖和乳杆菌活菌的组合物，适合用于调节阴道菌群、增强阴道酸度、清洁护理阴道、预防或治疗阴道乳杆菌稀少、阴道酸度减弱、细菌性阴道病和阴道菌群失调。乳杆菌活菌体的制备和在本发明的制备用途中的使用方法，在本领域普通专业人员的知识范围以内。
本发明还特别提供一种用于阴道的组合物，其特征在于：(1)含有0.05～20％(w/w)异麦芽酮糖；(2)含有总量为0.05～2.5％(w/w)的选自下组的防腐剂和/或抗菌剂：苯甲酸、苯甲酸钠、山梨酸、山梨酸钾、山梨酸钠、乙酸、乙酸钠、双乙酸、双乙酸钠、脱氢乙酸、脱氢乙酸钠、丙酸、丙酸钠、丙酸钙、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、乳铁蛋白肽中的一种或其组合；(3)含有一种或多种适用于人体阴道的非活性辅料成分。
根据本发明的组合物，其中在所述组合物中异麦芽酮糖的含量优选为1.5～12％(w/w)。
根据本发明的组合物，其中所述组合物包括但不限于下列的阴道用组合物产品或组合物制剂：非治疗性的阴道用健康产品、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，或治疗性的阴道用健康产品、或阴道用医疗器械、或阴道用药品(非处方药或处方药)，或为用于阴道的清洁剂、或养护剂、或除异味剂、或止痒剂、或清新剂、或润湿剂、或润滑剂、或消毒剂、或抗菌剂、或表面杀微生物剂、或微生态调节剂、或微生物调节剂。
阴道用组合物的剂型为包括但不限于下列的剂型：水溶性胶体剂、水溶液剂、气雾剂、霜剂、软膏剂、胶囊剂、微囊剂、栓剂、泡腾剂、片剂，优选水溶性胶体剂、霜剂。
根据本发明的组合物，其中所述组合物还可选择性地进一步含有有效量的选自下组的防腐剂和/或抗菌剂，所述防腐剂或抗菌剂包括：过氧化氢、维生素B1、维生素K3、维生素K4、对羟基苯甲酸酯类、防御素、抗菌肽。上述物质可进一步抑制组合物中的细菌、霉菌、假丝酵母菌等，进一步增强组合物的微生物稳定性。
根据本发明的组合物，其中所述组合物还可选择性地含有总量为0.001～1.0％(w/w)的雌激素类物质和/或植物雌激素类物质，包括但不限于：己烯雌酚、雌二醇、雌三醇、大豆甙(Daidzin)、大豆甙元(Daidzein)、染料木甙(Genistin)、染料木素(Genistein)、黄豆黄素(Glycitin)、黄豆黄素甙元(Glycitein)、鸡豆黄素(Biochanin A)、香豆雌酚(Coumestto)、芒柄花黄素(Formnonetin)。雌激素类物质、植物雌激素类物质可促进阴道黏膜血管新生、阴道黏膜上皮角化和阴道上皮损伤愈合，因而可进一步增强本发明的组合物的作用。上述各种雌激素类物质、植物雌激素类物质在本发明组合物中的选择和使用方法，在公开的技术和本领域专业人员的知识范围以内。
根据本发明的组合物，其中所述组合物还可选择性地含有有效量的选自下组的阴道黏膜细胞保护物质和/或抗氧化物质，包括但不限于：0.1～5.0％(w/w)芦荟提取物、0.1～5.0％(w/w)薰衣草提取物、0.001～1.0％(w/w)维生素E、0.001～1.0％(w/w)维生素A、0.001～1.0％(w/w)维生素D、0.001～1.0％ (w/w)维生素C，用于进一步营养、湿润、润滑、和保护阴道黏膜上皮细胞。上述各种物质在本发明组合物中的选择和使用方法，在公开的技术和本领域专业人员的知识范围以内。
根据本发明的组合物，其中所述组合物还可选择性地含有有效量的一种或多种选自下组的糖类物质，包括但不限于：葡萄糖、果糖、甘露糖、蔗糖、麦芽糖、异麦芽糖、乳糖、乳果糖、海藻糖、纤维二糖、蜜二糖、龙胆二糖、松二糖、壳二糖、棉子糖、龙胆糖、潘糖、松三糖、异麦芽三糖、蔗果三糖、异麦芽四糖、蔗果四糖、蔗果五糖、麦芽寡糖、低聚半乳糖、甘露低聚糖、葡聚糖、环糊精、糊精、淀粉和糖原。上述糖类物质在本发明组合物中的选择和使用方法，在公开的技术和本领域专业人员的知识范围以内。
根据本发明的组合物，其中所述组合物还可选择性地含有有效量的一种或多种选自下组的抗菌药物，包括但不限于氟康唑、曲康唑、布康唑、咪康唑、克霉唑、制霉菌素、甲硝唑、替硝唑、林可霉素、阿莫西林，优选为甲硝唑、替硝唑、氟康唑、克霉唑。
根据本发明的组合物，其中所述组合物还可选择性地含有乳杆菌活菌，其中所述乳杆菌活菌包括但不限于：卷曲乳杆菌、詹氏乳杆菌、格氏乳杆菌。乳杆菌活菌体用于直接补充患者阴道缺少的乳杆菌、或用于替代患者阴道内原有的乳杆菌，异麦芽酮糖用于促进该乳杆菌在阴道内生长。因而根据本发明的含异麦芽酮糖和乳杆菌活菌的组合物适合用于调节阴道菌群、增强阴道酸度、清洁护理阴道、预防或治疗阴道乳杆菌稀少、阴道酸度减弱、细菌性阴道病和阴道菌群失调。乳杆菌活菌体的制备和在本发明的组合物中的使用方法，在公开的技术和本领域专业人员的知识范围以内。
根据本发明的组合物，其中所述组合物优选阴道用水溶性胶体组合物，其特征在于：(1)水溶性胶体组合物中异麦芽酮糖的含量为0.1～20.0％(w/v)，优选为3.0～12.0％(w/v)；(2)还含有总量为0.1～2.5％(w/v)的选自下组的防腐剂和/或抗菌剂：苯甲酸、苯甲酸钠、山梨酸、山梨酸钾、山梨酸钠、乙酸、乙酸钠、双乙酸、双乙酸钠、脱氢乙酸、脱氢乙酸钠、丙酸、丙酸钠、丙酸钙、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、乳铁蛋白肽中的一种或其组合。(3)其中所述非活性辅料成分为非流动性、粘性、水溶性胶体基质；其中所述胶体基 质优选为黄原胶、卡波姆，特别优选为黄原胶；(4)其中所述组合物的pH值为3.5～6.0，特别是4.0～5.5的范围；(5)还可选择性地含有总量为0.0015～1.0％(w/v)的选自下组的雌激素类物质和/或植物雌激素类物质：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、芒柄花黄素；(6)还可选择性地含有选自下组的阴道黏膜细胞保护物质和/或抗氧化物质，包括但不限于：0.15～5.0％(w/v)芦荟提取物、0.15～5.0％(w/v)薰衣草提取物、0.0015～1.0％(w/v)维生素E、0.0015～1.0％(w/v)维生素A、0.0015～1.0％(w/w)维生素D、0.0015～1.0％(w/w)维生素C；(7)还可选择性含有选自下组的抑菌剂和/或杀菌剂：甲硝唑、替硝唑、克霉唑、氟康唑。当所述抑菌剂和/或杀菌剂为甲硝唑时，甲硝唑的浓度为0.00015～0.1％(w/v)，优选浓度为0.0015～0.01％(w/v)。
本发明还特别涉及一种向女性阴道内补充糖类物质的方法，包括向有此需要的女性阴道内给予有效量的本发明的含有异麦芽酮糖的阴道用组合物，使异麦芽酮糖的每日用量为5～2000毫克，优选150～1200毫克，可将每日用量分1～2次给予，使异麦芽酮糖的每次用量不超过1000毫克。
