Probiotic and folic acid compositions and methods of use

Abstract

Disclosed herein are oral formulations for treating, preventing, or ameliorating symptoms associated with bacterial vaginosis or yeast infection. The oral formulations disclosed herein comprise a probiotic composition and a supplement composition formulated as a single, multi-component formulation. Also described herein are methods of using the above oral formulations.

Description

[0001] background

[0002] The vaginal microbiome plays a key role in women's health. It is a dynamic environment and undergoes changes in the composition of the microbiota during the menstrual cycle and as women age due to changes in hormone levels. A healthy vaginal microbiome is dominated by bacteria of the genus Lactobacillus; typically, at least 90% of the entire vaginal microbiome includes Lactobacillus. It is believed that maintaining a healthy Lactobacillus microbiome in the vagina can help maintain a healthy pH (i.e., slightly acidic due to acid-producing Lactobacillus, pH of about 3.8-45) and cause competitive crowding, thereby preventing infection and other diseases. Therefore, the loss of the abundance of these Lactobacillus can lead to increased susceptibility to conditions such as yeast infections and bacterial vaginosis (BV). BV is caused by the replacement of Lactobacillus by anaerobic organisms, particularly Gardnerella vaginalis and Atopobium vaginae, and results in symptoms such as vaginal discharge, vaginal odor, vaginal itching, and painful urination, all of which are uncomfortable for women. BV is a common condition that affects many women worldwide, as it is estimated to affect up to 30% of women in the Western world and up to 50% of women in developing countries.

[0003] BV therapy according to the prior art generally includes small molecules such as imidazoles and antibiotics such as azithromycin, clarithromycin or erythromycin. Examples of BV therapy are metronidazole, clindamycin, miconazole, tinidazole and secnidazole. Although these therapies and other therapies such as yeast therapy can give relief of BV and its related symptoms, there is a high BV recurrence rate associated with these therapies. The BV recurrence rate after the application of the therapy of the prior art can be up to about 30% within 1 month after the application of the therapy, and up to 50% within 12 months. Although there is no definitive explanation for the high BV recurrence rate associated with conventional therapy, there is a theory that existing therapeutic agents indiscriminately target bacteria in the vaginal microbiome. Therefore, the therapy of the prior art not only kills non-beneficial organisms (anaerobic bacteria, such as vaginal Gardnerella and vaginal Atopobium), but also kills beneficial lactobacilli, so it can only temporarily provide relief of BV, and BV recurrence is caused by the reduction of lactobacilli content in the vaginal microbiome.

[0004] To address these shortcomings, researchers have suggested using adjunctive Lactobacillus probiotics to counteract the reduction in Lactobacillus after initial administration of prior art therapies, which have had some success in preventing recurrence of BV or yeast. In other cases, researchers have suggested using probiotics alone or in combination with other unconventional therapies (i.e., therapies not routinely used to treat BV or yeast) to prevent recurrence of such infections. Typically, these therapies are administered intravaginally, which can cause discomfort to the patient seeking treatment, and / or they require long-term administration (>1 month), which can lead to low patient compliance.

[0005] In view of these findings, the inventors have determined that there is a growing need to develop formulations that treat, prevent or improve BV, yeast or symptoms associated therewith while ensuring maximum patient comfort and compliance. The inventors have noted the relationship between the vaginal microbiome and its role in BV, yeast or symptoms associated therewith. Therefore, the inventors have discovered that the administration of an oral multi-component formulation provides superior and unexpected benefits compared to the individual components alone, the oral multi-component formulation comprising a probiotic composition of at least one Lactobacillus strain and at least one nutritional supplement at the same time. This discovery is novel and has not been discovered in the prior art. Therefore, by providing a probiotic composition and a nutritional supplement together as a medicament and / or dietary supplement, either individually, collectively, or in combination with other medicaments and / or dietary supplements, therapeutic benefits and nutritional medical benefits can be achieved.

[0006] Overview

[0007] Embodiments of the present disclosure are directed to novel oral formulations comprising at least one probiotic Lactobacillus bacterium and at least one nutritional supplement and their use in ameliorating, preventing and / or treating symptoms associated with BV or yeast infection.

[0008] These and other features, aspects and advantages of the embodiments of the present application will be understood with reference to the following description, appended claims and accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 A table is shown showing the results of respondents' responses to survey questions regarding their emotions regarding the above symptoms, and respondents reported improvements in their levels of frustration, concern about symptoms, embarrassment, levels of affection, and levels of desire for intimacy. DETAILED DESCRIPTION OF THE INVENTION

[0012] Some embodiments provide a composition comprising an amount of at least one Lactobacillus species formulated as a probiotic composition. The Lactobacillus species can be Lactobacillus jensenii, Lactobacillus rhamnosus, Lactobacillus fermentum, Lactobacillus casei, Lactobacillus salivarius, Lactobacillus gasseri, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus paracasei, Lactobacillus brevis, Lactobacillus reuteri, Lactobacillus bulgaricus, Lactobacillus crispatus, Lactobacillus johnsonii, Lactobacillus helveticus, or any combination thereof. Some embodiments may be formulated with varying amounts of one or more of the aforementioned Lactobacillus species.

