Foaming agent for adjusting vagina pH and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a foaming agent for vagina pH adjustment and a preparation method thereof. The foaming agent comprises the following components in parts by weight: 5-8 parts of lactobacillus microcapsules, 1-2 parts of fructo-oligosaccharide, 3-4 parts of glycogen, 0.2 part of phlorizin, 2 parts of lactic acid, 1 part of citric acid, 0.5 part of sodium citrate, 8-10 parts of a propellant, 3.0 parts of sodium alginate and the balance of water, wherein the total parts by weight of the components are 100. The lactobacillus microcapsule is prepared from the following components: lactobacillus, trehalose and chitosan. According to the present invention, the micro-ecology can be rapidly recovered on the basis of the direct killing of pathogenic microorganisms by using the conventional treatment drug in the spaced cooperation manner; the lactobacillus microcapsules can effectively protect stable existence of lactobacillus before colonization in vaginal mucosa; the fructo-oligosaccharide and the glycogen provide substrates for the lactobacillus, help the lactobacillus to proliferate quickly, continuously maintain an acid environment and eliminate pathogenic bacteria through competitive inhibition.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to a foam for adjusting the pH of the vagina and a preparation method thereof. BACKGROUND

[0002] The female reproductive organ is an open organ, which is exposed to a closed and non-breathable environment all year round, and is accompanied by menstruation, pregnancy, childbirth, abortion, contraception, sex, etc., resulting in the accumulation of many toxins in the vagina, which is prone to cause the breeding of bacteria and viruses. The inner wall of the vagina is an irregularly arranged wrinkled tissue, which is not easy to clean and discharge, and can cause a series of inflammations, such as vaginitis, cervicitis, endometritis, adnexitis, and pelvic inflammatory disease. According to the investigation of the World Health Organization on Chinese women: 41% of women of childbearing age have different degrees of gynecological inflammation, and the incidence of married women is as high as 70%. In China, 100,000 people are diagnosed with cervical cancer every year, and 20,000 people die from this disease. Globally, about 470,000 new cases of cervical cancer are found every year. The female vaginal micro-ecosystem is composed of the micro-ecological flora in the vagina, the endocrine regulation function of the body, and the anatomical structure, and is an important indicator of the health of the female reproductive system. The important indicator for the normal maintenance of the female vaginal micro-ecosystem is to maintain the pH of the vagina between 3.8-4.5. The imbalance of the vaginal micro-ecosystem can cause the invasion of pathogenic microorganisms in the vagina and cause various vaginitis, which seriously affects the health and quality of life of female patients. The large-scale reproduction of pathogenic microorganisms in the vagina can cause the pH of the vagina to deviate from the range of 3.8-4.5, further leading to the imbalance of the vaginal micro-ecosystem.

[0003] In conventional treatment, antibacterial drugs can kill pathogenic bacteria, but also have an impact on the already fragile beneficial flora, resulting in the fact that although the pathogenic bacteria are eliminated in a short time, the vaginal micro-ecosystem is not significantly improved, so that the pathogenic bacteria come back again. More time is needed to wait for the vaginal micro-ecosystem to recover itself, which reduces the treatment effect. SUMMARY

[0004] In order to solve the problem that conventional drugs mainly eliminate pathogenic bacteria and are difficult to restore the vaginal micro-ecosystem, the present application provides a foam for adjusting the pH of the vagina, which is used in combination with conventional treatment drugs, can quickly restore the micro-ecosystem on the basis of directly killing pathogenic microorganisms by conventional antibacterial / antifungal drugs (such as metronidazole and clotrimazole), shorten the treatment time, and improve the treatment effect.

[0005] In a first aspect, the present application provides a foam for adjusting the pH of the vagina, which adopts the following technical solution: A foam for vaginal pH adjustment, comprising the following components in parts by weight: Lactobacillus microcapsules 5-8 parts, fructo-oligosaccharides 1-2 parts, glycogen 3-4 parts, phloridzin 0.2 parts, lactic acid 2 parts, citric acid 1 part, sodium citrate 0.5 parts, propellant 8-10 parts, sodium alginate 3.0 parts, and water added to 100 parts; the Lactobacillus microcapsules comprise the following components: Lactobacillus, trehalose and chitosan.

