Probiotic and folic acid compositions and methods of use

Abstract

This specification discloses an oral combination for treating, preventing, or ameliorating symptoms associated with bacterial vaginosis or yeast infection. The oral combination disclosed herein contains a probiotic composition and a supplement composition formulated as a single multi-component combination. The specification also describes methods of utilizing the oral combination.

Description

[Technical Field]

[0001] background The vaginal microbiota plays a crucial role in women's health. It is a dynamic environment, and its composition changes due to changes in hormone levels during the menstrual cycle and with aging. A healthy vaginal microbiota is dominated by Lactobacillus bacteria, which typically account for at least 90% of the total vaginal flora. Maintaining a healthy vaginal Lactobacillus microbiota is thought to support the maintenance of a healthy pH (i.e., a slightly acidic pH (approximately 3.8-4.5) due to acid-producing Lactobacillus) and competitive crowding, thereby preventing infections and other diseases. Therefore, a decrease in Lactobacillus may increase susceptibility to conditions such as yeast infections and bacterial vaginosis (BV). BV results from the replacement of Lactobacillus with anaerobic organisms such as Gardnerella vaginalis and Atopobium vaginae, and can cause symptoms such as vaginal discharge, vaginal odor, vaginal itching, and painful urination, which can be uncomfortable for women. BV is a common condition that affects many women worldwide, estimated to affect up to 30% of women in Western countries and up to 50% of women in developing countries.

[0002] Conventional BV treatments generally include small molecule compounds such as imidazoles and antibiotics such as azithromycin, clarithromycin, or erythromycin. Examples of BV treatments include metronidazole, clindamycin, miconazole, tinidazole, and secnidazole. While these treatments may be used in combination with other medications, such as those used to treat yeast infections, to alleviate BV and its associated symptoms, these medications are associated with a high rate of BV recurrence. The recurrence rate of BV after conventional treatments is approximately 30% within one month and can reach 50% within 12 months. While a definitive explanation for the high recurrence rate of BV with conventional treatments has not been determined, one theory is that the medications indiscriminately target bacteria within the vaginal microbiome. Thus, because conventional treatments kill both non-beneficial organisms (anaerobes, e.g., Gardnerella vaginalis and Atopobium vaginae) and beneficial Lactobacillus species, relief of BV is only temporary, with recurrence due to a reduction in Lactobacillus species in the vaginal microbiota.

[0003] To address these shortcomings, researchers have proposed the adjunctive use of Lactobacillus probiotics to compensate for the loss of Lactobacillus after administration of conventional treatments, which has shown some success in preventing recurrence of BV or yeast infections. Researchers have also proposed the use of probiotics alone or in combination with other non-conventional treatments (treatments not traditionally used for BV or yeast infections) to prevent recurrence of BV or yeast infections. Generally, these treatments are administered intravaginally, which can cause discomfort to patients seeking treatment, and / or these treatments require long-term administration (more than one month), which can reduce patient compliance.

[0004] Based on these findings, the inventors identified a growing need for a combination product that treats, prevents, or improves BV, yeast infections, or related symptoms while maximizing patient comfort and compliance. The inventors focused on the relationship between the vaginal microbiota and its role in BV, yeast infections, or related symptoms. As a result, the inventors discovered that administering an oral multi-component combination containing at least one probiotic composition of Lactobacillus strains and at least one nutritional supplement simultaneously provides superior and unexpected benefits compared to administering each component alone. This discovery is novel and not apparent in the prior art. Therefore, by providing the probiotic composition and the nutritional supplement together as a pharmaceutical and / or nutritional supplement, therapeutic and nutritional benefits can be achieved individually, together, or in combination with other pharmaceuticals and / or nutritional supplements. Summary of the Invention

[0005] Aspects of the present disclosure relate to novel oral combinations containing 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 infections.