[0013] In some embodiments, the probiotic composition can include the first lactobacillus species and the second lactobacillus species, wherein the first lactobacillus species and the second lactobacillus species are prepared in proportion. In certain embodiments, the ratio of the first lactobacillus species and the second lactobacillus species can be about 4:1. In certain embodiments, the ratio of the first lactobacillus species and the second lactobacillus species can be about 1:1. In some embodiments, the ratio of the first lactobacillus species and the second lactobacillus species can be in the range of about 10:1 to about 1:10. In this regard, the ratio of the first lactobacillus species and the second lactobacillus species can be about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9 or about 1:10.

[0014] In some embodiments, the probiotic composition may include at least one Lactobacillus species in an amount of about 1 billion CFU to about 20 billion CFU or any ratio therebetween. For example, in some embodiments, the amount of at least one Lactobacillus species may be about 1 billion CFU to about 4 billion CFU. Some embodiments may include at least one Lactobacillus species in an amount of about 4 billion CFU or higher CFU. In certain embodiments, the amount of at least one Lactobacillus species may be about 4 billion CFU to about 10 billion CFU. In some embodiments, the amount of at least one Lactobacillus species may be about 10 billion CFU to about 20 billion CFU.

[0015] In some embodiments, the probiotic composition may include a certain amount of the first Lactobacillus species and the second Lactobacillus species. In certain embodiments, the amount of the first Lactobacillus species and the second Lactobacillus species may be from about 1 billion CFU to about 5 billion CFU. Some embodiments may include the first Lactobacillus species and the second Lactobacillus species in an amount of about 5 billion CFU or higher CFU. In certain embodiments, the amount of the first Lactobacillus species and the second Lactobacillus species may be from about 5 billion CFU to about 10 billion CFU. In some embodiments, the amount of the first Lactobacillus species and the second Lactobacillus species may be from about 10 billion CFU to about 20 billion CFU. In certain embodiments, the amount of the first Lactobacillus species may be from about 1 billion CFU to about 5 billion CFU, and the amount of the second Lactobacillus species may be from about 5 billion CFU to about 10 billion CFU. In some embodiments, the amount of the first Lactobacillus species may be from about 1 billion CFU to about 5 billion CFU, and the amount of the second Lactobacillus species may be from about 10 billion CFU to about 20 billion CFU. In some embodiments, the amount of the first Lactobacillus species can be about 5 billion CFU to about 10 billion CFU, and the amount of the second Lactobacillus species can be about 1 billion CFU to about 5 billion CFU. In certain embodiments, the amount of the first Lactobacillus species can be about 5 billion CFU to about 10 billion CFU, and the amount of the second Lactobacillus species can be about 10 billion CFU to about 20 billion CFU. In some embodiments, the amount of the first Lactobacillus species can be about 10 billion CFU to about 20 billion CFU, and the amount of the second Lactobacillus species can be about 1 billion CFU to about 5 billion CFU. In certain embodiments, the amount of the first Lactobacillus species can be about 10 billion CFU to about 20 billion CFU, and the amount of the second Lactobacillus species can be about 5 billion CFU to about 10 billion CFU.

[0016] In some embodiments, as described herein, the oral formulations described herein can include at least one probiotic Lactobacillus species and at least one nutritional supplement. Certain embodiments include a method of balancing a vaginal microbiome, the method comprising: identifying a subject having a pH level greater than about 4.5; administering an oral multi-component formulation, wherein the oral multi-component formulation comprises: a probiotic composition layer, wherein the probiotic composition layer comprises an amount of at least one Lactobacillus species; a supplement composition layer, wherein the supplement composition layer comprises an amount of at least one nutritional supplement ingredient; and an intermediate barrier layer disposed between the probiotic composition layer and the supplement composition layer, wherein the probiotic composition layer and the supplement composition layer are located on opposite sides of the intermediate barrier layer.

[0017] Certain embodiments include a method of regulating, restoring or balancing vaginal pH in a subject, the method comprising: identifying a subject in need; administering an oral formulation of one or more formulations described herein. In some embodiments, the oral formulation is a multi-component formulation. In some embodiments, the oral formulation comprises one or more of a probiotic composition and a nutritional supplement.