本发明还特别涉及一种非治疗性阴道日常保健、或日常养护、或日常湿润、或日常润滑、或日常清洁以增加阴道外阴的舒适感、或清新感的方法，包括向有此需要的女性阴道内给予有效量的本发明的阴道用组合物，使异麦芽酮糖的每日用量为5～2000毫克，优选150～1200毫克，可将每日用量分1～2次给予，使异麦芽酮糖的每次用量不超过1000毫克。本发明的方法可增加或保持阴道外阴的清洁感、舒适感、或清新感。
本发明还特别涉及一种于月经后、或同房后、或绝经后、或阴道冲洗后、或阴道用药后治疗后对阴道非治疗性地进行清洁、或保健、或养护、或湿润、或润滑，以增强阴道的自净作用、或增强阴道对病原菌的抵抗力的方法，其中所述方法包括向有此需要的女性阴道内给予有效量的本发明的阴道用组合物，使异麦芽酮糖的每日用量为5～2000毫克，优选150～1200毫克，可将每日用量分1～2次给予，使异麦芽酮糖的每次用量不超过1000毫克。本发 明的方法可增强阴道的自净作用、或增强阴道对病原菌的抵抗力，保持阴道的清洁、卫生、和健康。
本发明还特别涉及一种增强阴道酸度、或维护阴道酸度在3.5～4.5范围内的方法，包括向有此需要的女性阴道内给予有效量的、本发明的组合物，使异麦芽酮糖的每日用量为5～2000毫克，优选150～1200毫克，可将每日用量分为1～2次给予，使异麦芽酮糖的每次用量不超过1000毫克。本发明的方法能增强阴道的酸度，或维护阴道酸度在3.5～4.5的范围、特别是3.8～4.3的范围。
本发明还特别涉及一种促进阴道内的保护性乳杆菌生长，特别是促进保护性的卷曲乳杆菌、或詹氏乳杆菌、或格氏乳杆菌生长的方法，包括向有此需要的女性阴道内给予有效量的、本发明的组合物，使异麦芽酮糖的每日用量为5～2000毫克，优选150～1200毫克，可将每日用量分1～2次给予，使异麦芽酮糖的每次用量不超过1000毫克。本发明的方法可显著促进阴道内的保护性乳杆菌生长，特别是促进保护性的卷曲乳杆菌、或詹氏乳杆菌、或格氏乳杆菌的生长。
本发明还特别涉及一种消除或减轻阴道分泌物异味、或消除或减轻阴道外阴瘙痒、或消除或减轻阴道外阴干涩、或消除或减轻阴道外阴疼痛、性交痛等不适，或改善白带性状等的方法，包括向有此需要的女性阴道内给予有效量的、本发明的组合物，使异麦芽酮糖的每日用量为5～2000毫克，优选150～1200毫克，可将每日用量分1～2次给予，使异麦芽酮糖的每次用量不超过1000毫克。本发明的方法可显著改善白带性状、消除或减轻白带嗅味，以及消除或减轻阴道外阴瘙痒、干涩、疼痛等不适。
本发明还特别涉及一种调节阴道菌群、或抗菌治疗后恢复阴道有益菌群、或预防或治疗阴道菌群失调、或预防或治疗细菌性阴道病的方法，包括向有此需要的女性阴道内给予有效量的、本发明的组合物，使异麦芽酮糖的每日用量为5～2000毫克，优选150～1200毫克，可将每日用量分为1～2次给予，使异麦芽酮糖的每次用量不超过1000毫克。本发明还可用于调节阴道菌群、或用于预防或治疗阴道菌群失调、或用于抗菌治疗后恢复阴道有益菌群、或用于预防或治疗细菌性阴道病。
具体实施方式
组合物实施例
实施例1
按如下方法制备组合物：将异麦芽酮糖9.0克，苯甲酸钠0.05克，脱氢乙酸钠0.02克，丙酸钠0.5克，黄原胶2.7克混匀，加入蒸馏水100毫升，搅拌、混匀，使异麦芽酮糖、苯甲酸钠、脱氢乙酸钠和丙酸钠溶解，黄原胶溶胀呈均匀粘性胶体；调pH值至5.0；112.6℃、20分钟灭菌，即得本发明的水溶性胶体组合物。按单次剂量无菌、密封分装，每支5克。
实施例2
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖4.5克，脱氢乙酸钠0.02克，丙酸钠0.5克，纳他霉素2.5毫克，黄原胶2.6克，蒸馏水100毫升，pH 5.0，灭菌，单次剂量无菌密封包装，每支5.0克。
实施例3
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖12.0克，苯甲酸钠0.15克，脱氢乙酸钠0.01克，丙酸钠0.5克，黄原胶2.5克，蒸馏水100毫升，pH 4.8。
实施例4
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖20.0克，苯甲酸钠0.2克，黄原胶3.0克，蒸馏水100毫升，pH5.0。
实施例5
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖0.1克，苯甲酸钠0.2克，月桂酸0.1克，黄原胶2.5克，蒸馏水100毫升，pH6.5。
实施例6
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖8克，葵酸钠0.1克，乳铁蛋白1.0克，芦荟提取物5克，黄原胶2.5克，蒸馏水100毫升，pH6.5。
实施例7
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖1.5克，丙酸钠0.375克，辛酸钠0.15克，乳铁蛋白0.25克，黄原胶2.5克，蒸馏水100毫升，pH6.5。
实施例8
按下述配比称取原料，异麦芽酮糖45.0克，异麦芽糖443.5克，苯甲酸钠1.5克，嗜酸乳杆菌菌粉10克(含低聚果糖与活菌5X 1010CFU)；将以上成分充分混合均匀，分装胶囊1000粒，每粒胶囊含异麦芽酮糖45毫克、异麦芽糖443.5毫克、苯甲酸钠1.5毫克、嗜酸乳杆菌5X 107CFU。
实施例9
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖9.0克，丙酸钠0.45克，苯甲酸钠0.05克，脱氢乙酸钠0.025克，雌三醇0.1克，黄原胶3.0克，水87.375克，pH 5.0。
实施例10
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖10克，苯甲酸钠0.15克，纳他霉素2毫克，黄原胶3.0克，蒸馏水100毫升，pH 5.0。
实施例11
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖5.0克，苯甲酸钠0.2克，黄原胶2.5克，蒸馏水100毫升，pH 5.5。
实施例12
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖2.0克，丙酸钠0.7克，黄原胶2.5克，蒸馏水94.8克，pH 6.5。
实施例13
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖6.0克，丙酸钠0.5克，脱氢乙酸钠0.02克，辛酸钠0.05克，乳铁蛋白0.5克，纳他霉素10毫克、大豆总异黄酮0.02克，黄原胶2.5克，蒸馏水100毫升，pH 6.5。