[0006] These and other features, aspects, and advantages of the present embodiments will become apparent with reference to the following description, claims, and drawings. [Brief explanation of the drawings]

[0007] [Figure 1] Figure 1 is a table showing the results of responses to the questions about feelings about the aforementioned symptoms, with respondents reporting improvements in frustration, worry about symptoms, levels of embarrassment, levels of affection, and levels of deep need. DETAILED DESCRIPTION OF THE INVENTION

[0008] Detailed Description Some embodiments provide compositions containing at least one Lactobacillus species formulated as a probiotic composition. Species of the genus Lactobacillus include Lactobacillus jensenii, Lactobacillus rhamnosus, Lactobacillus fermentum, Lactobacillus casei, Lactobacillus salivarius, Lactobacillus gasseri, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus paracasei, Lactobacillus brevis, Lactobacillus reuteri, and Lactobacillus The lactobacillus species may be Lactobacillus bulgaricus, Lactobacillus crispatus, Lactobacillus johnsonii, Lactobacillus helveticus, or a combination thereof. Some embodiments may incorporate one or more of these Lactobacillus species in varying amounts.

[0009] In some embodiments, the probiotic composition can contain a first Lactobacillus species and a second Lactobacillus species, wherein the first Lactobacillus species and the second Lactobacillus species are blended in a certain ratio.In certain embodiments, the ratio of the first Lactobacillus species to the second Lactobacillus species can be about 4:1.In certain embodiments, the ratio of the first Lactobacillus species to the second Lactobacillus species can be about 1:1.In some embodiments, the ratio of the first Lactobacillus species to the second Lactobacillus species can be about 10:1 to about 1:10. In this regard, the ratio of the first Lactobacillus species to the second Lactobacillus species may 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.

[0010] In some embodiments, the probiotic composition can contain at least one Lactobacillus species in an amount between about 1 billion CFU and about 20 billion CFU, or any amount therebetween. For example, in some embodiments, the amount of at least one Lactobacillus species can be between about 1 billion CFU and about 4 billion CFU. Some embodiments can include at least 4 billion CFU or more of at least one Lactobacillus species. In certain embodiments, the amount of at least one Lactobacillus species can be between about 4 billion CFU and about 10 billion CFU. In some embodiments, the amount of at least one Lactobacillus species can be between about 10 billion CFU and about 20 billion CFU.

[0011] In some embodiments, the probiotic composition can contain a first Lactobacillus species and a second Lactobacillus species. In certain embodiments, the amount of the first Lactobacillus species and the second Lactobacillus species can be from about 1 billion CFU to about 5 billion CFU. Some embodiments can include more than about 5 billion CFU 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 can 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 can be from about 10 billion CFU to about 20 billion CFU. In certain embodiments, the amount of the first Lactobacillus species can be about 1 billion CFU to about 5 billion CFU, and the second Lactobacillus species can be about 5 billion CFU to about 10 billion CFU. In some embodiments, the amount of the first Lactobacillus species can be about 1 billion CFU to about 5 billion CFU, and 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 5 billion CFU to about 10 billion CFU, and 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 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 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 second Lactobacillus species can be about 5 billion CFU to about 10 billion CFU.

[0012] In some embodiments, the oral combination described herein may contain at least one probiotic Lactobacillus bacterium and at least one nutritional supplement. Certain embodiments include a method for maintaining a balance of vaginal microbiota, the method comprising: identifying a subject having a pH greater than about 4.5; and administering an oral multi-component combination comprising: a probiotic composition layer containing at least one Lactobacillus species; a supplement composition layer containing at least one nutritional supplement; 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.

[0013] Certain embodiments include methods of regulating, restoring, or balancing vaginal pH in a subject, the methods comprising: identifying a subject in need thereof; and administering one or more of the formulations described herein that are oral formulations. In some embodiments, the oral formulation is a multi-component formulation. In some embodiments, the oral formulation includes one or more of a probiotic composition and a nutritional supplement.

[0014] In some embodiments, the probiotic composition may further contain at least one additive that reduces sensitivity to moisture and / or extends the shelf life of the probiotic composition. In some embodiments, the amount of the at least one additive can be from about 10 mg to about 500 mg. For example, the amount of at least one additive in the probiotic composition may 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 a range or amount between any two of the foregoing values, and other ranges or amounts disclosed herein. In certain embodiments, the at least one additive may be lactoferrin. In certain embodiments, the additive may be lactoferrin, and the probiotic composition may contain from about 10 mg to about 500 mg of lactoferrin. 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 a range or amount between any two of the foregoing values, and other ranges or amounts disclosed herein.