[0018] In some embodiments, the probiotic composition may further include an amount of at least one additional additive that reduces sensitivity to moisture and / or extends the shelf-life of the probiotic composition. In some embodiments, the amount of at least one additional additive may be from about 10 mg to about 500 mg. For example, the amount of at least one additional additive in the probiotic composition can be about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, or any range or amount between any two of the foregoing values, as well as any other range or amount disclosed herein. In certain embodiments, the at least one additional additive can be lactoferrin. In certain embodiments, the additional additive can be lactoferrin, and the probiotic composition can include lactoferrin in an amount of about 10 mg to about 500 mg. For example, the amount of lactoferrin in the probiotic composition can be about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, or any range or amount between any two of the foregoing values, as well as any other range or amount disclosed herein.

[0019] Some embodiments provide a composition comprising at least one nutritional supplement ingredient formulated as a supplement composition.

[0020] In certain embodiments, at least one nutritional supplement ingredient can be an essential fatty acid, such as linolenic acid or linoleic acid, or an essential amino acid, such as tryptophan, lysine, methionine, phenylalanine, threonine, valine, leucine, isoleucine, arginine, or histidine, or any combination thereof.

[0021] In some embodiments, at least one nutritional supplement ingredient can be a vitamin, such as retinol (vitamin A), thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine, pyridoxamine or pyridoxal (vitamin B6), biotin (vitamin B7) or a pharmaceutically acceptable salt thereof, folic acid (vitamin B9) or a pharmaceutically acceptable salt thereof, cobalamin (vitamin B12), choline, ascorbic acid (vitamin C) or a pharmaceutically acceptable salt thereof, ergocalciferol (vitamin D2), calciferol (vitamin D3), 22-dihydroergocalciferol (vitamin D4), sitocalciferol (vitamin D5), tocopherol (vitamin E), phylloquinone (vitamin K1), menaquinone (vitamin K2), menadione (vitamin K3), or any combination of the foregoing.

[0022] In some embodiments, at least one nutritional supplement ingredient can be a dietary mineral, such as chromium (including chromium polynicotinate, chromium acetate, chromium histidinate, chromium nicotinate, chromium chloride, etc. or any pharmaceutically acceptable salt, hydrate, solvate or mixture thereof), bromine, cobalt, copper, fluorine, germanium, iodine, iron, magnesium, manganese, molybdenum, potassium, selenium, silicon, zinc, calcium, phosphorus, sodium, sulfur, vanadium or any combination thereof.

[0023] In certain embodiments, at least one nutritional supplement ingredient can be n-acetylcysteine, nicotinamide riboside, resveratrol, NAD+ precursor, coenzyme Q10, reduced coenzyme Q10, omega-3 fatty acids, bee pollen, cabbage powder, pterostilbene, nicotinamide mononucleotide, cranberry extract, turmeric or an extract thereof, royal jelly, acai berry ( berry, beet root or its extract, coral calcium, oyster shell, Gotu kola or its extract, Gingko biloba or its extract, lions mane mushroom, pomegranate, hibiscus flower, strawberry powder, dandelion root, celery powder, parsley powder, mint leaf, cinnamon bark powder, maca root, phycocyanin or its extract, pumpkin seed or its extract, Crataeva nurvala or its extract, Lindera aggregata or its extract, citrulline nitrate, creatine nitrate, beta-alanine, beta-alanine nitrate, or any combination thereof.

[0024] In some embodiments, the amount of the nutritional supplement ingredients disclosed herein can be about 10 μg to about 1 g. For example, the amount of the ingredient can be about 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300μg, 325μg, 350μg, 375μg, 400μg, 425μg, 450μg, 475μg, 500μg, 525μg, 575μg, 600μg, 625 μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, or any range or amount between any two of the foregoing values, as well as any other range or amount disclosed herein.

[0025] Some embodiments may be formulated as a multi-component formulation, which may include a nutritional supplement and / or probiotic composition as disclosed herein, which is set as the central layer of the formulation; a nutritional supplement composition as disclosed herein, which is set as the outer layer of the formulation; and an intermediate barrier layer disposed between the first two, wherein the probiotic composition layer and the nutritional supplement composition layer are located on opposite sides of the intermediate barrier layer. The multi-component formulation may be formulated as a tablet, a hard capsule, a soft capsule, a plant-derived capsule, a gel capsule, a caplet, etc. The probiotic composition may be formulated as a solid, such as a powder, granules, an amorphous solid, a crystalline solid, or the like, the nutritional supplement may be formulated as a solid, such as a powder, granules, an amorphous solid, a crystalline solid, or the composition may be formulated as a liquid, such as an aqueous solution, an oil-based solution, an aqueous suspension, an oil suspension, an emulsion, a syrup, an elixir, etc. Some embodiments may include a combination of the above-mentioned formulation forms.

