CN111135157A - Use of a combination of 3-phenyllactic acid and prebiotics for improving the bacterial phase - Google Patents
Use of a combination of 3-phenyllactic acid and prebiotics for improving the bacterial phase Download PDFInfo
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- CN111135157A CN111135157A CN201910466553.9A CN201910466553A CN111135157A CN 111135157 A CN111135157 A CN 111135157A CN 201910466553 A CN201910466553 A CN 201910466553A CN 111135157 A CN111135157 A CN 111135157A
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- phenyllactic acid
- combination
- prebiotics
- bacterial phase
- bacterial
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- 235000013406 prebiotics Nutrition 0.000 title claims abstract description 31
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 239000000832 lactitol Substances 0.000 claims description 9
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- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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Images
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7016—Disaccharides, e.g. lactose, lactulose
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- 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
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- 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
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- 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
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
本发明涉及3‑苯乳酸的新用途领域，尤其是一种3‑苯乳酸及益生质的组合用于改善菌相的用途，本发明3‑苯乳酸及益生质的组合的功效在于：可通过调节与改善女性阴道内的菌相，降低病原菌生长，达到保健女性私密处的功效。The present invention relates to the new use field of 3-phenyllactic acid, especially the use of a combination of 3-phenyllactic acid and prebiotics for improving bacterial phase, and the effect of the combination of 3-phenyllactic acid and prebiotics of the present invention is: Adjust and improve the bacterial phase in the vagina of women, reduce the growth of pathogenic bacteria, and achieve the effect of health care of women's private parts.
Description
Technical Field
The invention relates to the field of new application of 3-phenyllactic acid, in particular to application of a combination of 3-phenyllactic acid (3-phenyllactic acid) and prebiotics (probiotics) in improving a bacterial phase.
Background
Under normal circumstances, the vagina of a woman secretes a little secretion, which has the effect of lubricating the vagina and is indispensable to the vagina. However, in the case of poor hygiene or decreased resistance, vaginal discharge increases, color changes and an unpleasant odor sometimes occur, i.e., vaginitis is developed. These abnormal secretions can cause extreme itching or pain in the affected part of the patient, thus causing great psychological and physiological discomfort to the patient. The secretion produced by vaginitis may cause red swelling and itching and pain of vulva, so called vulvitis, and vaginitis and vulvitis are commonly called pudendum infection. The common causes of pudendal infections in women include: 1. candida spp, such as Candida albicans, is susceptible to growth in warm and humid environments, and is susceptible to repeated infections (such as insufficient sleep, colds, premenstrual and pregnancy) when the resistance of an individual is insufficient, and symptoms after infection include itching, burning, swelling of the vulva, white secretions in the form of cheese lumps, sore and swollen urethra, painful urination, and the like, and are particularly uncomfortable before and after menstruation. 2. Bacterial infections, common symptoms include a large amount of off-white or yellow secretions after sexual intercourse, with a fishy smell, and most patients without itching. Too frequent sexual intercourse or too frequent vaginal douches can lead to an increase in vaginal pH, which is a major cause of bacterial infection, since bacteria that cause infection are suitably present in a more alkaline environment (pH > 4.5). Bacteria causing bacterial infection include Escherichia coli (Escherichia coli), Gardnerella vaginalis (Gardnerella vagianalis), Streptococcus (Streptococcus), and the like.
The normal vaginal environment is not sterile and comprises approximately six species of bacteria, among which staphylococci, coliforms, diphtheroids, candida species and Lactobacillus species (Lactobacillus spp.). The lactobacillus species with the largest content are probiotics, and staphylococcus, escherichia coli, diphtheroid bacteria, candida species and the like are pathogenic bacteria, but when the quantity of the pathogenic bacteria is small, the negative influence on the health of the vagina is avoided, and as long as the vagina is maintained in a normal bacterial phase, namely when the probiotics are dominant, the pathogenic bacteria are not bred in large quantity, so that the infection cannot happen. In addition, the normal pH value of the vagina is about pH 3.8-4.2, i.e. the vagina is weak in acidity, and if the pH value of the vagina is changed to be neutral or alkaline, infection can occur. The lactobacillus species can maintain the pH value of the vagina to be 3.8-4.2, and most pathogenic bacteria causing vaginal infection cannot grow in the weak acidic environment, so that the vagina can be kept healthy.