[0015] Some embodiments provide compositions containing at least one nutritional ingredient formulated as a supplement composition.

[0016] In certain embodiments, the at least one nutritional supplement component can be an essential fatty acid, such as linolenic acid or linoleic acid, an essential amino acid, such as tryptophan, lysine, methionine, phenylalanine, threonine, valine, leucine, isoleucine, arginine, or histidine, or a combination thereof.

[0017] In some embodiments, the at least one nutritional supplement 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), cytocalciferol (vitamin D5), tocopherol (vitamin E), phylloquinone (vitamin K1), menaquinone (vitamin K2), menadione (vitamin K3), or a combination thereof.

[0018] In some embodiments, the at least one nutraceutical ingredient can be a nutrient mineral such as chromium, bromine, cobalt, copper, fluorine, germanium, iodine, iron, magnesium, manganese, molybdenum, potassium, selenium, silicon, zinc, calcium, phosphorus, sodium, sulfur, vanadium, or a combination thereof, including chromium polynicotinate, chromium acetate, chromium histidinate, chromium nicotinate, chromium chloride, or the like, or a pharmaceutically acceptable salt, hydrate, solvate, or mixture thereof.

[0019] In certain embodiments, the at least one nutraceutical ingredient is selected from the group consisting of n-acetylcysteine, nicotinamide riboside, resveratrol, NAD+ precursors, 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, beetroot or an extract thereof, coral calcium, oyster shell, gotu kola or an extract thereof, ginkgo biloba or an extract thereof, erinaceus herb, pomegranate, hibiscus flower, strawberry powder, dandelion root, celery powder, parsley powder, peppermint leaf, cinnamon bark powder, maca root, phycocyanin or an extract thereof, pumpkin seed or an extract thereof, Crataeva nurvala or an extract thereof, Lindera aggregata) or an extract thereof, citrulline nitrate, creatine nitrate, beta-alanine, beta-alanine nitrate, or a combination thereof.

[0020] In some embodiments, the amount of the nutritional supplement disclosed herein can be from about 10 μg to about 1 g. For example, the amount of the composition 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, 300 μg, 400 μg, 450 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg, 1000 μg, 1250 μg, 1500 μg, 1750 μg, 2000 μg, 2250 μg, 2500 μg, 2750 μg, 3000 μg, 400 μg, 450 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg, 1000 μg, 1250 μg, 1500 μg, 1750 μg, 2000 μg, 2250 μg, 2500 μg, 2750 g, 325μg, 350μg, 375μg, 400μg, 425μg, 450μg, 475μg, 500μg, 525μg, 575μg, 600μg, 625μg, 650 μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975 μg, 1000 μg, 5 mg, 10 mg, 25 mg, 50 mg, 75 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, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 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 a range or amount between any two of the foregoing values, and other ranges or amounts disclosed herein.

[0021] Some embodiments can be formulated as a multi-component formulation that can include a nutritional supplement and / or probiotic composition disclosed herein disposed as a central layer of the formulation, a nutritional supplement composition disclosed herein disposed as an outer layer of the formulation, and an intermediate barrier layer disposed therebetween, where the probiotic composition layer and the nutritional supplement composition layer are located on opposite sides of the intermediate barrier layer. The multi-component formulation can be formulated as a tablet, hard capsule, soft capsule, vegetable capsule, gel capsule, caplet, etc. The probiotic composition can be formulated as a solid, such as a powder, granules, amorphous solid, or crystalline solid. The nutritional supplement can be formulated as a solid, such as a powder, granules, amorphous solid, or crystalline solid. Alternatively, 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, or an elixir. Some embodiments can include combinations of the aforementioned formulation forms.