[0026] In certain embodiments, the multi-component formulation can be formulated as a tablet, a hard capsule, a soft capsule, a plant-derived capsule, a gel capsule, a caplet, etc. The multi-component formulation can include a probiotic composition arranged as a layer, a nutritional supplement composition arranged as a layer, and a barrier layer arranged therebetween, wherein the probiotic composition layer and the supplement composition layer are located on opposite sides of the intermediate barrier layer. The probiotic composition can be formulated as a solid, such as a powder, granules, microparticles, amorphous solids, crystalline solids, etc., and the nutritional supplement can be formulated as a solid, such as a powder, granules, amorphous solids, crystalline solids, or the composition can be formulated as a liquid, such as an aqueous solution, an oil-based solution, an aqueous suspension, an oil suspension, an emulsion, a syrup, an elixir, etc. Certain embodiments may include a combination of the above-mentioned formulation forms.

[0027] In certain embodiments, the intermediate barrier layer as described herein may include an excipient that separates the probiotic composition from the supplement composition. The barrier layer may be included in the formulation by coating or layering procedures recognized in the art. The barrier layer may include pharmaceutically acceptable compounds, such as, for example, sugar, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc., which may be used alone or in a mixture. Additives, such as plasticizers, colorants, pigments, fillers, anti-tacking agents and antistatic agents, may be optionally included in the barrier layer, including magnesium stearate, titanium dioxide, talc and other additives. In some embodiments, the intermediate barrier layer portion includes controlled release, sustained release or enteric coating to control or delay the release of the internal contents of the formulation.

[0028] In some embodiments, multi-component formulations as described herein include outer coatings. The outer coatings are used to provide immediate release, controlled release, sustained release or enteric coatings to control or delay the release of supplement compositions and probiotic compositions. An outer coating layer (or more outer coating layers) can be applied by coating or layering procedures well established in the relevant field. The outer coating layer can be selected from at least one of the pharmaceutically acceptable compounds of the group consisting of: sugar, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and combinations thereof. Additives can be optionally included in the outer coatings, and the additives include plasticizers, colorants, pigments, fillers, anticaking agents and antistatic agents. In some embodiments, the outer coatings regulate the release of supplement compositions and / or probiotic compositions from tablets, capsules, caplets, etc. Controlled release, sustained release and / or enteric coating technology have been well established in pharmaceutical and formulation fields. The compositions described herein can be formulated as sustained release or slow release, which is designed to be released into the gastrointestinal tract of a patient at a specified delivery rate.

[0029] In some embodiments, the probiotic composition, supplement composition, intermediate barrier layer and / or outer coating described herein may include one or more excipients, such as sweeteners, flavoring agents, colorants, coating agents, preservatives, lubricants, binders, surfactants, fillers, disintegrants, suspending agents, dispersants, wetting agents, thickeners. In certain embodiments, one or more excipients may be one or more of the following: glycerol, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate, silicon dioxide, calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate, corn starch, alginic acid, starch, gelatin, gum arabic (acacia), stearic acid, talc, glyceryl monostearate, glyceryl distearate, kaolin, peanut oil, liquid paraffin, olive oil, oil of the genus Arachis, sesame oil, coconut oil, sucrose, saccharin, beeswax, hard paraffin, xanthan gum, cetyl alcohol, sorbitol, or any combination of the foregoing substances. The excipients that may be included in any composition, intermediate layer or coating as described herein are not particularly limited.

[0030] In certain embodiments, a multi-component formulation comprising a probiotic composition and a supplement composition according to the present disclosure can be administered to a subject to treat, improve or prevent BV or a yeast infection. In some embodiments, a multi-component formulation comprising a probiotic composition and a supplement composition as described herein can be administered to a subject to treat, improve or prevent symptoms associated with BV or a yeast infection (e.g., vaginal odor, vaginal itching, vaginal discharge, painful urination, or any combination thereof), even if the subject does not suffer from BV or a yeast infection.

[0031] In some embodiments, a multi-component formulation comprising a probiotic composition and a supplement composition according to the present disclosure may be administered to a subject to restore or maintain healthy or optimal levels of Lactobacilli in the vaginal microbiome.

[0032] In some embodiments, a multi-component formulation comprising a probiotic composition and a supplement composition as described herein can be administered to a subject at least once a day for a period of time to prevent BV / yeast, vaginal odor, vaginal itching, vaginal discharge, dysuria, or any combination thereof. In certain embodiments, the period of administration at least once a day can include administering the formulation to the subject once a day for about 2 consecutive days to about 20 consecutive days. For example, the period of administration at least once a day can include administering the formulation to the subject once a day for about 15 consecutive days. In some embodiments, the period of administration at least once a day can be repeated monthly. For example, the period of administration at least once a day can include administering the formulation to the subject once a day for about 15 consecutive days, and the period can be repeated monthly for at least 1 consecutive month, 6 consecutive months, 12 consecutive months, or longer. The dosing period can be once a month, once every 15 days, once every 10 days, once every 5 days, once every two days, or a daily dose.