[0006] By adopting the technical scheme, the application provides a dual acidification system, lactic acid provides a core substrate for a vaginal acidic environment, citric acid enhances the acidic buffering capacity, and the two work together to rapidly reduce the vaginal pH to the healthy range of 4.0-4.5, thereby inhibiting the reproduction of pathogens (such as Gardnerella and Candida). Sodium citrate acts as a pH stabilizer to prevent excessive acidity (pH<3.5) from damaging the mucosa or the activity of Lactobacillus, and to maintain environmental suitability.

[0007] The Lactobacillus is prepared in the form of microcapsules, which can effectively protect the Lactobacillus, help the Lactobacillus to stably exist before colonizing the vaginal mucosa. Fructo-oligosaccharides and glycogen are good prebiotics, which provide metabolic substrates for Lactobacillus to produce lactic acid, continuously maintain the acidic environment, and exclude pathogenic bacteria through competitive inhibition.

[0008] The foam for vaginal pH adjustment of the application is mainly used in combination with conventional therapeutic drugs. Conventional antibacterial / antifungal drugs (such as metronidazole and clotrimazole) directly kill pathogenic microorganisms, but simultaneously damage the natural Lactobacillus population in the vagina. Drug residues can temporarily increase the vaginal pH, which is not conducive to the recovery of the microecology. Subsequent spraying of the foam for vaginal pH adjustment can neutralize the residual alkalinity of the drug, the microencapsulated Lactobacillus avoids the bactericidal peak concentration of the drug residues, and secretes lactic acid and hydrogen peroxide after colonization to rebuild the bacteriostatic barrier.

[0009] The application can quickly restore the microecology on the basis of the direct killing of pathogenic microorganisms by conventional antibacterial / antifungal drugs (such as metronidazole and clotrimazole) by using the foam for vaginal pH adjustment in combination with conventional therapeutic drugs. The specific mechanism is that the dual acidification system composed of lactic acid and citric acid rapidly and continuously reduces the vaginal pH to the healthy range of 4.0-4.5, the Lactobacillus microcapsules can effectively protect the Lactobacillus to stably exist before colonizing the vaginal mucosa, and the prebiotics composed of fructo-oligosaccharides and glycogen provide substrates for Lactobacillus, help the Lactobacillus to rapidly proliferate after colonizing the vaginal mucosa, continuously maintain the acidic environment, and exclude pathogenic bacteria through competitive inhibition.

[0010] Preferably, the Lactobacillus microcapsules comprise Lactobacillus crispatus microcapsules, Lactobacillus gasseri microcapsules and Lactobacillus jensenii microcapsules.

[0011] By adopting the technical scheme, the lactobacillus crispatus mainly adheres to the vaginal squamous epithelial cells to form a dense biofilm and strongly occupies a position to block the attachment of pathogens (such as gardnerella). The lactobacillus gasseri is mainly positioned in the middle part of the vaginal mucus layer to secrete a high concentration of hydrogen peroxide to directly kill anaerobes and candida albicans. The lactobacillus jensenii is enriched in the low-oxygen area such as the posterior fornix of the vagina to rapidly proliferate and repair at the mucosal damage.

[0012] The three bacteria cover the surface of the vaginal epithelial cells, the mucus layer and the deep folds, eliminate the blind area of single bacterial colonization and make pathogens have no place to attach. The lactobacillus crispatus preferentially utilizes glycogen to produce acid, and the lactobacillus gasseri / lactobacillus jensenii specifically hydrolyze fructooligosaccharides to promote proliferation. The three bacteria cross-utilize prebiotics to avoid nutritional competition and rapidly increase the density of the bacterial community.

[0013] Preferably, the mass ratio of the lactobacillus crispatus microcapsules, the lactobacillus gasseri microcapsules and the lactobacillus jensenii microcapsules is 4:3:3.

[0014] By adopting the technical scheme, the mass ratio of the three bacteria is 4:3:3, which is relatively appropriate. Otherwise, when the proportion of the lactobacillus crispatus microcapsules is too large, the glycogen is consumed too much, which leads to a lack of sugar source for the lactobacillus gasseri / lactobacillus jensenii, which is not conducive to the large-scale proliferation of the lactobacillus gasseri / lactobacillus jensenii. When the proportion of the lactobacillus gasseri / lactobacillus jensenii microcapsules is too large, the acid production rate is slow, the acidification capacity is insufficient, and the pathogens cannot be quickly inhibited.