However, when the bacterial phase in the vagina is destroyed, the aforementioned infection condition occurs. The existing method for treating female pudendum infection generally adopts medicines such as antibiotics, steroids and the like for treatment, but probiotics and pathogenic bacteria are killed together, so that the vaginal environment is in a sterile state in the early treatment period, and the probiotics and the pathogenic bacteria compete with each other, but the pathogenic bacteria grow better than the probiotics as a result of the competition, so that the situation of repeated infection is easy to occur, and the treatment needs to be carried out repeatedly. However, repeated use of antibiotics and steroids is likely to cause drug resistance of pathogenic bacteria and even cause damage to the immune system of human body. In addition, most of the currently marketed vaginal care products contain iodine, and although the infection symptoms can be alleviated in a short period of time, the pH value of the vaginal care products is neutral, and the pH value of the vaginal care products rises after use, and the vaginal care products are changed into an environment suitable for the growth of pathogenic bacteria, so that the symptoms easily recur, and the symptoms are difficult to be cured.
In order to solve the above problems, those skilled in the art need to develop a novel pharmaceutical composition with the efficacy of improving bacterial flora to benefit the population.
Disclosure of Invention
In view of the above, the present invention provides the use of a combination of 3-phenyllactic acid and prebiotics for the preparation of a composition having an improved bacterial phase.
In one embodiment of the invention, the prebiotic is lactitol.
In one embodiment of the present invention, the bacterial phase is a bacterial phase within a female vagina.
In one embodiment of the invention, the bacterial phase includes Lactobacillus species (Lactobacillus spp.), Gardnerella vaginalis (Gardnerella vagianalis), Candida species (Candida spp.) and Escherichia coli (Escherichia coli).
In one embodiment of the invention, the combination of 3-phenyllactic acid and prebiotics increases the number of Lactobacillus species and decreases the number of Gardnerella vaginalis, Candida species and E.coli.
In one embodiment of the present invention, the volume ratio of 3-phenyllactic acid to lactitol is 1: 10-25.
In one embodiment of the present invention, the composition is a pharmaceutical composition.
In one embodiment of the present invention, the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
In one embodiment of the present invention, the pharmaceutical composition is in a form for topical administration.
In one embodiment of the present invention, the pharmaceutical composition is in the form of a sanitary napkin or spray.
In one embodiment of the present invention, 3-phenyllactic acid is purified by High Performance Liquid Chromatography (HPLC).
In summary, the efficacy of the combination of 3-phenyllactic acid and prebiotics of the present invention lies in: can reduce the growth of pathogenic bacteria by adjusting and improving the bacterial facies in the vagina of the female, thereby achieving the effect of protecting the private parts of the female.
The following examples are presented to illustrate the present invention and are not to be construed as limiting the scope of the invention, which is intended to be limited only by the appended claims.
Drawings
FIG. 1 is a graph of data showing the efficacy of a combination of 3-phenyllactic acid and prebiotics of the present invention in improving the bacterial phase in subject 1;
FIG. 2 is a graph of data showing the efficacy of the combination of 3-phenyllactic acid and prebiotics of the present invention in improving the bacterial phase in subject 2;
FIG. 3 is a graph of data showing the efficacy of the combination of 3-phenyllactic acid and prebiotics of the present invention in improving the bacterial phase in subject 3;
FIG. 4 is a graph of data showing the efficacy of the combination of 3-phenyllactic acid and prebiotics of the present invention in improving the bacterial phase in subject 4;
FIG. 5 is a graph of data showing the efficacy of the combination of 3-phenyllactic acid and prebiotics of the present invention in improving the mean bacterial phase in 4 subjects.