[0033] In certain embodiments, treating, improving, or preventing yeast / BV, vaginal odor, vaginal itching, vaginal discharge, dysuria, or any combination thereof can result in improvement of the subject's symptoms after about one period of time as described herein. For example, improvement and / or treatment of BV or symptoms associated therewith can be observed in a subject after administering the formulation as disclosed herein for 15 consecutive days within 1 consecutive month. In addition, a subject is more likely to prevent infection with BV or experience symptoms associated therewith after administering the formulation as disclosed herein for 15 consecutive days within 1 consecutive month.

[0034] Without being bound by any particular theory, it is believed that yeast infections, BV, or symptoms associated therewith result from a decrease in the concentration of lactobacilli in the vaginal microbiota. Thus, it is believed that by supplementing the vaginal microbiota with lactobacilli, BV, yeast, or symptoms associated therewith can be treated, prevented, and improved. It is believed that the embodiments disclosed herein maintain and / or restore the concentration of lactobacilli in the vaginal microbiome to a healthy level or an optimal level by multiple mechanisms.

[0035] First, it is believed that providing at least one Lactobacillus strain effectively restores the lactobacilli content of the vaginal microbiome by directly increasing the content of lactobacilli in the vaginal flora and, in some cases, by controlling the growth of other microorganisms (non-lactobacilli) in the vaginal flora. For example, in some embodiments, the at least one Lactobacillus strain can be Lactobacillus acidophilus, which ferments sugars to produce lactic acid and thrives in an acidic environment (pH < 5). Both the lactic acid compound and the low pH (the result of recycled lactic acid) can be unfavorable to non-lactobacilli microorganisms, thereby increasing the relative concentration of lactobacilli in the vaginal microbiome.

[0036] Secondly, it is believed that by co-administering at least one lactobacillus strain with a nutritional supplement, the nutritional supplement increases the effective amount of lactobacillus delivered to the vagina. It is also believed that once in the subject, the nutritional supplement improves the vitality of at least one lactobacillus strain. For example, in some embodiments, the nutritional supplement can be folic acid or a pharmaceutically acceptable salt thereof. It is believed that once the preparation is located in the body and the nutritional supplement and the lactobacillus strain are "mixed" (they are separated in different compartments in the multi-component preparation), folic acid or a pharmaceutically acceptable salt thereof increases the amount (CFU count) of the lactobacillus strain, thereby compared with the amount (CFU count) of the lactobacillus strain present in the absence of folic acid or a pharmaceutically acceptable salt thereof, the amount (CFU count) of the lactobacillus strain in the presence of folic acid or a pharmaceutically acceptable salt thereof is significantly higher. This increase results in a higher "effective dose" in the preparation, and therefore a higher dose is delivered to the vagina of the individual being treated. It is also believed that the nutritional supplement can reduce the delivery barrier of at least one lactobacillus strain. For example, in some embodiments, the nutritional supplement can be folic acid or a pharmaceutically acceptable salt thereof. It is believed that folic acid or a pharmaceutically acceptable salt thereof can increase the permeability of the gastrointestinal tract. Therefore, higher permeability leads to greater uptake of the Lactobacillus strain at the desired site (ie, the vagina), thereby increasing the "effective dose".

[0037] Third, it is believed that by combining an additional additive that reduces sensitivity to moisture with at least one Lactobacillus strain, the effective amount of Lactobacillus in the formulation is maintained at a higher level than when the additional additive is not present. For example, in some embodiments, the probiotic composition may also include lactoferrin. It is believed that lactoferrin increases the stability of the Lactobacillus strain, such that the viability and therefore the amount (CFU count) of the Lactobacillus strain stored in the presence of lactoferrin is higher than that of the Lactobacillus strain stored in the absence of lactoferrin. Therefore, this increase results in a higher "effective dose" in the formulation, and therefore a higher dose is delivered to the vagina of the individual being treated.

[0038] As used herein, the term "barrier layer" refers to an impermeable structural element of a multi-component formulation that isolates the probiotic composition and the supplement composition from each other to the extent that the two compositions do not mix.

[0039] As used herein, the term "identifying" refers to detecting or selecting a subject from a population of potential subjects, for example, to determine that a particular subject has certain characteristics or traits. "Identifying" can include, for example, self-identification, self-diagnosis, and diagnosis by a medical professional.