[0015] Preferably, the preparation method of the lactobacillus microcapsules comprises the following steps: Mixing and freeze-drying: the lactobacillus is cultured to obtain a bacterial solution, then the bacterial solution is mixed with a trehalose solution, and then freeze-drying is performed to obtain freeze-dried bacterial powder; Microencapsulation: the freeze-dried bacterial powder is mixed with a chitosan solution, and spray drying is performed to obtain lactobacillus microcapsules.

[0016] Preferably, the propellant comprises at least one of tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1-difluoroethane, trans-1,3,3,3-tetrafluoropropene, cis-1,1,1,4,4,4-hexafluoro-2-butene, nitrogen and carbon dioxide.

[0017] In a second aspect, the application provides a preparation method of a foam agent for vaginal pH adjustment, which adopts the following technical scheme: A preparation method of a foam agent for vaginal pH adjustment is used to prepare the above-mentioned foam agent for vaginal pH adjustment, and comprises the following steps: S1. A formula amount of sodium citrate and sodium alginate is added to water to obtain solution one; S2. A formula amount of lactic acid, citric acid, fructooligosaccharide, glycogen and phloridzin is added to water to mix to obtain solution two; S3. Add solution two to solution one, then add the formula amount of Lactobacillus microcapsules, suspend after adding water to the final amount of 100 parts, and obtain the liquid medicine; S4: After vacuum filling the liquid medicine into the aluminum tank, install the valve, then fill the propellant into the aluminum tank, seal the opening, and obtain the foam for vaginal pH adjustment.

[0018] Preferably, in the step of S2, the formula amount of lactic acid, citric acid, prebiotic microcapsules, and phlorizin is added to water to obtain solution two; The preparation method of the prebiotic microcapsules comprises the following steps: Pre1: Homogenize the formula amount of fructooligosaccharides and glycogen in water to obtain a homogenate; Pre2: Add the homogenate to the chitosan oligosaccharide solution, then add the crosslinking agent solution, and spray dry to obtain the prebiotic microcapsules; the crosslinking agent solution comprises at least one of a zinc alginate solution and a pectin calcium solution.

[0019] By adopting the above technical solution, when the foam for vaginal pH adjustment just enters the vagina, pathogenic bacteria mainly exist in the vagina at this time, and the pH of the vaginal environment is also >4.5. If fructooligosaccharides and glycogen are exposed in the vagina, pathogenic bacteria will start to proliferate by using a small amount of fructooligosaccharides and glycogen.

[0020] Preparation of fructooligosaccharides and glycogen into prebiotic microcapsules can lock prebiotics by using a physical barrier. Glycoside hydrolase secreted by pathogenic bacteria is difficult to penetrate the microcapsule pores, effectively preventing the hydrolysis of fructooligosaccharides and glycogen.

[0021] Preferably, the crosslinking agent solution is a zinc alginate solution.

[0022] By adopting the above technical solution, zinc alginate can block Candida albicans hyphal switching genes, inhibit biofilm formation, and strongly inhibit Gardnerella sialidase. Zinc ions are also the cofactor of Lactobacillus crispatus glycogen transport protein (glgP), which improves the utilization rate of glycogen. In short, zinc alginate is not only a crosslinking agent component, but also an active antibacterial factor + prebiotic synergist, while pectin calcium only has a physical crosslinking function.

[0023] More importantly, zinc alginate rapidly releases prebiotics at a healthy vaginal pH (4.2-4.5), while automatically locks at a pathological pH (>5.0) to avoid nutrients being plundered by pathogenic bacteria. While pectin calcium has started to gradually release prebiotics at a pathological pH (>5.0).

[0024] Preferably, S2. Add the formula amount of lactic acid, citric acid, and phlorizin to water to obtain solution two; S3. The solution two is added to the solution one, then the mixed microcapsules are added, water is added to make up to 100 parts, and the mixture is suspended to obtain a liquid medicine; The preparation method of the mixed microcapsules comprises the following steps: Step one: formula amount of fructooligosaccharide and glycogen are added to water for homogenization to obtain a homogenate; Step two: the homogenate and formula amount of lactobacillus microcapsules are added to a chitosan oligosaccharide solution for mixing, then a crosslinking agent solution is added for mixing, and spray drying is performed to obtain mixed microcapsules; the crosslinking agent solution comprises at least one of a zinc alginate solution and a pectin calcium solution.