实施例14
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖1.5克，脱氢乙酸钠0.025克，黄原胶3.0克，蒸馏水100毫升，pH 6.5。
实施例15
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖8.5克，脱氢乙酸钠0.02克，辛酸钠0.1克，乳铁蛋白0.5克，黄原胶2.8克，蒸馏水100毫升，pH 6.5。
实施例16
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖8.0克，丙酸钠0.5克，黄原胶2.8克，蒸馏水100毫升，pH 6.2。
实施例17
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖8.0克，丙酸钠0.5克，脱氢乙酸钠0.02克，乳铁蛋白0.5克，黄原胶2.8克，蒸馏水100毫升，pH 6.2。
实施例18
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖9.0克，苯甲酸钠0.2克，氟康唑0.2克，黄原胶3.0克，蒸馏水100毫升，pH 6.5。
实施例19
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖1.5克，丙酸钠0.5克，脱氢乙酸钠0.025克，黄原胶2.5克，蒸馏水100毫升，pH 5.4。
实施例20
按下述配比称取原料：异麦芽酮糖20.0克，丙酸钠0.5克，苯甲酸钠0.05克，脱氢乙酸钠0.02克，甲硝唑0.005克，黄原胶2.5克，蒸馏水100毫升。
先将异麦芽酮糖、丙酸钠、苯甲酸钠、脱氢乙酸钠、黄原胶混合均匀，加蒸馏水90毫升，搅拌，加热并搅拌，灭菌；加入无菌甲硝唑液10毫升(含甲硝唑0.005克)，调pH 5.0并混合均匀。
实施例21
按下述配比称取原料：异麦芽酮糖35克，异麦芽糖63克，苯甲酸钠0.5克，甲硝唑0.01克，克霉唑0.01克，硬脂酸镁1.48克，混合均匀，压片，每片0.5克；每片含异麦芽酮糖175毫克，异麦芽糖315毫克，苯甲酸钠2.5毫克，甲硝唑0.05毫克，克霉唑0.05毫克，硬脂酸镁7.4毫克。
实施例22
按下述配比称取原料，基本按实施例1的方法制备了组合物：异麦芽酮糖10克，苯甲酸0.05克，多聚卡波菲(Polycarbophil)2.0克，蒸馏水100毫升，pH 4.0
实施例23
按下述配比称取原料，基本按实施例1的方法制备了组合物：苯甲酸0.15克，异麦芽酮糖3.0克，异麦芽糖9.0克，氟康唑0.15克，黄原胶2.5克，蒸馏水100克，pH 5.4。
实施例24
按下述配比和方法制备水溶液组合物：称取异麦芽酮糖12克，苯甲酸钠0.2克，加入蒸馏水100毫升中，搅拌、溶解，调pH值5.0，灭菌，即得水溶液组合物。
实施例25
按下述配比和方法制备水溶液组合物：称取异麦芽酮糖12克，丙酸钠0.5克，脱氢乙酸钠0.02克，辛酸钠0.1克，加入蒸馏水100毫升中，搅拌、溶解，调pH值5.0，灭菌。
以下参照下列实验实施例说明本发明的制备用途和方法的有益效果。
实验实施例1：
1、实验目的：
观察异麦芽酮糖对BV细菌产酸的促进作用，并与异麦芽糖、蔗糖、麦芽糖的作用比较。
2、实验方法：
(1)实验分组：
①异麦芽酮糖组：含1％(w/v)异麦芽酮糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.5％(w/v)黄原胶，pH5.4；
②异麦芽糖组：含1％(w/v)异麦芽糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.5％(w/v)黄原胶，pH5.4；
③蔗糖组：含1％(w/v)蔗糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.5％(w/v)黄原胶，pH5.4；
④麦芽糖组：含1％(w/v)麦芽糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.5％(w/v)黄原胶，pH5.4；
各组凝胶的配制，基本按照组合物实施例1的方法进行，完成之后灭菌，加小牛血清，分装试管每支5克，备用。
(2)BV分泌物标本：5例BV病人的阴道分泌物，纳入标准为：
①符合临床诊断BV的Amsel标准，其中阴道分泌物的pH＞4.6；
②阴道分泌物涂片、Gram染色、镜检，Nugent评分≥7分；
③无其它阴道疾病，且两周内未使用过抗菌药物。
(3)符合入选标准的BV阴道分泌物标本，采样后立即接种前述4种含糖凝胶，37℃、微需氧培养46小时，分别于14小时、36小时和46小时用精密pH试纸检测凝胶基质的pH值。
3、实验结果：
如表1所示，BV分泌物标本在4种含糖凝胶中培养，14小时，各实验管pH值由初始的5.4，分别下降到3.8～5.1范围内，其中异麦芽酮糖凝胶的pH值最低，蔗糖凝胶的pH值最高，异麦芽糖凝胶、麦芽糖凝胶的pH值居中。培养36小时，四种含糖凝胶的pH值均降至4.6以下，仍以异麦芽酮糖凝胶的pH值最低，蔗糖凝胶的pH值最高。培养46小时，四种含糖凝胶的pH值相同，均≤3.8。
表1.四种糖类物质对BV细菌产酸的影响
Figure PCTCN2015073978-appb-000001
Figure PCTCN2015073978-appb-000002
4、讨论
本实施例的含糖凝胶接种BV分泌物标本、微需氧培养14小时，4/5异麦芽酮糖凝胶的pH值降至4.1以下，4/5异麦芽糖凝胶和4/5麦芽糖凝胶的pH值降至4.4以下，而4/5蔗糖凝胶的pH值仍在4.4或以上。
继续培养至36小时，3/3异麦芽酮糖凝胶的pH值均降至3.8或以下，2/3蔗糖凝胶的pH值仍高于4.4，2/3异麦芽糖凝胶和2/3麦芽糖凝胶的pH值降至3.8或以下。
当继续培养至46小时，分别接种2例标本的四种含糖凝胶的pH值无差异，均≤3.8。
所述结果显示：BV菌群代谢异麦芽酮糖产酸，快于其代谢异麦芽糖和麦芽糖产酸，尤其快于其代谢蔗糖产酸。
阴道正常pH值一般认为在3.5～4.5的范围，BV病人阴道分泌物的pH值高于4.6。各种细菌生长均有其最适宜的pH值范围，当pH值为5.4时嗜中性细菌的生长与产酸代谢受到抑制，而耐酸的乳杆菌、双歧杆菌等细菌仍能生长、产酸，所以乳杆菌选择性培养基的pH值一般为5.4。乳酸也被认为在维护阴道菌群正常、抵抗BV菌群和其它病原菌中起主要作用[12]。本实施例含糖凝胶的初始pH值5.4，在这样的pH条件下，BV菌群、主要是其中的乳酸菌代谢糖类物质产酸。凝胶pH值下降越快，对BV有害细菌的抑制作用也越快，对BV菌群的调节作用也将更快。