[0022] In certain embodiments, the multi-component formulation can be formulated as a tablet, hard capsule, soft capsule, botanical capsule, gel capsule, caplet, etc. The multi-component formulation can include a probiotic composition arranged as a layer, a nutraceutical composition arranged as a layer, and a barrier layer disposed 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, particles, amorphous solid, crystalline solid, etc. The nutraceutical can be formulated as a solid, such as a powder, granules, amorphous solid, crystalline solid, etc., or the probiotic 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. Some embodiments can include combinations of the aforementioned formulation forms.

[0023] In certain embodiments, the intermediate barrier layer described herein can be composed of an excipient that separates the probiotic composition from the supplement composition. The barrier layer can be incorporated into the formulation by art-recognized coating or lamination procedures. The barrier layer may be composed of pharmaceutically acceptable compounds, such as sugars, polyethylene glycols, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc., used alone or in mixtures. The barrier layer can optionally contain additives such as plasticizers, colorants, pigments, fillers, anti-blocking and anti-static agents, including magnesium stearate, titanium dioxide, talc, and other additives. In some embodiments, the intermediate barrier portion is composed of a controlled-release, delayed-release, or enteric coating to control or delay the release of the formulation's contents.

[0024] In some embodiments, the multi-component formulations described herein include an outer coating. The outer coating serves to provide immediate-release, controlled-release, delayed-release, or enteric coating to control or delay the release of the supplement composition and probiotic composition. The outer coating layer(s) can be applied by coating or lamination procedures well established in the relevant art. The outer coating layer can be at least one pharmaceutically acceptable compound selected from the group consisting of sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and combinations thereof. The outer coating can optionally include additives including plasticizers, colorants, pigments, fillers, anti-stick and anti-static agents. In some embodiments, the outer coating controls the release of the supplement composition and / or probiotic composition from tablets, capsules, caplets, or the like. Controlled-release, delayed-release, and / or enteric coating technologies are well established in the pharmaceutical and formulation fields. The compositions described herein can be formulated as sustained or extended release, designed to be released into the patient's gastrointestinal tract at a specific delivery rate.

[0025] In some embodiments, the probiotic compositions, supplement compositions, intermediate barrier layers, and / or outer coatings described herein may include one or more excipients from the following classes of agents: sweeteners, flavoring agents, coloring agents, coating agents, preservatives, lubricants, binders, surfactants, fillers, disintegrants, suspending agents, dispersing agents, wetting agents, thickeners, etc. In certain embodiments, the one or more excipients may be one or more of glycerin, 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, stearic acid, talc, glyceryl monostearate, glyceryl distearate, kaolin, peanut oil, liquid paraffin, olive oil, peanut oil, sesame oil, coconut oil, sucrose, saccharin, beeswax, hard paraffin, xanthan gum, cetyl alcohol, sorbitol, or combinations thereof. The excipients that may be included in the compositions, intermediate layers, or coatings described herein are not particularly limited.

[0026] In certain embodiments, a multi-component combination containing a probiotic composition and a supplement composition according to the present disclosure can be administered to a subject to treat, ameliorate, or prevent BV or a yeast infection. In some embodiments, a multi-component combination containing a probiotic composition and a supplement composition described herein can be administered to a subject to treat, ameliorate, or prevent symptoms associated with BV or a yeast infection, such as vaginal odor, vaginal itching, vaginal discharge, painful urination, or a combination thereof, even if the subject does not have BV or a yeast infection.

[0027] In some aspects, a multi-component combination containing a probiotic composition and a supplement composition according to the present disclosure can be administered to a subject to restore or maintain healthy or optimal levels of Lactobacillus in the vaginal microbiota.

[0028] In some embodiments, the multi-component combination containing a probiotic composition and a supplement composition for preventing BV / yeast infection, vaginal odor, vaginal itching, vaginal discharge, painful urination, or a combination thereof described herein can be administered to a subject at least once daily in a periodic cycle. In certain embodiments, the periodic cycle of administration at least once daily can include administering the combination to a subject once daily for about 2 consecutive days to about 20 consecutive days. For example, the periodic cycle of administration at least once daily can include administering the combination to a subject once daily for about 15 consecutive days. In some embodiments, the periodic cycle of administration at least once daily can be repeated monthly. For example, the periodic cycle of administration at least once daily can include administering the combination to a subject once daily for about 15 consecutive days, and the periodic cycle can be repeated monthly for at least 1 consecutive month, 6 consecutive months, 12 consecutive months, or longer. The dosing cycle can be once a month, once every 15 days, once every 10 days, once every 5 days, once every 2 days or daily dosing.