[0025] By adopting the technical scheme, in addition to the beneficial effects of the probiotic microcapsules, the mixed microcapsules have other beneficial effects. The probiotic and the lactobacillus microcapsules in the mixed microcapsules are closer, the probiotic is released synchronously to activate the lactobacillus, and the acidic environment is quickly reconstructed. The main reason is that a cascade reaction can be formed in the mixed microcapsules. The specific process is that the probiotic is released to provide nutrition for the lactobacillus at zero distance, the lactobacillus metabolizes to produce lactic acid, and the lactic acid can dissolve the outer microcapsules, so as to further release the probiotic.

[0026] Preferably, the crosslinking agent solution is a zinc alginate solution.

[0027] In summary, the present application has the following beneficial effects: 1. Since the present application is used in combination with conventional therapeutic drugs, it can quickly restore the microecology on the basis of directly killing pathogenic microorganisms by conventional antibacterial / antifungal drugs (such as metronidazole and clotrimazole). The specific mechanism is that the double acidification system composed of lactic acid and citric acid quickly and continuously reduces the vaginal pH to the healthy range of 4.0-4.5, and the lactobacillus microcapsules can effectively protect the lactobacillus from being stably present in the vaginal mucosa; the probiotic composed of fructooligosaccharide and glycogen provides a substrate for the lactobacillus, helps the lactobacillus to colonize and proliferate rapidly in the vaginal mucosa, continuously maintains the acidic environment, and excludes pathogenic bacteria through competitive inhibition; 2. The present application prepares fructooligosaccharide and glycogen into probiotic microcapsules in advance, which can lock the probiotic by a physical barrier; the glycoside hydrolase secreted by pathogenic bacteria is difficult to penetrate the microcapsule pores, effectively preventing the hydrolysis of fructooligosaccharide and glycogen; 3. The present application prepares fructooligosaccharide, glycogen, and lactobacillus microcapsules into mixed microcapsules in advance, which can effectively protect the probiotic, shorten the distance between the probiotic and the lactobacillus, produce a cascade reaction, and enhance the effect. DETAILED DESCRIPTION

[0028] In the present application, the raw materials include the following parts: Propellant: at least one of tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1-difluoroethane, trans-1,3,3,3-tetrafluoropropene, cis-1,1,1,4,4,4-hexafluoro-2-butene, nitrogen, and carbon dioxide can be used as the propellant in this application. The following examples and comparative examples are only illustrated by using nitrogen. Trehalose: Uses commercially available products with CAS number 6138-23-4; Chitosan: The product used is a commercially available product with CAS number 9012-76-4; Fructooligosaccharides: Commercially available products with CAS number 308066-66-2 are used; Glycogen: Uses a commercially available product with CAS number 9005-79-2; Phlorizin: The commercially available product with CAS number 60-81-1 is used; Sodium alginate: Uses commercially available products with CAS number 9005-38-3; Chitosan oligosaccharide: The product used is a commercially available product with CAS number 148411-57-8; Pectin: Uses commercially available products with CAS number 9000-69-5; The present application will be further described in detail below with reference to embodiments and comparative examples.

[0029] Example 1 A method for preparing Lactobacillus microcapsules includes the following steps: Mixed freeze-drying: Lactobacillus was inoculated into MRS medium and anaerobically cultured at 37°C for 24 hours to obtain a bacterial suspension. The concentration of Lactobacillus in the suspension was 0.8 × 10⁻⁶. 10 CFU-1.2×10 10 CFU / mL, then 100mL of bacterial culture was mixed with 200mL of trehalose solution (trehalose concentration 10wt%), and then freeze-dried to obtain freeze-dried bacterial powder; Microencapsulation: The freeze-dried bacterial powder was mixed with 50 mL of chitosan solution (2 wt% chitosan) and spray-dried to obtain Lactobacillus microcapsules with a particle size of 60-80 μm.