从本实施例的研究结果看，微需氧条件下异麦芽酮糖更易于被BV细菌代谢产酸，因而其优于异麦芽糖和麦芽糖，尤其显著优于蔗糖，故异麦芽酮糖更适合用于制备本发明的阴道用组合物。
实验实施例2：
1、实验目的：
观察异麦芽酮糖对BV细菌产酸的促进作用，并与葡萄糖、果糖、甘露糖、蔗糖、麦芽糖、异麦芽糖的作用比较。
2、实验方法：
(1)实验分组：
①葡萄糖组：含1.5％(w/v)葡萄糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4；
②果糖组：含1.5％(w/v)果糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4；
③甘露糖组：含1.5％(w/v)甘露糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4；
④蔗糖组：含1.5％(w/v)蔗糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4；
⑤麦芽糖组：含1.5％(w/v)麦芽糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4；
⑥异麦芽糖组：含1.5％(w/v)异麦芽糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4；
⑦异麦芽酮糖组：含1.5％(w/v)异麦芽酮糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4；
各组半固体琼脂的配制，基本按照组合物实施例1的方法进行，完成之后灭菌，加小牛血清，分装试管每支5克，备用。
(2)BV分泌物标本：5例BV病人的阴道分泌物，纳入标准为：
①符合临床诊断BV的Amsel标准，其中阴道分泌物的pH＞4.6；
②阴道分泌物涂片、Gram染色、镜检，Nugent评分≥7分；
③无其它阴道疾病，且两周内未使用过抗菌药物。
(3)符合入选标准的BV阴道分泌物标本，采样后立即床旁接种前述7种无菌含糖半固体琼脂，37℃、厌氧培养24小时，用精密pH试纸检测琼脂基质的pH值。
3、实验结果：
如表2所示，5例BV分泌物标本分别在7种含糖半固体琼脂中厌氧培养24小时，所有半固体琼脂的pH值均下降，由初始时的5.4，降至3.8～4.6。按pH值由低到高排序，最低为异麦芽酮糖和麦芽糖，异麦芽糖次之，第三为蔗糖，第四为葡萄糖、最后为果糖和甘露糖。
表2.七种糖类物质对BV细菌产酸的影响
Figure PCTCN2015073978-appb-000003
4、讨论
本实施例的7种半固体琼脂分别接种5例BV分泌物标本、厌氧培养24小时，各培养管的pH值均下降，下降的幅度反映了厌氧条件下BV细菌代谢各种糖产酸的效率。总体上，双糖半固体琼脂的pH下降幅度，大于单糖半固体琼脂的pH值下降幅度。双糖中，又以异麦芽酮糖和麦芽糖半固体琼脂的pH值下降幅度，大于蔗糖、异麦芽糖半固体琼脂的pH值下降幅度。显示BV菌群代谢双糖、尤其是代谢异麦芽酮糖和麦芽糖产酸，快于其代谢蔗糖和异麦芽糖产酸，更快于代谢单糖产酸。
阴道正常pH值一般认为在3.5～4.5的范围，BV病人阴道分泌物的pH值高于4.6。各种细菌生长均有其最适宜的pH值范围，当pH值为5.4时嗜中性细菌的生长与产酸代谢受到抑制，而耐酸的乳杆菌、双歧杆菌等细菌仍能生长、产酸，所以乳杆菌选择性培养基的pH值一般为5.4。乳酸也被认为在维护阴道菌群正常、抵抗BV菌群和其它病原菌中起主要作用[12]。本实施例含糖凝胶的初始pH值5.4，在这样的pH条件下，BV菌群、主要是其中 的乳酸菌代谢糖类物质产酸。凝胶pH值下降越快，对BV有害细菌的抑制作用也越快，对BV菌群的调节作用也会更快。
终上所述，本实施例结果显示：厌氧条件下异麦芽酮糖具有较强的促进阴道菌群代谢产酸的作用，适合用于制备本发明的阴道用组合物。
实验实施例3：
1、实验目的：
观察异麦芽酮糖与抗菌剂联合，对BV细菌产酸的影响，并与蔗糖和异麦芽糖进行比较。
2、实验方法：
(1)实验分组：
①蔗糖防腐剂组：含1.5％(w/v)蔗糖、0.5％(w/v)丙酸钠、0.025％(w/v)脱氢乙酸钠、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4；
②异麦芽糖防腐剂组：含1.5％(w/v)异麦芽糖、0.5％(w/v)丙酸钠、0.025％(w/v)脱氢乙酸钠、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4；
③异麦芽酮糖防腐剂组：含1.5％(w/v)异麦芽酮糖、0.5％(w/v)丙酸钠、0.025％(w/v)脱氢乙酸钠、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4；
④蔗糖对照组：含1.5％(w/v)蔗糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4；
⑤异麦芽糖对照组：含1.5％(w/v)异麦芽糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4；
⑥异麦芽酮糖对照组：含1.5％(w/v)异麦芽酮糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4
各组半固体琼脂的配制，基本按照组合物实施例1的方法进行，完成之后灭菌，加小牛血清，分装试管每支5克，备用。
(2)BV分泌物标本：2例BV病人的阴道分泌物，纳入标准为：
①符合临床诊断BV的Amsel标准，其中阴道分泌物的pH＞4.6；
②阴道分泌物涂片、Gram染色、镜检，Nugent评分≥7分；
③无其它阴道疾病，且两周内未使用过抗菌药物。
(3)符合入选标准的BV阴道分泌物标本，采样后立即床旁接种前述3种含糖和防腐剂的半固体琼脂、3种对照组琼脂，37℃、厌氧培养40小时，分别于培养30～32小时、培养40～48小时，用精密pH试纸检测琼脂基质的pH值。
3、实验结果：
如表3所示，培养30～32小时，不含抗菌剂的各对照组半固体琼脂的pH值均降至3.8、或3.8～4.1。
各含糖和防腐剂的半固体琼脂、厌氧培养30～32小时，半固体琼脂基质的pH值均下降，但仍然高于4.4。培养40～48小时，2例异麦芽酮糖半固体琼脂基质的pH值低于4.1；2例蔗糖半固体琼脂基质的pH值分别为4.1、4.4；2例异麦芽糖半固体琼脂基质的pH值分别为4.4、4.6。
表3.糖类物质与抗菌剂联合作用对BV细菌产酸的影响
Figure PCTCN2015073978-appb-000004
4、讨论：
含相同防腐剂的三种含糖半固体琼脂接种BV标本、培养30～48小时，异麦芽酮糖组琼脂基质的pH值最低，40～48小时降至3.8、3.8～4.1，显著低于蔗糖组的4.1、4.4，和异麦芽糖组的4.4、4.6。