[0040] As used herein, the terms "prevention," "treating," "treatment," "amelioration," and the like, are used herein to refer generally to obtaining a desired pharmacological and physiological effect, and may also refer to a nutritional or nutraceutical effect, the scope and meaning of which will be clear to the skilled person based on the context in which the terms are used. The effect may be preventive in the sense of preventing or partially preventing a disease, symptom, or condition thereof, and / or the effect may be therapeutic in the sense of partially or completely curing a disease, condition, symptom, or adverse reaction attributable to the disease. The term "treatment," as used herein, includes any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the onset of a disease in a subject who may be susceptible to the disease but has not yet been diagnosed as having the disease; (b) inhibiting the disease or preventing its development; or (c) relieving the disease, resulting in regression of the disease and / or its symptoms, conditions, and co-morbidities.

[0041] As used herein, the meaning of the terms "vaginal odor", "vaginal itching", "vaginal discharge" and "painful urination" will immediately come to the mind of the skilled artisan. The skilled artisan will understand that the etiology of these terms refers to common symptoms caused by BV or yeast. However, the compositions described herein can also be administered to treat, ameliorate, prevent or reduce vaginal odor, vaginal itching, vaginal discharge and painful urination that are not caused by BV or yeast infection.

[0042] As used herein, the term "excipient" refers to any compound that is an inactive ingredient part of a formulation, i.e., a compound that has no associated biological activity, and which is added to the formulation to provide specific characteristics to the dosage form, including, for example, providing protection for the active ingredient from chemical degradation, facilitating release of the tablet or caplet from the device in which it is formed, etc.

[0043] As used herein, the terms "restore" or "maintain" refer to producing a physiological change in a subject or patient using a formulation as described herein. In some embodiments, "restoring" or "maintaining" a "healthy" or "optimal" level of Lactobacilli in the vaginal microbiome refers to producing a physiological change in a subject or patient using a formulation as described herein, wherein the physiological change results in the subject or patient forming a vaginal microbiome comprising at least 90% Lactobacilli. "Restoring", "maintaining" a "healthy" or "optimal" level of Lactobacilli in the vaginal microbiome can also refer to using a formulation as described herein to keep or restore the vaginal pH to a specific pH, namely about 3.8 to 5.0. In some embodiments, "restoring" or "maintaining" a "healthy" or "optimal" level of Lactobacilli in the vaginal microbiome refers to producing a physiological change in a subject or patient using a formulation as described herein, wherein the physiological change results in the subject or patient having a vaginal microbiome composition that is substantially similar to that of the subject or patient before the subject or patient experienced yeast, BV, symptoms associated therewith, or both.

[0044] For the sake of providing a more concise description, some quantitative expressions given herein are not qualified with the term "about". It should be understood that whether or not the term "about" is explicitly used, each quantity given herein refers to the actual given value, and it also refers to the approximation of the given value reasonably inferred based on ordinary skill in the art, including the approximation of the given value due to experimental and / or measurement conditions.

[0045] In addition, the appropriate dosage of the composition can depend on, for example, the condition to be treated, the severity and course of the condition, whether the composition is administered for preventive or therapeutic purposes, previous treatments, the patient's clinical history and response to the composition, the type of composition used, and the judgment of the attending physician. The composition can be appropriately administered to the patient in a single treatment or in a series of treatments, and can be administered to the patient at any time starting from the diagnosis. The composition can be administered as the sole treatment, or in combination with other drugs or therapies available for treating the condition under discussion.

[0046] The present disclosure includes supplement compositions and probiotic compositions that can be used to treat, prevent, and / or improve BV / yeast and related systems. Some embodiments provide a multi-component formulation that comprises a supplement composition and a probiotic composition as disclosed herein. The embodiments described herein that comprise a probiotic composition and a supplement composition present the compositions in a non-natural form, i.e., the probiotic composition and the supplement composition comprise components that are present in a form different from their naturally occurring form.

[0047] For purposes of this disclosure, "subject" or "patient" as used herein refers to human females. In certain embodiments, a "subject" or "patient" may suffer from BV or yeast, regardless of whether they show symptoms associated with BV or yeast. In other embodiments, a "subject" or "patient" may be experiencing symptoms such as vaginal odor, vaginal itching, vaginal discharge, and / or painful urination, regardless of whether they have been diagnosed with an infection. In some embodiments, a "subject" or "patient" may not have an infection and have no associated symptoms, but may have previously suffered from BV, yeast, or associated symptoms. In all cases, the embodiments disclosed herein are effective in treating or ameliorating the symptoms (BV, yeast, or both) of a "subject" or "patient" and are effective in preventing future symptoms (BV, yeast, or both) of a "subject" or "patient."