[0030] The types of lactobacilli mentioned above include Lactobacillus curvaturei, Lactobacillus gasseri, and Lactobacillus janniae, so Lactobacillus curvaturei microcapsules, Lactobacillus gasseri microcapsules, and Lactobacillus janniae microcapsules can be prepared.

[0031] A method for preparing a foaming agent for vaginal pH adjustment includes the following steps: S1. Add 0.5g sodium citrate and 3g sodium alginate to 30g water to obtain solution one; S2. 2 g of lactic acid, 1 g of citric acid, 1.5 g of fructooligosaccharide, 3.5 g of glycogen, and 0.2 g of phloridzin were added to 20 g of water to obtain solution two; S3. Solution two was added to solution one, then 7 g of Lactobacillus mixed microcapsules were added, and 22.3 g of water was added (to make up to a final amount of 100 g) to obtain a liquid medicine; the mass ratio of Lactobacillus crispatus microcapsules, Lactobacillus gasseri microcapsules, and Lactobacillus jensenii microcapsules in the 7 g of Lactobacillus mixed microcapsules was 4:3:3; S4: After the liquid medicine was vacuum filled into an aluminum can, a valve was installed, 9 g of nitrogen was filled into the aluminum can, and then the aluminum can was sealed to obtain a foam for vaginal pH adjustment.

[0032] Example 2-3 Example 2-3 was prepared based on the preparation method of Example 1, and the content of each component of the foam for vaginal pH adjustment was adjusted, as shown in Table 1.

[0033] Performance detection test The foams for vaginal pH adjustment of Examples 1-3 and Comparative Examples 1-2 were subjected to the following performance detection, and the detection results are shown in Table 1.

[0034] Total concentration of lactobacillus and pathogen clearance rate Preparation of strain solution: vaginal Gardnerella cultivation was performed, and then 1 mL of a strain solution with a concentration of 1*10 8 CFU / mL was taken as an infection bacterial solution.

[0035] Pre-treatment: adult female mice were selected, and estradiol sustained-release tablets (0.1 mg / tablet) were implanted subcutaneously to maintain estrus for 7 days. 50 μL of an antibiotic solution (ampicillin 10 mg / mL + streptomycin 5 mg / mL) was lavaged into the vagina daily for 3 consecutive days to remove lactobacillus in the vagina.

[0036] 20 μL of the infection bacterial solution was taken from each mouse and injected into the vagina, and the vaginal orifice was clamped for 1 h, once a day for 5 consecutive days. Vaginal secretion was taken on the 5th day after the last inoculation for smear examination, and Gardnerella was positive under a microscope, indicating that the modeling was successful. The concentration C of Gardnerella was determined.

[0037] The experimental animals in which the modeling was successful in the above step were divided into 6 groups, 24 in each group. 40 μL of 0.75 wt% metronidazole gel was perfused every day, and then 100 μL of the foam for vaginal pH adjustment of Example 1-3 was used for treatment 8 hours later, and the treatment was continuously performed for 7 days. The total concentration of lactobacillus was determined 48 h after the administration of the foam for vaginal pH adjustment on the 7th day. The concentration D of Gardnerella was determined 48 h after the administration of the foam for vaginal pH adjustment on the 7th day, and then the pathogen clearance rate = (C-D / C)*100%.

[0038] The control group was treated with only 40 μL of 0.75 wt% metronidazole gel perfusion every day, without the foam for vaginal pH adjustment, and was still administered continuously for 7 days.

[0039] Table 1: Content of each component of the foam for vaginal pH adjustment of Examples 1-3 and performance test table of the control group As shown in Table 1, according to the above-mentioned formula, the foam for vaginal pH adjustment prepared according to Comparative Examples 1-3 and the control group has a good therapeutic effect on bacterial vaginosis. Metronidazole directly kills pathogenic microorganisms quickly, and the foam for vaginal pH adjustment sprayed after 8 hours can neutralize the residual alkalinity of the drug, and the microencapsulated lactobacillus also avoids the bactericidal peak concentration of the drug residue, and secretes lactic acid and hydrogen peroxide after colonization to rebuild the bacteriostatic barrier. The two are mutually synergistic to improve the therapeutic effect.