三个对照组分别含有3种糖，不含防腐剂。其琼脂基质的pH值下降较快，30～32小时5/6的pH值即降至3.8，1/6的pH值降至3.8～4.1，显著低于 含防腐剂的琼脂基质，显示防腐剂对阴道细菌产酸有显著影响，其中对阴道细菌代谢蔗糖和异麦芽糖产酸的影响最突出，产酸减少、基质pH值下降慢，至40～48小时3/4的琼脂基质pH值仍为4.4或以上，1/4为4.1。异麦芽酮糖亦受防腐剂的影响，但程度相对较轻，一方面其琼脂基质pH值在40～48小时可降至3.8或3.8～4.1，同时又避免了过度产酸和pH值下降得过低。本实施例的结果显示，异麦芽酮糖显著优于蔗糖和异麦芽糖，更适合与防腐剂联合用于制备本发明的含有防腐剂和/或抗菌剂的阴道用组合物。
实验实施例4
1、实验目的：
观察异麦芽酮糖凝胶对BV细菌生长的促进作用，并与异麦芽糖凝胶、蔗糖凝胶、麦芽糖凝胶的作用比较。
2、实验方法：
(1)实验分组：
①异麦芽酮糖组：含1％(w/v)异麦芽酮糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.5％(w/v)黄原胶，pH5.4；
②异麦芽糖组：含1％(w/v)异麦芽糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.5％(w/v)黄原胶，pH5.4；
③蔗糖组：含1％(w/v)蔗糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.5％(w/v)黄原胶，pH5.4；
④麦芽糖组：含1％(w/v)麦芽糖、无糖MRS基础培养液、5％(w/v)小牛血清、0.5％(w/v)黄原胶，pH5.4；
各组凝胶的配制，基本按照组合物实施例1的方法进行，完成之后灭菌，加小牛血清，分装试管每支5克，备用。
(2)BV分泌物样本：20例BV病人的阴道分泌物，纳入标准为：
①符合临床诊断BV的Amsel标准；
②阴道分泌物涂片、Gram染色、镜检，Nugent评分≥7分；
③无其它阴道疾病，且两周内未使用过抗菌药物。
(3)符合入选标准的BV阴道分泌物样本，采样后立即接种前述四种含糖凝胶，37℃、微需氧培养48小时，转种含1％(w/v)葡萄糖、5％(w/v) 小牛血清的改良MRS平皿，微需氧培养20～48小时，分纯、增菌，作16s rDNA测序鉴定菌种。
3、实验结果：
(1)如表4所示，分别用4种含糖凝胶培养BV阴道分泌物，异麦芽酮糖凝胶、异麦芽糖凝胶、蔗糖凝胶均从9例BV分泌物培养出乳杆菌，麦芽糖凝胶自8例BV分泌物培养出乳杆菌，均未培养出惰性乳杆菌。培养出乳杆菌的9例BV，其中4例为詹氏乳杆菌，2例为格氏乳杆菌，各1例卷曲乳杆菌、黏膜乳杆菌、淀粉乳杆菌。显示这四种含糖凝胶对詹氏乳杆菌、格氏乳杆菌、以及卷曲乳杆菌等的促生长作用较强，对惰性乳杆菌的促生长作用弱。
表4.四种含糖凝胶对BV分泌物中的乳杆菌的选择性促生长作用
Figure PCTCN2015073978-appb-000005
注1：数字“4”指詹氏乳杆菌培养阳性样本的总例数，表2、3同此；
注2：括号内的数字指詹氏乳杆菌培养阳性的样本的编号，表2、3同此。
(2)如表5所示，分别用4种含糖凝胶培养BV阴道分泌物，仅麦芽糖凝胶自1例BV分泌物培养出了两岐双歧杆菌，其余3种凝胶均未培养出短双歧杆菌、齿双歧杆菌和长双歧杆菌，显示异麦芽酮糖、异麦芽糖、蔗糖这3种含糖凝胶对BV菌群中常见双歧杆菌的生长促进作用较弱。
表5.四种含糖凝胶对BV分泌物中的双歧杆菌的选择性促生长作用
Figure PCTCN2015073978-appb-000006
Figure PCTCN2015073978-appb-000007
(3)如表6所示，分别用4种含糖凝胶培养BV阴道分泌物，其中麦芽糖凝胶自6例BV分泌物培养出阴道加德纳菌，蔗糖凝胶自3例BV分泌物培养出阴道加德纳菌，异麦芽酮糖凝胶、异麦芽糖凝胶自2例BV分泌物培养出阴道加德纳菌，显示麦芽糖凝胶有利于阴道加德纳菌生长。
表6.四种含糖凝胶对BV分泌物中的阴道加德纳菌的选择性促生长作用
Figure PCTCN2015073978-appb-000008
4、讨论
相关研究发现[14]，BV菌群复杂，以阴道加德纳菌、普雷沃氏菌、巨型球菌、动弯杆菌、消化链球菌、微单胞菌属、厌氧球菌属、纤毛菌属等为优势菌，其中阴道加德纳菌(Gardnerella vaginalis)的16S rRNA基因序列的拷贝数量占BV病人阴道总菌群16S rRNA基因序列的拷贝数量的29.1％，居第一位，是第二位的普氏菌属(Prevotella)13.2％的两倍多，是第三位巨型球菌属(Megasphaera)9.8％的三倍。在中间型BV，阴道加德纳菌的16S rRNA基因序列的拷贝数量，占中间型BV病人阴道总菌群16S rRNA基因序列的拷贝数量的30.5％，排列在惰性乳杆菌之后居第二位。可见，阴道加德纳菌是BV病人阴道菌群最有代表性的优势菌之一。
BV菌群中乳杆菌减少，其中惰性乳杆菌(L.iners)的16S rRNA基因序列的拷贝数量以6.6％在BV总菌群16S rRNA基因序列的拷贝数量排序中居第六位，卷曲乳杆菌仅为0.3％，而詹氏乳杆菌、格氏乳杆菌更少，与其它种类的乳杆菌加在一起总计才0.2％。但在中间型BV，惰性乳杆菌的16S rRNA基因序列的拷贝数量占阴道总菌群16S rRNA基因序列的拷贝数量则达到了 43.9％，居第一位，卷曲乳杆菌占1.2％，詹氏乳杆菌、格氏乳杆菌与其它乳杆菌的数量总计为6.1％。
本实施例选用20例典型BV病人阴道分泌物，分别用4种含糖凝胶进行培养，其中异麦芽酮糖凝胶、异麦芽糖凝胶、蔗糖凝胶自9例BV分泌物培养出乳杆菌，麦芽糖凝胶自8例BV分泌物培养出乳杆菌。培养出的乳杆菌的种类，以BV菌群中稀少的詹氏乳杆菌、格氏乳杆菌为主，其次为BV菌群中稀少的卷曲乳杆菌、黏膜乳杆菌和淀粉乳杆菌。BV菌群中数量最多的惰性乳杆菌，反而未培养出来。提示含异麦芽酮糖、异麦芽糖、蔗糖、麦芽糖的4种凝胶对BV分泌物中的乳杆菌具有选择性，促进詹氏乳杆菌、格氏乳杆菌、卷曲乳杆菌等生长的作用强，而对惰性乳杆菌生长的促进作用弱。
BV菌群中阴道加德纳菌最多。本实施例中，麦芽糖凝胶自6例BV分泌物培养出阴道加德纳菌，蔗糖凝胶自3例BV分泌物培养出阴道加德纳菌，异麦芽酮糖凝胶、异麦芽糖凝胶自2例BV分泌物培养出阴道加德纳菌，提示麦芽糖凝胶更适合阴道加德纳菌生长，而异麦芽酮糖凝胶、异麦芽糖凝胶相对不适应阴道加德纳菌生长。
BV菌群中的双歧杆菌多为两岐双歧杆菌、短双歧杆菌、齿双歧杆菌和长双歧杆菌。本实施例中，仅麦芽糖凝胶自1例BV分泌物培养出两歧双歧杆菌，而异麦芽酮糖凝胶、异麦芽糖凝胶、蔗糖凝胶均未培养出双歧杆菌，提示异麦芽酮糖、异麦芽糖、和蔗糖对BV分泌物中的双歧杆菌无显著促生长作用。