Detailed Description
Definition of
As used herein, the numerical values are approximations and all numerical data are reported to be within the 20 percent range, preferably within the 10 percent range, and most preferably within the 5 percent range.
According to the present invention, 3-phenyllactic acid (3-phenyllactic acid) has the following formula (I):
as used herein, the term "prebiotic" means a substance that exerts a biological effect on a body by selectively stimulating the growth or biological activity of beneficial microorganisms.
According to the invention, lactitol has the following formula (II):
in accordance with the present invention, the pharmaceutical composition may be formulated into a form suitable for topical (topically) administration using techniques well known to those skilled in the art, including, but not limited to, sprays, gels, lotions, creams, ointments, tampons, powders, tissues, tampons, and tablets.
According to the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier (pharmaceutically acceptable carrier) which is widely used in pharmaceutical manufacturing technology. For example, the pharmaceutically acceptable carrier may comprise one or more agents selected from the group consisting of: solvents (solvent), buffers (buffer), emulsifiers (emulsifying), suspending agents (suspending agent), disintegrating agents (disintegrant), disintegrating agents (disintegrating agent), dispersing agents (dispersing agent), binding agents (binding agent), excipients (excipient), stabilizers (stabilizing agent), chelating agents (chelating agent), diluents (diluent), gelling agents (gelling agent), preservatives (preserving), wetting agents (wetting agent), lubricants (lubricating), absorption delaying agents (absorption delaying agent), liposomes (liposome) and the like. The selection and amounts of such agents are within the skill and routine skill of those skilled in the art.
According to the present invention, the pharmaceutically acceptable carrier comprises a solvent selected from the group consisting of: water, normal saline (normal saline), Phosphate Buffered Saline (PBS), aqueous alcohol-containing solutions (aqueous solution linking alcohol), and combinations thereof.
Example 1.3 preparation of a combination of phenyllactic acid (3-phenyllactic acid) and prebiotics
First, the procedure for isolating Lactobacillus plantarum (Lactobacillus plantarum) TCI378 is as follows:
(1) screening
A homogeneous material of kimchi (including kimchi and sauce) was mixed with MRS broth (MRS broth) at a volume ratio of 1: 100, and subjected to anaerobic culture (oxygen concentration less than 5%) at 37 ℃ for 18 hours. Thereafter, the aforementioned culture solution was spread on MRS solid medium (MRS agar) and placed at 37 ℃ for anaerobic culture to generate different colonies. Next, to ensure the uniqueness of the strain, a colony was picked using a sterile inoculating loop, streaked on a solid medium, and cultured in an anaerobic incubator at 37 ℃ until a single colony (single colony) appeared.
(2) Identification
The single colony strain isolated in the above screening process was subjected to gene family profiling (phylogenetic analysis), and confirmed to have the nucleotide sequence shown in SEQ ID NO: 11 (16S) ribosomal ribonucleic acid (16S rRNA). Alignment using the ncbi (national Center for Biotechnology information) online database confirmed the SEQ ID NO: 11 and 16S ribosomal ribonucleic acid (16S rRNA) fragment of Lactobacillus plantarum strain, so the target strain was identified as Lactobacillus plantarum by relativity and named as Lactobacillus plantarum TCI378, wherein Lactobacillus plantarum TCI378 was deposited in the center for food industry research and development institute for biological resource conservation and research on 2016, 12, 27, with accession number BCRC910760, see taiwan patent No. TWI 645854.
(3) Preservation of
The strain with single property obtained in the above screening process was cultured in MRS culture solution by liquid culture to provide a bacterial solution, 25% glycerol was added to the bacterial solution, and the resulting mixture was transferred to a cryopreservation tube and stored at-80 ℃.