[0040] Comparing the control group, it can be found that without lactobacillus, only metronidazole alone has poor effect and needs a longer treatment time. In addition, the present application is only exemplified with metronidazole, and in fact, it can be combined with a variety of therapeutic drugs. For example, miconazole nitrate, econazole nitrate, sertaconazole nitrate, isoconazole nitrate, clotrimazole, metronidazole, policresulen, nifuratel, nystatin, Fungitell, Ornidazole, and the like, which are not exemplified one by one.

[0041] In addition, comparing Examples 1-3, it is found that the performance of Example 1 is the best, and therefore, Example 1 is preferred.

[0042] Examples 4-8 Examples 4-6 are based on the preparation method of Example 1, and the mixed lactobacillus microcapsules are replaced by single lactobacillus microcapsules, and the specific types are shown in Table 2.

[0043] Examples 7-8 are based on the preparation method of Example 1, and the mass ratio of the three kinds of lactobacillus microcapsules in the mixed lactobacillus microcapsules is adjusted, and the specific adjustment is shown in Table 2.

[0044] The foam for vaginal pH adjustment of Examples 4-8 is subjected to the performance test as above, and the test results are shown in Table 2.

[0045] Table 2: Lactobacillus microcapsule types and mass ratio of three kinds of lactobacillus microcapsules of Example 1 and Examples 4-8 and performance test table As shown in Table 2, the three Lactobacillus microcapsules are better than the single Lactobacillus microcapsule. The reason is that the three bacteria cover the surface of the vaginal epithelial cells, the mucus layer and the three-dimensional space of the deep folds, eliminating the blind area of single bacterial colonization and making it difficult for pathogens to attach. Lactobacillus crispatus preferentially produces acid using glycogen, and Lactobacillus gasseri / jensenii specifically hydrolyzes fructooligosaccharides to promote proliferation. The three bacteria cross-utilize prebiotics to avoid nutrient competition and rapidly increase the density of the bacterial population.

[0046] The mass ratio of the three bacteria is 4:3:3, which is relatively appropriate. The reason is that when the proportion of Lactobacillus crispatus microcapsules is too high, it consumes a large amount of glycogen, leading to a lack of sugar source for Lactobacillus gasseri / jensenii, which is not conducive to its proliferation. When the proportion of Lactobacillus gasseri / jensenii microcapsules is too high, the acid production rate is slow, the acidification capacity is insufficient, and it cannot quickly inhibit pathogens.

[0047] Examples 9-12 Example 9 adjusts the preparation method of the foam for vaginal pH regulation based on the preparation method of Example 1, and the specific adjustments are as follows: In the step of S2, 2g of lactic acid, 1g of citric acid, prebiotic microcapsules, and 0.2g of phloridzin are added to 20g of water to obtain solution two. The preparation method of the prebiotic microcapsules includes the following steps: Pre1: 1.5g of fructooligosaccharides and 3.5g of glycogen are added to 300mL of water to obtain a homogeneous solution. Pre2: The homogeneous solution is added to 500mL of chitosan oligosaccharide solution (chitosan 10g) and mixed, then zinc alginate solution is added and mixed, and spray drying is performed to obtain prebiotic microcapsules; the zinc alginate solution is prepared by dissolving 1.5g of sodium alginate and 0.75g of zinc chloride in 50mL of water and stirring at 50°C until clear.

[0048] Example 10 adjusts the preparation method of the foam for vaginal pH regulation based on the preparation method of Example 1, and the specific adjustments are as follows: In the step of S2, 2g of lactic acid, 1g of citric acid, prebiotic microcapsules, and 0.2g of phloridzin are added to 20g of water to obtain solution two. The preparation method of the prebiotic microcapsules includes the following steps: Pre1: 1.5g of fructooligosaccharides and 3.5g of glycogen are added to 300mL of water to obtain a homogeneous solution. Pre2: The homogeneous solution is added to 500mL of chitosan oligosaccharide solution (chitosan 10g) and mixed, then pectin calcium solution is added and mixed, and spray drying is performed to obtain prebiotic microcapsules; the pectin calcium solution is prepared by dissolving 2g of pectin and 0.5g of calcium chloride in 50mL of water and ultrasonic degassing for 10min.