5、结论：异麦芽酮糖凝胶、异麦芽糖凝胶、蔗糖凝胶和麦芽糖凝胶均具有选择性促进BV分泌物中的詹氏乳杆菌、格氏乳杆菌、卷曲乳杆菌、黏膜乳杆菌和淀粉乳杆菌生长的作用，但对惰性乳杆菌生长无明显促进作用。
异麦芽酮糖凝胶、异麦芽糖凝胶、蔗糖凝胶对BV分泌物中的双歧杆菌无明显促生长作用。
麦芽糖凝胶可能对BV阴道分泌物中的阴道加德纳菌生长具有一定促进作用，而异麦芽酮糖凝胶、异麦芽糖凝胶对阴道加德纳菌的促生长作用不明显。
综上所述，本实施例的研究结果提示在调节菌群的作用方面，异麦芽酮糖优于麦芽糖，更适合用于制备本发明的阴道用组合物。
实验实施例5：
1、实验目的：了解白色假丝酵母菌对异麦芽酮糖的代谢，并与异麦芽糖、蔗糖、麦芽糖比较。
2、实验方法：
(1)实验分组：
异麦芽酮糖组：含1.5％(w/v)异麦芽酮糖、无糖MRS基础培养液、5％(w/v)小牛血清，pH7.0；
异麦芽糖组：含1.5％(w/v)异麦芽糖、无糖MRS基础培养液、5％(w/v)小牛血清，pH值7.0；
蔗糖组：含1.5％(w/v)蔗糖、无糖MRS基础培养液、5％(w/v)小牛血清，pH7.0；
麦芽糖组：含1.5％(w/v)麦芽糖、无糖MRS基础培养液、5％(w/v)小牛血清，pH7.0；
严格无菌操作配制上述各组培养液，分装试管每管5毫升，备用。
(2)实验菌株：白色假丝酵母菌2株，均分离自假丝酵母菌阴道炎患者。
(3)无菌操作，分别接种2株白色假丝酵母菌菌液于各试验管，37℃、需氧培养72小时，80℃、30分钟灭菌，离心分离上清，每支5毫升，用HPLC高效液相色谱法检测各管的糖含量。
3、实验结果：
如表7所示，用浓度均为1.5％(w/v)的异麦芽酮糖培养液、异麦芽糖培养液、蔗糖培养液、麦芽糖培养液培养白色假丝酵母菌72小时，四种糖的浓度不同程度降低，下降幅度依次为麦芽糖、异麦芽酮糖、异麦芽糖、蔗糖。麦芽糖浓度由1.5％(w/v)降至0.05％(w/v)以下。
表7.白色假丝酵母菌对四种糖的代谢利用
Figure PCTCN2015073978-appb-000009
注1：检出限0.05％(w/v)。
4、讨论：
据相关文献报道，假丝酵母菌阴道外阴炎的病原菌85％以上为白色假丝酵母菌。两株白色假丝酵母菌分别用四种含糖培养液培养72小时，麦芽糖的残余浓度两株菌均低于0.05％(w/v)，异麦芽酮糖的残余浓度一株为0.11％(w/v)，一株为0.12％(w/v)，异麦芽糖的残余浓度一株为0.74％(w/v)，另一株为0.76％(w/v)，蔗糖的残余浓度最高，一株1.04％(w/v)，一株0.95％(w/v)。显示四种糖均能被白色假丝酵母菌代谢利用，其中对麦芽糖的代谢能力相对最强，对蔗糖的代谢能力相对最弱。从本实施例的研究结果看，蔗糖、异麦芽糖、异麦芽酮糖，优于麦芽糖，更适合用于制备本发明的阴道用组合物。
实验实施例6
1、实验目的：
观察异麦芽酮糖与防腐剂联合，对BV细菌生长的影响。
2、实验方法：
(1)异麦芽酮糖琼脂：1.5％(w/v)异麦芽酮糖、0.05％(w/v)苯甲酸钠、0.5％(w/v)丙酸钠、0.025％(w/v)脱氢乙酸钠、无糖MRS基础培养液、5％(w/v)小牛血清、0.45％(w/v)琼脂，pH5.4。
基本按照组合物实施例1的方法配制，完成之后灭菌，加小牛血清，分装试管每支5克，备用。
(2)BV分泌物标本：1例BV病人的阴道分泌物，纳入标准为：
①符合临床诊断BV的Amsel标准，其中阴道分泌物的pH＞4.6；
②阴道分泌物涂片、Gram染色、镜检，Nugent评分≥7分；
③无其它阴道疾病，且两周内未使用过抗菌药物。
(3)符合入选标准的BV阴道分泌物标本，阴道拭子采样后床旁洗脱于无糖MRS基础培养液中，立即接种异麦芽酮糖琼脂，37℃、厌氧培养40小时，取琼脂基质和分泌物标本液，送上海Sangon Biotech(Shanghai)Co.，Ltd.，做16s rDNA宏基因检测分析，和做qPCR检测乳杆菌属、卷曲乳杆菌、惰性乳杆菌、詹氏乳杆菌、格式乳杆菌、阴道加德纳菌、和普雷沃氏菌。
3、实验结果：
(1)如表8所示，此例BV病人的阴道分泌物的细菌以Sneathia(43.02％)、Prevotella(19.44％)、Gardnerella(12.68％)为优势菌。接种异麦芽酮糖琼脂、厌氧培养40小时，则乳杆菌占91％，阴道加德纳菌6％。
(2)如表9所示，其中所列各DNA拷贝数，分别为0.12毫升琼脂基质、0.12标本悬液中所含的细菌DNA拷贝数。qPCR检测BV分泌物标本中的7种细菌，普雷沃氏菌、阴道加德纳菌数量大，乳杆菌属、卷曲乳杆菌、惰性乳杆菌数量少，詹氏乳杆菌极少，格式乳杆菌未检出。qPCR检测异麦芽酮糖琼脂中的7种细菌，卷曲乳杆菌属的数量巨大，詹氏乳杆菌数量稀少，格式乳杆菌未检出。惰性乳杆菌、普雷沃氏菌的数量减少。阴道加德纳菌的数量有所增加。
表8.异麦芽酮糖与抗菌剂联合对BV细菌生长的影响
Figure PCTCN2015073978-appb-000010
Figure PCTCN2015073978-appb-000011
*：暂无中文名
表9.异麦芽酮糖对BV细菌生长的影响
Figure PCTCN2015073978-appb-000012
4、讨论：
上述实验结果显示，BV细菌在含抗菌剂的异麦芽酮糖琼脂、厌氧培养40小时，宏基因检测显示乳杆菌大量生长成为优势菌，而Sneathia、普雷沃氏菌(Prevotella)、阴道加德纳菌(Gardnerella)在菌群构成比中的比例显著下降。进一步做qPCR检测，验证了优势的乳杆菌为卷曲乳杆菌，其DNA序列的拷贝数由2355增加至889000000，增长377494倍，而惰性乳杆菌的DNA序列拷贝数，却由56296减少至33167。普雷沃氏菌数量减少。詹氏乳杆菌的数量仍极为稀少。注意到卷曲乳杆菌的DNA拷贝数多于乳杆菌属的DNA拷贝数，与Sangon Biotech(Shanghai)Co.，Ltd.的专家讨论，认为可能因为乳杆菌属的引物没有包括属下面所有的菌、以及卷曲乳杆菌引物扩出的不止包括卷曲乳杆菌一种菌这两方面的原因。阴道加德纳菌的绝对数量也有所增加，增加4.27倍，可能与琼脂 基质所含小牛血清支持阴道加德纳菌生长有关。
本实施例结果显示，异麦芽酮糖对保护性的卷曲乳杆菌的生长具有显著促进作用，对惰性乳杆菌的生长则无促进作用，提示异麦芽酮糖与抗菌剂联合，适合用于制备本发明的组合物。
实验实施例7
1、实验目的：
观察不同防腐剂对假丝酵母菌与乳杆菌的抗菌作用。
2、实验方法：
(1)配制含不同防腐剂的培养液
以基础培养液【含0.5％(w/v)异麦芽酮糖、无糖MRS培养液、5％(w/v)小牛血清】配制以下含不同浓度防腐剂的培养液：
A.0.1％(w/v)苯甲酸钠
B.0.2％(w/v)苯甲酸钠