[0029] In certain embodiments, treating, ameliorating, or preventing yeast infection / BV, vaginal odor, vaginal itching, vaginal discharge, painful urination, or a combination thereof, as described herein, may improve a subject's symptoms after about one periodic cycle. For example, after administering the combination disclosed herein for 15 consecutive days for one month, a subject may experience improvement and / or treatment of BV or symptoms associated therewith. Furthermore, after administering the combination disclosed herein for 15 consecutive days for one month, a subject may be more likely to be prevented from contracting BV or experiencing symptoms associated therewith.

[0030] Without being bound by any particular theory, it is believed that yeast infection, BV or related symptoms are caused by a decrease in the proportion of Lactobacillus in vaginal flora.Therefore, it is believed that by supplementing vaginal flora with Lactobacillus, BV, yeast infection or related symptoms can be treated, prevented or improved.It is believed that the embodiments disclosed herein maintain and / or restore the proportion of Lactobacillus in vaginal flora to a healthy or optimal level through multiple mechanisms.

[0031] First, providing at least one Lactobacillus strain is believed to directly increase the amount of Lactobacillus, and in some cases, by controlling the growth of other microorganisms (other than Lactobacillus) in vaginal flora, effectively restore the amount of Lactobacillus in vaginal microflora.For example, in some embodiments, at least one Lactobacillus strain can be Lactobacillus acidophilus, which ferments sugar to produce lactic acid and grows in an acidic environment (pH<5).Both lactic acid compounds and low pH (resulting from the circulation of lactic acid) are unsuitable for microorganisms other than Lactobacillus, and this can increase the relative proportion of Lactobacillus in vaginal microflora.

[0032] Secondly, by co-administering at least one Lactobacillus strain with a nutritional supplement, the nutritional supplement is believed to increase the effective amount of Lactobacillus delivered to the vagina.The nutritional supplement is also believed to increase the viability of at least one Lactobacillus strain when it enters the body of a subject.For example, in some embodiments, the nutritional supplement may be folic acid or a pharmaceutically acceptable salt thereof.Folic acid or a pharmaceutically acceptable salt thereof is believed to increase the amount (CFU number) of Lactobacillus strains when the formulation enters the body and the nutritional supplement and the Lactobacillus strains (which are divided into different compartments in the multi-component formulation) are "mixed", and the amount (CFU number) of Lactobacillus strains is significantly increased in the presence of folic acid or a pharmaceutically acceptable salt thereof compared to the amount (CFU number) of Lactobacillus strains in the absence of folic acid or a pharmaceutically acceptable salt thereof.This increase results in a higher "effective dose" in the formulation, and as a result, a higher dose is delivered to the vagina of the individual being treated. It is also believed that nutritional supplements can reduce the barrier to delivery of at least one Lactobacillus strain.For example, in some embodiments, nutritional supplements can be folic acid or its pharmaceutically acceptable salt.It is believed that folic acid or its pharmaceutically acceptable salt can increase the permeability of gastrointestinal tract.Therefore, the higher the permeability, the more Lactobacillus strains can be absorbed at desired site (vagina), and thus the "effective dose" increases.

[0033] Third, by incorporating at least one Lactobacillus strain with an additive that reduces sensitivity to moisture, the effective amount of Lactobacillus in the formulation is believed to be maintained at a higher level than in the absence of said additive.For example, in some embodiments, probiotic compositions can further contain lactoferrin.Lactoferrin increases the stability of Lactobacillus strain, and the survival rate and amount (CFU number) of Lactobacillus strain when stored in the presence of lactoferrin are believed to be higher than when stored in the absence of lactoferrin.Therefore, this increase results in a higher "effective dose" in the formulation, and as a result, a higher dose is delivered to the vagina of the individual being treated.