[0049] Example 11 is based on the preparation method of Example 1, and the preparation method of the foam for vaginal pH adjustment is adjusted as follows: S2. 2g lactic acid, 1g citric acid, and 0.2g phloridzin are added to 20g water to obtain solution two; S3. Solution two is added to solution one, then mixed microcapsules are added, and water is added to make up to a final volume of 100g to obtain a medicinal liquid; The preparation method of the mixed microcapsules comprises the following steps: Step one: 1.5g fructooligosaccharide and 3.5g glycogen are added to 300mL water to obtain a homogenate; Step two: the homogenate and 7g lactobacillus microcapsules are added to 500mL chitosan oligosaccharide solution (chitosan 15g) to mix, then zinc alginate solution is added to mix, and spray drying is performed to obtain mixed microcapsules; the zinc alginate solution is prepared by dissolving 2g sodium alginate and 1g zinc chloride in 100mL water and stirring at 50°C until clear.

[0050] Example 12 is based on the preparation method of Example 1, and the preparation method of the foam for vaginal pH adjustment is adjusted as follows: S2. 2g lactic acid, 1g citric acid, and 0.2g phloridzin are added to 20g water to obtain solution two; S3. Solution two is added to solution one, then mixed microcapsules are added, and water is added to make up to a final volume of 100g to obtain a medicinal liquid; The preparation method of the mixed microcapsules comprises the following steps: Step one: 1.5g fructooligosaccharide and 3.5g glycogen are added to 300mL water to obtain a homogenate; Step two: the homogenate and 7g lactobacillus microcapsules are added to 500mL chitosan oligosaccharide solution (chitosan 15g) to mix, then zinc alginate solution is added to mix, and spray drying is performed to obtain mixed microcapsules; the zinc alginate solution is prepared by dissolving 2g sodium alginate and 1g zinc chloride in 100mL water and stirring at 50°C until clear.

[0051] The foam for vaginal pH adjustment of Examples 9-12 is subjected to the performance test as above, and the test results are shown in Table 3.

[0052] Table 3 Pre-treatment conditions and crosslinking agent types of Examples 1 and 9-12 and performance test table As shown in Table 3, the comparative example 1 and examples 9-12 show that the pre-preparation of fructooligosaccharide and glycogen into probiotic microcapsules or the preparation of fructooligosaccharide, glycogen and lactobacillus microcapsules into mixed microcapsules is more conducive to the function of the foam. The reason is that the probiotic microcapsules can lock the probiotics by using a physical barrier. Glycoside hydrolases secreted by pathogenic bacteria are difficult to penetrate the microcapsule pores, effectively preventing the hydrolysis of fructooligosaccharide and glycogen.

[0053] The mixed microcapsules are more effective because, in addition to the beneficial effects of the probiotic microcapsules described above, the probiotics and lactobacillus microcapsules in the mixed microcapsules are closer together, and the release of probiotics synchronously activates lactobacillus, quickly rebuilding the acidic environment. The main reason is that a cascade reaction can occur in the mixed microcapsules. The specific process is that the release of probiotics provides nutrition for lactobacillus at zero distance, lactobacillus metabolizes to produce lactic acid, and lactic acid can dissolve the outer microcapsules, thereby further releasing probiotics.

[0054] Regardless of the probiotic microcapsules or the mixed microcapsules, the use of zinc alginate as the cross-linking agent is more effective. The reason is that zinc alginate, compared to calcium pectin, can block the Candida albicans hyphae conversion gene, inhibit biofilm formation, and effectively inhibit the sialidase of Gardnerella. Zinc ions are also the cofactor of the lactobacillus glycogen transport protein (glgP), which improves the utilization rate of glycogen. In short, zinc alginate is not only a cross-linking agent component, but also an active antibacterial factor + probiotic synergist, while calcium pectin only has a physical cross-linking function. More importantly, zinc alginate quickly releases probiotics at a healthy vaginal pH (4.2-4.5), and automatically locks at a pathological pH (>5.0) to avoid the nutrients being plundered by pathogenic bacteria. While calcium pectin has started to gradually release probiotics at a pathological pH (>5.0).