C.0.02％(w/v)脱氢乙酸钠
D.0.25％(w/v)丙酸钠组
E.0.5％(w/v)丙酸钠组
F.0.02％(w/v)脱氢乙酸钠+0.25％(w/v)丙酸钠组
G.0.02％(w/v)脱氢乙酸钠+0.5％(w/v)丙酸钠组
各组培养液的pH值均调至5.4，灭菌分装试管，每管2毫升。
(2)试验菌株接种与培养：各试验管分别接种(1～5)×105cfu/ml光滑假丝酵母菌分离株菌悬液、(1～5)×105cfu/ml詹氏乳杆菌分离株菌悬液。光滑假丝酵母菌37℃、需氧培养72小时，詹氏乳杆菌微需氧培养22小时。
(3)结果观察：于22小时观察詹氏乳杆菌培养管浊度，于72小时观察光滑假丝酵母菌培养管浊度。
3、试验结果
如表10所示，0.1％(w/v)苯甲酸钠对乳杆菌即有较强抑制作用，0.2％(w/v)苯甲酸钠可在22小时完全抑制乳杆菌生长。0.02％(w/v)脱氢乙酸钠、0.5％(w/v)丙酸钠，对乳杆菌生长抑制作用弱，22小时乳杆菌浊度显著增加。
0.2％(w/v)苯甲酸钠、0.02％(w/v)脱氢乙酸钠、0.5％(w/v)丙酸钠分别单独作用，对光滑假丝酵母菌抑制作用均较弱，72小时光滑假丝酵母菌浊度显著增加。
脱氢乙酸钠、丙酸钠对光滑假丝酵母菌具有协同抑制作用，0.02％(w/v)脱氢乙酸钠与0.5％(w/v)丙酸钠联合，72小时可完全抑制光滑假丝酵母菌生长，其浊度无变化。而对詹氏乳杆菌抑制作用相对较弱，22小时其浊度增加。
表10.防腐剂对乳杆菌、假丝酵母菌生长的影响
Figure PCTCN2015073978-appb-000013
*：表10中的浓度均为“w/v”
4、结论
本实验实施例结果证实，0.02％(w/v)脱氢乙酸钠与0.5％(w/v)丙酸钠联合，其对光滑假丝酵母菌的抑制作用较0.2％(w/v)苯甲酸钠的作用强。
0.02％(w/v)脱氢乙酸钠与0.5％(w/v)丙酸钠联合，其对詹氏乳杆菌的抑制作用，则比0.2％(w/v)苯甲酸钠的抑制作用弱。
实验实施例8
筛选雌性恒河猴2只，其阴道分泌物pH值分别为5.1、4.8，阴道细菌以阴性杆菌、阳性球菌为主，未见粗大阳性杆菌，白细胞少。给予组合物实施例1的异麦芽酮糖凝胶0.5克、每天1次、连续5天，复查，阴道pH值分别为3.8、4.1，阴道细菌以粗大阳性杆菌为主。
实验实施例9
女性，28岁，健康，无不适。月经周期规律，于月经干净后三天取阴道拭子，测pH值4.8，涂片革兰氏染色镜检，见较多粗大阳性杆菌、多种阳性球菌，及少数阴性杆菌，白细胞少见。自愿用组合物实施例2的组合物做阴道清洁护理，每次3克、连续两天，再取阴道拭子，测pH值4.1，涂片革兰氏染色镜检，查见较多粗大阳性杆菌，阳性球菌、阴性杆菌减少。自觉阴部更干净、舒适、清爽。
实验实施例10
女性，52岁，绝经1年多。常感觉阴部干涩，偶有轻微刺痛。取阴道拭子，测pH值5.1，涂片革兰氏染色镜检，细菌少，多为阳性球菌，偶见阳性杆菌，白细胞少见。自愿用组合物实施例13的组合物做阴道清洁护理，每次5克、连续5天，再取阴道拭子，测pH值4.1，涂片染色镜检，粗大阳性杆菌多、其她种类的细菌少，自觉阴部舒适，无干涩或刺痛。
实验实施例11
女性35岁。因白带增多、有异味在医院诊断为“阴道炎”，用含甲硝唑、克霉唑、醋酸氯己定的“双唑泰栓”治疗，每天1次、连续5天，白带减少、异味消失。取阴道拭子，测pH值5.4，涂片革兰氏染色镜检，细菌稀少，未查见白细胞。自愿用组合物实施例6的组合物做阴道清洁护理，每天1次、每次5克，连续3天，再取阴道拭子，测pH值3.8，涂片革兰氏染色镜检，查见较多粗大阳性杆菌。自觉舒适、自在。
实验实施例12
女性41岁。体检时阴道分泌物涂片检查，怀疑“阴道菌群失调”，但平时无明显不适。取阴道拭子，测pH值为4.6，涂片染色镜检，粗大阳性杆菌少，阳性球菌多，可见染色不定小杆菌，Nugent评分5分，白细胞少，符合中间型BV表现。自愿用组合物实施例17的组合物做阴道清洁护理，每天1次、每次5克，连续5天，复查，阴道分泌物pH值3.8，阴道细菌以粗大阳性杆菌为主，阳性球菌、阴性小杆菌显著减少。自觉白带干净、清爽。
实验实施例13
女性45岁，反复白带增多、伴阴部瘙痒多年，用抗菌药物治疗后症状减轻或消失，但常于月经后复发。取阴道拭子，测pH值5.4，涂片染色镜检，粗大阳性杆菌稀少，细菌以多种阴性杆菌、阴性球菌、阳性球菌为主，白细胞少，符合细菌性阴道病表现。自愿用组合物实施例20的组合物清洁护理阴道，每天1次、每次5克，连续5天，复查阴道分泌物pH值4.1，阴道细菌以粗大阳性杆菌为主，阴性杆菌、阴性球菌、阳性杆菌显著减少，无不适。
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Claims (33)

  1. 异麦芽酮糖在制备阴道用组合物中的用途，其中所述组合物中异麦芽酮糖的含量为0.05～20.0％(w/w)。
  2. 如权利要求1所述的用途，其特征在于，所述组合物还含有总量为0.05～2.5％(w/w)的防腐剂和/或抗菌剂。
  3. 如权利要求2所述的用途，其特征在于，所述防腐剂和/或抗菌剂包括：苯甲酸、苯甲酸钠、山梨酸、山梨酸钾、山梨酸钠、乙酸、乙酸钠、双乙酸、双乙酸钠、脱氢乙酸、脱氢乙酸钠、丙酸、丙酸钠、丙酸钙、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、乳铁蛋白肽中的一种或其组合。
  4. 如权利要求1所述的用途，其特征在于，所述组合物还含有总量为0.001～1.0％(w/w)的雌激素类和/或植物雌激素类的物质。
  5. 如权利要求4所述的用途，其特征在于，所述雌激素类和/或植物雌激素类的物质包括：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、芒柄花黄素中的一种或其组合。
  6. 如权利要求1所述的用途，其特征在于，所述组合物还含有阴道黏膜细胞保护物质和/或抗氧化物质。
  7. 如权利要求1所述的用途，其特征在于，所述组合物中还包括：0.1～5.0％(w/w)的芦荟提取物、0.1～5.0％(w/w)的薰衣草提取物、0.001～1.0％(w/w)的维生素E、0.001～1.0％(w/w)的维生素A、0.001～1.0％(w/w)的维生素D、0.001～1.0％(w/w)的维生素C中的一种或其组合。
  8. 如权利要求1至7任一项所述的用途，其特征在于，所述用途为制备包括但不限于下列的用于阴道的组合物产品或组合物制剂：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，或治疗性的阴道用健康产品、阴道用医疗器械、或阴道用药品，或为用于阴道的清洁剂、或养护剂、或除异味剂、或止痒剂、或清新剂、或润湿剂、或润滑剂、或消毒剂、或抗菌剂、或表面杀微生物剂、或微生态调节剂、或微生物调节剂。