[0048] The present disclosure includes nutritional and therapeutic oral formulations comprising probiotic compositions and supplement compositions and methods of use thereof. Some embodiments provide solid dosage forms of the compositions disclosed herein. Some embodiments provide aqueous solutions of the compositions disclosed herein. The embodiments described herein comprising the compositions disclosed herein refer to compositions disclosed herein that exist in a non-natural form different from the naturally occurring form (e.g., in the form of pills, capsules, etc., formulated as layers in the form of powders, solutions, etc.), or oral formulations, probiotic compositions, or supplement compositions result in non-natural supplements that cannot be achieved by non-supplemented diets. Example

[0049] Example 1

[0050] An open-label pilot trial was conducted to determine the efficacy of treating BV or its associated symptoms. Pilot trial participants received BV treatment. Participants took an oral formulation containing 400mcg of folic acid (L-5-methyltetrahydrofolate), 5 billion CFU of a lactobacillus mixture (e.g., 4 billion CFU of Lactobacillus acidophilus and 1 billion CFU of Lactobacillus rhamnosus), and 50mg of lactoferrin, which was administered once a day and the results were measured as described herein.

[0051] The trial began with 31 women and assessed safety and efficacy endpoints using the Vulvovaginal Symptom Questionnaire (VSQ), which was sent out at baseline and every two weeks over the course of 3-6 months. The VSQ collected trial participants' ratings of the severity of vaginal symptoms, including vaginal itching, discharge, burning, and odor, using a four-level scale (none, mild, moderate, severe). The demographics of the subjects were as follows:

[0052] Age: 47.3+ / -15.1 years

[0053] Height: 63.4 + / - 2.2 inches

[0054] Weight: 159.3 + / - 28.8 lbs

[0055] BMI (kg / m2): 28.0+ / -5.4

[0056] 22 White / Caucasian, 3 Black / African American, 6 Hispanic

[0057] Regarding efficacy, clinical data indicate that the treatment has shown that it is effective in alleviating the symptoms listed on the VSQ. Clinical data also indicate that the treatment evaluated is safe. In this context, "safe" means that the treatment has a statistically insignificant incidence of symptoms and / or adverse events from the treatment.

[0058] The results obtained during treatment are as follows:

[0059] When asked, “During the past week, have you experienced any unpleasant odor from your vulva or vagina?”, respondents (n=31) reported significant reductions (p<0.001) from baseline (week 0) at weeks 2, 4, 6, 8, 10, and 12 as follows:

[0060]

[0061] When asked to rate the severity of their vaginal odor over the past week (none, mild, moderate, severe), respondents (n=31) went from reporting mild to severe symptoms at baseline to reporting significant reductions (p<0.001) at weeks 2, 4, 6, 8, 10, and 12 as follows:

[0062]

[0063] Relief was reported by mild, moderate, and severe subjects.

[0064] When asked to rate the severity of their vaginal odor over the past week (none, mild, moderate, severe), respondents (n=21) went from reporting moderate to severe symptoms at baseline to reporting significant reductions (p<0.001) at weeks 2, 4, 6, 8, 10, and 12 as follows:

[0065]

[0066] Moderate and severe subjects reported relief.

[0067] When asked to rate the severity of their vaginal pruritus over the past week (none, mild, moderate, severe), respondents (n = 15) reported mild to severe symptoms at baseline and reported significant reductions (P < 0.01) at weeks 6, 8, 10, and 12 as follows:

[0068]

[0069] Relief was reported by mild, moderate, and severe subjects.

[0070] When asked to rate the severity of their vaginal irritation in the past week (none, mild, moderate, severe), respondents (n = 19) went from reporting mild to severe symptoms at baseline to reporting significant reductions (P < 0.01) at Weeks 10 and 12 as follows:

[0071]

[0072] Relief was reported by mild, moderate, and severe subjects.

[0073] When asked to rate the severity of their vaginal dryness over the past week (none, mild, moderate, severe), respondents (n=25) went from reporting mild to severe symptoms at baseline to reporting significant reductions at Weeks 4 and 12, with a continued reduction in dryness severity between Weeks 2 and 12 as follows:

[0074]

[0075] Relief was reported by mild, moderate, and severe subjects.

[0076] When asked to rate the severity of vaginal burning in the past week (none, mild, moderate, severe), respondents (n = 14) reported mild to severe symptoms at baseline and reported significant reductions (P < 0.05) at weeks 4, 8, 10, and 12 as follows:

[0077]

[0078] Relief was reported by mild, moderate, and severe subjects.

[0079] Respondents also responded to survey questions about their moods regarding the above symptoms, and reported improvements in their levels of depression, worry about their symptoms, embarrassment, levels of affection, and desire for intimacy. Figure 1 Shown in.

[0080] Other tests are also conducted according to similar protocols, in which compounds of the present disclosure are administered to subjects to determine the improvement in the severity of vaginal symptoms, including itching, discharge, burning, odor, pain during intercourse, spotting (bleeding) during intercourse, and other indicators, such as sexual desire and pleasure during intercourse.