[0055] The specific embodiments are merely an explanation of the present application, which is not a limitation of the present application. Those skilled in the art can make modifications to the embodiments without creative contributions after reading the present specification, but as long as the modifications are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. A foaming agent for vaginal pH adjustment, characterized in that, The product comprises the following components in parts by weight: 5-8 parts of Lactobacillus microcapsules, 1-2 parts of fructooligosaccharides, 3-4 parts of glycogen, 0.2 parts of phlorizin, 2 parts of lactic acid, 1 part of citric acid, 0.5 parts of sodium citrate, 8-10 parts of propellant, 3.0 parts of sodium alginate, and water to a total of 100 parts; the Lactobacillus microcapsules comprise the following components: Lactobacillus, trehalose, and chitosan.

2. The foaming agent for vaginal pH adjustment according to claim 1, characterized in that: The lactobacillus microcapsules include curly lactobacillus microcapsules, lactobacillus gassieri microcapsules, and lactobacillus janniae microcapsules.

3. The foaming agent for vaginal pH adjustment according to claim 2, characterized in that: The mass ratio of the Lactobacillus curvature microcapsules, Lactobacillus gasseri microcapsules, and Lactobacillus janniae microcapsules is 4:3:

3.

4. The foaming agent for vaginal pH adjustment according to claim 1, characterized in that: The method for preparing the Lactobacillus microcapsules includes the following steps: Mixed freeze-drying: The Lactobacillus is cultured to obtain a bacterial solution, then the bacterial solution is mixed with a trehalose solution and freeze-dried to obtain freeze-dried bacterial powder; Microencapsulation: The freeze-dried bacterial powder was mixed with chitosan solution and spray-dried to obtain lactobacillus microcapsules.

5. The foaming agent for vaginal pH adjustment according to claim 1, characterized in that: The propellant includes at least one of tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1-difluoroethane, trans-1,3,3,3-tetrafluoropropene, cis-1,1,1,4,4,4-hexafluoro-2-butene, nitrogen, and carbon dioxide.

6. The method for preparing the foaming agent for vaginal pH adjustment according to any one of claims 1-5, characterized in that: S1. Add the prescribed amounts of sodium citrate and sodium alginate to water to obtain solution one; S2. Add the prescribed amounts of lactic acid, citric acid, fructooligosaccharides, glycogen, and phlorizin to water and mix to obtain solution two; S3. Add the second solution to the first solution, then add the prescribed amount of lactobacillus microcapsules, add water to make up to a final volume of 100 parts, suspend, and obtain the drug solution; S4: After vacuum filling the liquid medicine into an aluminum can, install a valve, fill the aluminum can with propellant, and then seal it to obtain a foaming agent for vaginal pH adjustment.

7. The method for preparing the foaming agent for vaginal pH adjustment according to claim 6, characterized in that: In step S2, the formulated amounts of lactic acid, citric acid, prebiotic microcapsules, and phlorizin are added to water and mixed to obtain solution two. The method for preparing the prebiotic microcapsules includes the following steps: Preliminary step 1: Add the prescribed amounts of fructooligosaccharides and glycogen to water and homogenize to obtain a homogenized solution; Preliminary 2: The homogenized liquid is added to the chitosan oligosaccharide solution and mixed, then a cross-linking agent solution is added and mixed, and spray-dried to obtain prebiotic microcapsules; the cross-linking agent solution includes at least one of zinc alginate solution and calcium pectin solution.

8. The method for preparing the foaming agent for vaginal pH adjustment according to claim 7, characterized in that: The crosslinking agent solution is a zinc alginate solution.

9. The method for preparing the foaming agent for vaginal pH adjustment according to claim 6, characterized in that: S2. Add the prescribed amounts of lactic acid, citric acid, and phlorizin to water and mix to obtain solution two; S3. Add the second solution to the first solution, then add the mixed microcapsules, and add water to make up to a final volume of 100 parts, then suspend to obtain the drug solution; The method for preparing the hybrid microcapsules includes the following steps: Step 1: Add the prescribed amounts of fructooligosaccharides and glycogen to water and homogenize to obtain a homogenized solution; Step 2: Add the homogenized liquid and the formulated amount of Lactobacillus microcapsules to the chitosan oligosaccharide solution and mix, then add the cross-linking agent solution and mix, and spray dry to obtain mixed microcapsules; the cross-linking agent solution includes at least one of zinc alginate solution and calcium pectin solution.

10. The method for preparing the foaming agent for vaginal pH adjustment according to claim 9, characterized in that: The crosslinking agent solution is a zinc alginate solution.

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