Then, after the Lactobacillus plantarum TCI378 strain preservation tube is activated once, the Lactobacillus plantarum TCI378 strain preservation tube is cultured in an MRS culture medium with the germ quantity of 1-10% and cultured for 18 hours at 37 ℃. Subsequently, the bacterial suspension was centrifuged at 5,000rpm for 20 minutes, and then the supernatant was collected and taken as an analysis sample.
Then, 2L of the supernatant was taken and concentrated under reduced pressure to a volume of 300mL, followed by column chromatography over macroporous resin (Diaion HP-20, 100 cm. times.8 cm) with gradient from water to methanol to give 5 fractions (fraction 1: 0% methanol, fraction 2: 20% methanol, fraction 3: 40% methanol, fraction 4: 60% methanol, fraction 5: 100% methanol). Next, fraction 3 was subjected to RP-C18 flash column Chromatography (HPLC column: Luna 5u RP-C18, 250X 10mm, Phenomenex, USA) with a linear gradient from 20% methanol to 100% methanol, and Thin Layer Chromatography (TLC) (Silica gel 60F)254；RP-18 F254S, Merck, EMD milopore co, germany) yielded 8 sub-layers. Thereafter, fraction 7 was subjected to column chromatography on Sephadex LH-20 gel (Pharmacia, Piscataway, NJ, USA) and subjected to thin layer chromatography to obtain 8 fractions. The compound was purified by reverse phase-high performance liquid chromatography (RP-HPLC) from fraction 5 (methanol/water: 2/3) to give the compound.
Subsequently, the compound was analyzed by 1H and 13C Nuclear Magnetic Resonance (NMR) (Ascend 400' 54400 MHz, Bruker co., germany), Heteronuclear Single Quantum Correlation (HSQC), Heteronuclear Multiple Bond Correlation (HMBC), Correlation Magnetic Resonance Spectroscopy (COSY), and electrospray ionization mass spectrometry (ESIMS), confirming that the chemical structure was 3-phenyllactic acid. Then, 1-5% (w/w) lactitol is added to the fermentation culture solution of Lactobacillus plantarum TCI378 containing 3-phenyllactic acid, so as to obtain a combination of 3-phenyllactic acid and prebiotics (i.e. lactitol).
Example 2.3 evaluation of the effectiveness of the combination of phenyllactic acid and prebiotics on improving the phases of bacteria
In this example, a combination of 3-phenyllactic acid and a prebiotic (e.g., lactitol) was used to evaluate the effectiveness of the improvement in bacterial phase in the female vagina.
The combination of 3-phenyllactic acid and prebiotics was administered in the form of feminine hygiene pads in an amount of 4 pads/day. First, 4 adult women were recruited as subjects, and then one piece of a sanitary napkin containing a combination of 3-phenyllactic acid and prebiotics was replaced after three meals a day and before bedtime. Subsequently, smear sampling of the vaginal opening was performed with a cotton swab before bathing at time points of 0, 3, 7 and 14 days. The sampling process is as follows: the method comprises the steps of smearing a sterilized cotton swab on the upper part of the female perineum back and forth for 5-6 times, and then putting the smeared cotton swab head into a sampling tube containing 0.5mL of preservation solution (17mM sodium citrate, 13mM EDTA, 46.7% (w/v) ammonium sulfate and having a pH value of 5.2). And then, breaking the upper part of the cotton swab, leaving the cotton swab head in the preservation solution, screwing the sampling tube cover, and preserving at normal temperature until the sampling tube cover is delivered to a laboratory for analysis.
Then, the sampled Swab was taken, and the microbial samples in the Swab were extracted and purified by using a Presto burcal Swab DNA Extraction kit (Presto burcal Swab DNA Extraction kit) (genetic aid, cat. No. gsk300-DG), and the concentration and purity of the extracted DNA samples were measured. Then, quantitative real-time polymerase chain reaction (qRT-PCR) detection of 16S ribosomal gene (16Sribosomal gene) was performed for Lactobacillus species (Lactobacillus spp.) as probiotic, and Gardnerella vaginalis (Gardnerella vagiana), Candida spp (Candida spp.) and Escherichia coli (Escherichia coli) as pathogenic bacteria. The bacterial facies composition in 4ng DNA samples was analyzed by qRT-PCR, and triplicate experiments were performed for each sample. The reaction conditions for qRT-PCR are shown in Table 1.