[0034] As used herein, the term "barrier layer" refers to an impermeable structural element of a multi-component formulation that separates the probiotic and supplement compositions from each other to the extent that the two compositions do not mix.

[0035] As used herein, the term "identifying" refers to detecting or selecting a subject from a potential population of subjects, for example, to establish that a particular subject has a particular trait or characteristic. "Identifying" may include, for example, self-identification, self-diagnosis, and diagnosis by a medical professional.

[0036] As used herein, terms such as "prevent," "treat," "treatment," "ameliorate," and the like are used generally to refer to obtaining a desired pharmacological and physiological effect and can also refer to a nutritional or nutraceutical effect, the scope and meaning of which will be apparent to one of skill in the art based on the context in which the terms are used. The effect may be prophylactic, in terms of preventing or partially preventing a disease, symptom, or condition thereof, and / or therapeutic, in terms of partially or completely curing a disease, condition, symptom, or adverse effects resulting from a disease. The term "treatment," as used herein, encompasses 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 affected but has not yet been diagnosed as affected; (b) inhibiting or arresting the progression of a disease; or (c) alleviating the disease and causing regression of the disease and / or its symptoms, conditions, and co-morbidities.

[0037] As used herein, the terms "vaginal odor," "vaginal itching," "vaginal discharge," and "painful urination" have meanings that would be readily apparent to one of ordinary skill in the art. It is understood by those skilled in the art that these terms refer to the general symptoms resulting from BV or a yeast infection. 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 a yeast infection.

[0038] As used herein, the term "excipient" refers to a compound that is not an active ingredient, i.e., that has no associated biological activity, but is part of a formulation that is added to the formulation to provide certain properties, including, for example, protecting the active ingredient from chemical degradation, facilitating removal of the tablet or caplet from manufacturing equipment, etc.

[0039] As used herein, the terms "restoring" or "maintaining" refer to using the compositions described herein to induce a physiological change in a subject or patient. In some embodiments, "restoring" or "maintaining" a "healthy" or "optimal" level of Lactobacillus in the vaginal microbiota refers to using the compositions described herein to induce a physiological change in a subject or patient, such that the vaginal microbiota of the subject or patient is at least 90% Lactobacillus. "Restoring" or "maintaining" a "healthy" or "optimal" level of Lactobacillus in the vaginal microbiota can also refer to using the compositions described herein to maintain or return the vaginal pH to a specific pH, i.e., a pH of about 3.8 to 5.0. In some embodiments, "restoring" or "maintaining" "healthy" or "optimal" levels of Lactobacillus in the vaginal microbiota refers to using the combinations described herein to produce a physiological change in a subject or patient, such that the subject's or patient's vaginal microbiota has a substantially similar vaginal microbiota composition to that of the subject or patient before the subject or patient experienced a yeast infection, BV, symptoms associated therewith, or both.

[0040] For the sake of brevity, some of the quantitative expressions set forth in the specification are not modified with the term "about." Whether or not the term "about" is explicitly used, all quantities set forth in the specification are understood to refer to the actual indicated value, and also to refer to approximations to such indicated values ​​that a person skilled in the art would reasonably estimate, including approximations resulting from experimental and / or measurement conditions for such indicated values.

[0041] Further, appropriate dosages of the compositions may depend on, for example, the condition being treated, the severity and course of the condition, whether the composition is being administered for prophylactic or therapeutic purposes, previous therapy, the patient's medical history and response to the composition, the type of composition used, and the judgment of the attending physician. The compositions may be suitably administered to the patient at one time or over a series of treatments, or may be administered to the patient at any time following diagnosis. The compositions may be administered as the sole treatment or in combination with other drugs or therapies useful in treating the condition in question.

[0042] The present disclosure includes supplemental and probiotic compositions useful for treating, preventing, and / or ameliorating BV / yeast infections and related systems. Some embodiments provide multi-ingredient combinations containing the supplemental and probiotic compositions disclosed herein. Embodiments including the probiotic and supplemental compositions described herein present the compositions in a non-natural form, i.e., the probiotic and supplemental compositions contain ingredients that exist in a form different from that found in nature.