[0081] Although the present invention has been described in some detail for purposes of clarity and understanding, it will be recognized that various changes in form and details may be made without departing from the true scope of the invention.

Claims

1. An oral multi-component preparation, comprising: a probiotic composition layer, wherein the probiotic composition layer comprises an amount of at least one Lactobacillus species; a supplement composition layer, wherein the supplement composition layer comprises an amount of at least one nutritional supplement ingredient; and An intermediate barrier layer is disposed between the probiotic composition layer and the supplement composition layer, wherein the probiotic composition layer and the supplement composition layer are located on opposite sides of the intermediate barrier layer. 2 . The oral multi-component formulation according to claim 1 , wherein the probiotic composition layer comprises an amount of Lactobacillus acidophilus and an amount of Lactobacillus rhamnosus . 3 . The oral multi-component preparation according to claim 2 , wherein the Lactobacillus acidophilus is Lactobacillus acidophilus, and the Lactobacillus rhamnosus is Lactobacillus rhamnosus.

4. The oral multi-component preparation according to claim 2, wherein the ratio of the amount of Lactobacillus acidophilus to the amount of Lactobacillus rhamnosus is about 4:

1.

5. The oral multi-component formulation of claim 1, wherein the at least one nutritional supplement ingredient comprises an amount of folic acid or a pharmaceutically acceptable salt of folic acid.

6. The oral multi-component formulation of claim 2, wherein the at least one nutritional supplement ingredient comprises an amount of folic acid or a pharmaceutically acceptable salt of folic acid.

7. The oral multi-component formulation of claim 4, wherein the at least one nutritional supplement ingredient comprises an amount of folic acid or a pharmaceutically acceptable salt of folic acid.

8. The oral multi-component preparation according to claim 1, wherein the probiotic composition layer further comprises a certain amount of lactoferrin.

9. The oral multi-component preparation according to claim 6, wherein the probiotic composition layer further comprises a certain amount of lactoferrin.

10. The oral multi-component formulation according to claim 7, wherein the probiotic composition layer further comprises a certain amount of lactoferrin.

11. A method for balancing vaginal microbiome, the method include: identifying subjects having a pH level above about 4.5; Administering an oral multi-component formulation, wherein the oral multi-component formulation comprises: a probiotic composition layer, wherein the probiotic composition layer comprises an amount of at least one Lactobacillus species; a supplement composition layer, wherein the supplement composition layer comprises an amount of at least one nutritional supplement ingredient; as well as An intermediate barrier layer is disposed between the probiotic composition layer and the supplement composition layer, wherein the probiotic composition layer and the supplement composition layer are located on opposite sides of the intermediate barrier layer.

12. The method of claim 11, wherein the oral multi-component formulation is administered once a month.

13. The method of claim 12, wherein the oral multi-component formulation is administered once every 15 days.

14. The method of claim 11, wherein the probiotic composition layer comprises an amount of Lactobacillus acidophilus and an amount of Lactobacillus rhamnosus, and the at least one nutritional supplement ingredient comprises an amount of folic acid or a pharmaceutically acceptable salt of folic acid.

15. The method of claim 11, wherein the probiotic composition layer further comprises an amount of lactoferrin.

16. A method for treating, preventing or ameliorating at least one symptom selected from the group consisting of vaginal odor, vaginal discharge, vaginal itching, painful urination and any combination thereof, wherein the method include: identifying the at least one symptom in the subject; Administering an oral multi-component formulation, wherein the oral multi-component formulation comprises: a probiotic composition layer, wherein the probiotic composition layer comprises an amount of at least one Lactobacillus species; a supplement composition layer, wherein the supplement composition layer comprises an amount of at least one nutritional supplement ingredient; as well as An intermediate barrier layer is disposed between the probiotic composition layer and the supplement composition layer, wherein the probiotic composition layer and the supplement composition layer are located on opposite sides of the intermediate barrier layer.

17. The method of claim 16, wherein the subject has bacterial vaginosis.

18. The method of claim 16, wherein the subject does not have bacterial vaginosis.

19. The method of claim 16, wherein the probiotic composition layer comprises an amount of Lactobacillus acidophilus and an amount of Lactobacillus rhamnosus, and the at least one nutritional supplement ingredient comprises an amount of folic acid or a pharmaceutically acceptable salt of folic acid.

20. The method of claim 16, wherein the probiotic composition layer further comprises an amount of lactoferrin.

21. A method of regulating, restoring or balancing the vaginal pH of a subject, the method include: Identification of subjects in need; The oral formulation is administered to regulate, restore or balance the vaginal pH of the subject.

22. The method of claim 21, wherein the vaginal pH of the subject is adjusted, restored or balanced to about 3.8 to 5.0.

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