TABLE 1
The target microorganism, primer sequence and amplicon (amplicon) size for qRT-PCR analysis are shown in table 2.
TABLE 2
The results of this example are shown in fig. 1 to 5. FIG. 1 is a graph of data showing the efficacy of the combination of 3-phenyllactic acid and prebiotics of the present invention in improving the bacterial phase in subject 1. FIG. 2 is a graph of data showing the efficacy of the combination of 3-phenyllactic acid and prebiotics of the present invention in improving the bacterial phase in subject 2. FIG. 3 is a graph of data showing the efficacy of the combination of 3-phenyllactic acid and prebiotics of the present invention in improving the bacterial phase in subject 3. FIG. 4 is a graph of data showing the efficacy of the combination of 3-phenyllactic acid and prebiotics of the present invention in improving the bacterial phase in subject 4. FIG. 5 is a graph of data showing the efficacy of the combination of 3-phenyllactic acid and prebiotics of the present invention in improving the mean bacterial phase in 4 subjects. As can be seen from fig. 1 to 5, compared to day 0, subjects had an increased number of probiotics (i.e., lactobacillus species) and a decreased number of pathogenic bacteria (including gardnerella vaginalis, candida species, and escherichia coli) after administration of the sanitary napkin containing a combination of 3-phenyllactic acid and prebiotics, with the improvement being most significant in the 1 st subject and no significant difference in the 2 nd subject due to their own pathogen-free infection.
In conclusion, the combination of 3-phenyllactic acid and prebiotics of the present invention can regulate and improve the bacterial phase in the female vagina, reduce the growth of pathogenic bacteria, reduce inflammation and achieve the effect of protecting the private parts of the female.
The foregoing is by way of example only, and not limiting. It is intended that all equivalent modifications or variations without departing from the spirit and scope of the present invention shall be included in the appended claims.
Claims (11)
1. Use of a combination of 3-phenyllactic acid and a prebiotic for the preparation of a composition having an improved bacterial phase.
2. Use according to claim 1, characterized in that the prebiotic is lactitol (lactitol).
3. The use of claim 1, wherein said bacterial phase is a bacterial phase within a female vagina.
4. Use according to claim 3, characterized in that the bacterial phase comprises Lactobacillus species (Lactobacillus spp.), Gardnerella vaginalis (Gardnerella vagenalis), Candida species (Candidapsp.) and Escherichia coli (Escherichia coli).
5. The use according to claim 4, wherein said combination of 3-phenyllactic acid and prebiotics increases the number of Lactobacillus species and decreases the number of Gardnerella vaginalis, Candida species and E.coli.
6. Use according to claim 2, wherein the volume ratio of 3-phenyllactic acid to lactitol is between 1: 10 and 25.
7. Use according to claim 1, wherein the composition is a pharmaceutical composition.
8. The use of claim 7, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
9. The use of claim 7, wherein the pharmaceutical composition is in a form for topical administration.
10. Use according to claim 7, wherein the pharmaceutical composition is in the form of a sanitary napkin or spray.
11. The use according to claim 1, wherein the 3-phenyllactic acid is purified by High Performance Liquid Chromatography (HPLC).
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| WO2022144351A3 (en) * | 2020-12-30 | 2022-09-15 | F. Hoffmann-La Roche Ag | Compositions and methods for detection of bacteria and fungi associated with bacterial and candida vaginosis |
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| WO2022144351A3 (en) * | 2020-12-30 | 2022-09-15 | F. Hoffmann-La Roche Ag | Compositions and methods for detection of bacteria and fungi associated with bacterial and candida vaginosis |
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