[0043] In this disclosure, a "subject" or "patient" refers to a human female. In certain embodiments, a "subject" or "patient" may be suffering from BV or a yeast infection, regardless of whether they exhibit symptoms associated with BV or a yeast infection. 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 be suffering from an infection or exhibiting associated symptoms, but may have previously suffered from or exhibited symptoms associated with BV or a yeast infection. In all cases, the embodiments disclosed herein are effective in treating or ameliorating symptoms of BV, a yeast infection, or both in a "subject" or "patient," and in preventing future symptoms of BV, a yeast infection, or both in a "subject" or "patient."

[0044] The present disclosure includes nutritional and therapeutic oral formulations containing probiotic and supplement compositions, and methods of use thereof. Some embodiments provide solid formulations of the compositions disclosed herein. Some embodiments provide aqueous solutions of the compositions disclosed herein. Embodiments that include the compositions disclosed herein mean that the compositions disclosed herein are present in a non-natural form different from that in nature (e.g., formulated as a layer in a pill, capsule, etc., present as a powder, solution, etc.) or that the oral formulation, probiotic composition, or supplement composition is a non-natural supplement that would not be achieved in an unsupplemented diet. [Example]

[0045] Example 1 An open-label study was conducted to determine the effectiveness of treatment for BV or related symptoms. Study participants received treatment for BV. Participants received an oral combination consisting of 400 mcg of folate (L-5-methyltetrahydrofolate), 5 billion CFU of a Lactobacillus blend (e.g., 4 billion CFU of Lactobacillus acidophilus and 1 billion CFU of Lactobacillus rhamnosus), and 50 mg of lactoferrin, administered once daily. Results were measured as described in the product description.

[0046] The study enrolled 31 women and assessed safety and efficacy endpoints using the Vulvovaginal Symptom Questionnaire (VSQ) at baseline and every two weeks for three to six months. The VSQ asked study participants to rate the severity of their vaginal symptoms, including vaginal itching, discharge, burning, and odor, on a four-point scale (none, mild, moderate, severe). Demographics of the participants included: Age: 47.3±15.1 years Height: 63.4±2.2 inches Weight: 159.3 ± 28.8 lbs BMI (kg / m 2 ):28.0±5.4 22 were White / Caucasian, 3 were Black / African American, and 6 were Hispanic

[0047] With regard to efficacy, clinical data demonstrated that the treatment was effective in reducing the symptoms listed in the VSQ. Clinical data also demonstrated that the evaluated treatment was safe. As used herein, "safe" refers to a statistically insignificant lack of symptom prevalence and / or adverse events from treatment.

[0048] The results of the treatment are as follows:

[0049] In response to the question, "During the past week, have you experienced any odor from your vulva or vagina?", respondents (n=31) reported a significant reduction (p<0.001) from baseline (week 0) at weeks 2, 4, 6, 8, 10, and 12, as follows:

[0050] [Table 1]

[0051] When asked to rate the severity of vaginal odor over the past week (none, mild, moderate, severe), respondents (n=31) who started with mild to severe symptoms at baseline reported significant reductions (p<0.001) at weeks 2, 4, 6, 8, 10, and 12, as follows:

[0052] [Table 2] Reporting of mild, moderate and severe subject reductions

[0053] In response to a question asking respondents to rate the severity of their vaginal odor over the past week (none, mild, moderate, severe), respondents who started with moderate to severe symptoms at baseline (n=21) reported significant reductions (p<0.001) at weeks 2, 4, 6, 8, 10, and 12, as follows:

[0054] [Table 3] Reporting of moderate and severe subject reduction

[0055] In response to a question rating the severity of vaginal pruritus over the past week (none, mild, moderate, severe), respondents (n=15) who started with mild to severe symptoms at baseline reported significant reductions (p<0.01) at weeks 6, 8, 10, and 12, as follows:

[0056] [Table 4] Reporting of mild, moderate and severe subject reductions

[0057] When asked to rate the severity of vaginal pruritus over the past week (none, mild, moderate, severe), respondents who started with mild to severe symptoms at baseline (n=19) reported a significant reduction (p<0.01) at weeks 10 and 12, as follows:

[0058] [Table 5] Reporting of mild, moderate and severe subject reductions

[0059] In response to a question asking for a rating of the severity of vaginal dryness over the past week (none, mild, moderate, severe), respondents who started with mild to severe symptoms at baseline (n=25) reported significant reductions at weeks 4 and 12, with sustained reductions in dryness severity from weeks 2 to 12, as follows:

[0060] [Table 6] Reporting of mild, moderate and severe subject reductions

[0061] When asked to rate the severity of vaginal burning over the past week (none, mild, moderate, severe), respondents who started with mild to severe symptoms at baseline (n=14) reported significant reductions (p<0.05) at weeks 4, 8, 10, and 12, as follows:

[0062] [Table 7] Reporting of mild, moderate and severe subject reductions

[0063] Respondents also answered questions about their feelings about the aforementioned symptoms, and reported improvements in their frustration, worry about symptoms, embarrassment levels, affection levels, and deep desire levels. These results are shown in Figure 1.

[0064] Additional studies will be conducted using similar protocols, administering compounds of the present disclosure to subjects to determine improvement in the severity of vaginal symptoms, including itching, discharge, burning, odor, pain during intercourse, spotting (bleeding) during intercourse, along with other measures such as sexual desire and pleasure during intercourse.

[0065] Although the invention has been described in some detail for purposes of clarity and understanding, it will be understood that the invention has been described in some detail for purposes of clarity and understanding, and that various changes in form and detail may be made without departing from the true scope of the invention.

Claims

1. a probiotic composition layer containing at least one Lactobacillus species; a supplement composition layer containing 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 on opposite sides of the intermediate barrier layer; An oral multi-component combination drug which is a multi-component combination drug containing

2. 2. The oral multi-component combination preparation of claim 1, wherein the probiotic composition layer contains Lactobacillus acidophilus and Lactobacillus rhamnosus.

3. 3. The oral multi-component combination preparation of claim 2, wherein the Lactobacillus acidophilus is Lactobacillus acidophilus and the Lactobacillus rhamnosus is Lactobacillus rhamnosus.

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

1.

5. 10. The oral multi-component combination of claim 1, wherein the at least one nutritional supplement comprises folic acid or a pharmaceutically acceptable salt thereof.

6. 3. The oral multi-component combination of claim 2, wherein the at least one nutritional supplement comprises folic acid or a pharmaceutically acceptable salt thereof.

7. 5. The oral multi-component combination of claim 4, wherein the at least one nutritional supplement comprises folic acid or a pharmaceutically acceptable salt thereof.

8. 2. The oral multi-component formulation according to claim 1, wherein the probiotic composition layer further contains lactoferrin.

9. 7. The oral multi-component formulation according to claim 6, wherein the probiotic composition layer further contains lactoferrin.

10. The oral multi-component formulation according to claim 7, wherein the probiotic composition layer further contains lactoferrin.

11. 1. A method for balancing the vaginal microflora, comprising: identifying a subject having a pH greater than about 4.5; a probiotic composition layer containing at least one Lactobacillus species; a supplement composition layer containing 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 on opposite sides of the intermediate barrier layer; administering an oral multi-component combination containing A method comprising:

12. 12. The method of claim 11, wherein the oral multi-component combination is administered monthly.

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

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

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

16. 1. 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 combinations thereof, comprising: identifying said at least one symptom in the subject; a probiotic composition layer containing at least one Lactobacillus species; a supplement composition layer containing 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 on opposite sides of the intermediate barrier layer; administering an oral multi-component combination containing Including. Method.

17. 17. The method of claim 16, wherein the subject is suffering from bacterial vaginosis.

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

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

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

21. 1. A method of regulating, restoring, or balancing vaginal pH in a subject, comprising: identifying a subject in need thereof; and administering an oral formulation to regulate, restore, or balance vaginal pH in said subject.

22. 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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