  9. 如权利要求1至7任一项所述的用途，其特征在于，所述用途为制备包括但不限于下列用于阴道的组合物剂型：水溶性胶体剂、或水溶液剂、或气雾剂、或软膏剂、或霜剂、或胶囊剂、或微囊剂、或栓剂、或泡腾剂、或片剂。
  10. 如权利要求1至7任一项所述的用途，其特征在于，所述组合物中异麦芽酮糖的含量为1.5～12.0％(w/w)。
  11. 如权利要求1至7任一项所述的用途，其特征在于，所述组合物适用于增强阴道酸度，或维护阴道酸度在pH值3.5～4.5的范围内。
  12. 如权利要求1至7任一项所述的用途，其特征在于，所述组合物用于促进阴道内的保护性乳杆菌生长，所述保护性乳杆菌为卷曲乳杆菌、或詹氏乳杆菌、或格氏乳杆菌。
  13. 一种用于阴道的组合物，其特征在于，所述组合物含有0.05～20.0％(w/w)的异麦芽酮糖。
  14. 如权利要求13所述的组合物，其特征在于，所述组合物还含有总量为0.05～2.5％(w/w)的防腐剂和/或抗菌剂。
  15. 如权利要求14所述的组合物，其特征在于，所述防腐剂和/或抗菌剂包括：苯甲酸、苯甲酸钠、山梨酸、山梨酸钾、山梨酸钠、乙酸、乙酸钠、双乙酸、双乙酸钠、脱氢乙酸、脱氢乙酸钠、丙酸、丙酸钠、丙酸钙、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、乳铁蛋白肽中的一种或其组合。
  16. 如权利要求13所述的组合物，其特征在于，所述组合物还含有总量为0.001～1.0％(w/w)的雌激素类物质和/或植物雌激素类物质。
  17. 如权利要求14所述的组合物，其特征在于，所述组合物还含有总量为0.001～1.0％(w/w)的雌激素类物质和/或植物雌激素类物质。
  18. 如权利要求16所述的组合物，其特征在于，所述雌激素类物质和/或植物雌激素类物质包括：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、芒柄花黄素中的一种或其组合。
  19. 如权利要求13所述的组合物，其特征在于，所述组合物还含有阴道黏膜细胞保护物质和/或抗氧化物质。
  20. 如权利要求13所述的组合物，其特征在于，所述组合物还包括：0.1～5.0％(w/w)的芦荟提取物、0.1～5.0％(w/w)的薰衣草提取物、0.001～1.0％(w/w)的维生素E、0.001～1.0％(w/w)的维生素A、0.001～1.0％(w/w)的维生素D、0.001～1.0％(w/w)的维生素C中的一种或其组合。
  21. 如权利要求14所述的组合物，其特征在于，所述组合物还包括：0.1～5.0％(w/w)的芦荟提取物、0.1～5.0％(w/w)的薰衣草提取物、0.001～1.0％(w/w)的维生素E、0.001～1.0％(w/w)的维生素A、0.001～1.0％(w/w)的维生素D、0.001～1.0％(w/w)的维生素C中的一种或其组合。
  22. 如权利要求13所述的组合物，其特征在于，所述组合物中异麦芽酮糖的含量为1.5～12.0％(w/w)。
  23. 如权利要求13所述的组合物，其中所述组合物为非流动性、粘性、水溶性胶体剂，其特征在于：
    (1)所述组合物含有0.1～20％(w/v)的异麦芽酮糖；
    (2)所述组合物还含有总量为0.1～2.5％(w/v)的下述防腐剂和/或抗菌剂：苯甲酸、苯甲酸钠、山梨酸、山梨酸钾、山梨酸钠、乙酸、乙酸钠、双乙酸、双乙酸钠、脱氢乙酸、脱氢乙酸钠、丙酸、丙酸钠、丙酸钙、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、乳铁蛋白肽中的一种或其组合；
    (3)所述组合物还含有非流动性、粘性、水溶性胶体基质，其中所述胶体基质为黄原胶、卡波姆；
    (4)所述水溶性胶体的pH值为3.5～6.0。
  24. 如权利要求23所述的组合物，其特征在于，所述组合物含有3.0～12％(w/v)的异麦芽酮糖。
  25. 如权利要求13至24任一项所述的组合物，其特征在于，所述组合物为包括但不限于下列用于阴道的组合物产品或组合物制剂：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、或阴道卫生用品、或阴道清洁用品，或治疗性的阴道用健康产品、阴道用医疗器械、或阴道用药品，或为用于阴道的清洁剂、或养护剂、或除异味剂、或止痒剂、或清新剂、或润湿剂、或润滑剂、或消毒剂、或抗菌剂、或表面杀微生物剂、或微生态调节剂、或微生物调节剂。
  26. 如权利要求13至24任一项所述的组合物，其特征在于，所述组合物为包括但不限于下列的阴道用剂型：水溶性胶体剂、或水溶液剂、或气雾剂、或霜剂、或软膏剂、或胶囊剂、或微囊剂、或栓剂、或泡腾剂、或片剂。
  27. 一种向女性阴道内补充糖类物质的方法，其特征在于，所述方法包括向女性阴道内给予如权利要求13至24任一项所述组合物。
  28. 一种非治疗性的女性阴道日常保健、或日常养护、或日常湿润、或日常润滑、或日常清洁以增加阴道外阴的舒适感、或清新感的方法，其特征在于，所述方法包括向女性阴道内给予如权利要求13至24任一项所述的组合物。
  29. 一种于月经后、或同房后、或绝经后、或阴道冲洗后、或阴道用药治疗后对阴道非治疗性地进行清洁、或保健、或养护、或润滑、或湿润，以增强阴道的自净作用、或增强阴道对病原菌的抵抗力的方法，其特征在于，所述方法包括向女性阴道内给予如权利要求13至24任一项所述的组合物。
  30. 一种增强阴道酸度或者维护阴道酸度的方法，其特征在于，所述方法包括向女性阴道内给予如权利要求13至24任一项所述的组合物；所述方法能够增强阴道酸度、或维护阴道酸度在pH值3.5～4.5的范围内。
  31. 一种促进阴道内的保护性乳杆菌生长的方法，其特征在于，所述保护性乳杆菌为卷曲乳杆菌、或詹氏乳杆菌、或格氏乳杆菌，所述方法包括向女性阴道内给予如权利要求13至24任一项所述的组合物。
  32. 一种消除或减轻阴道分泌物异味、或消除或减轻阴道外阴瘙痒、或消除或减轻阴道外阴干涩、或消除或减轻阴道外阴疼痛、性交痛等不适感，或改善白带性状的方法，其特征在于，所述方法包括向女性阴道内给予如权利要求13至24任一项所述的组合物。
  33. 一种调节阴道菌群、或抗菌治疗后恢复阴道有益菌群、或预防或治疗阴道菌群失调、或预防或治疗细菌性阴道病的方法，其特征在于，所述方法包括向女性阴道内给予如权利要求13至24任一项所述的组合物。
PCT/CN2015/073978 2014-03-13 2015-03-11 一种阴道用组合物与该组合物的用途 WO2015135470A1 (zh)

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