WO2017069793A1

WO2017069793A1 - Vaginal gel compositions and methods of use thereof

Info

Publication number: WO2017069793A1
Application number: PCT/US2016/016163
Authority: WO
Inventors: Maureen MCGRATH
Original assignee: Enertopia Corp
Current assignee: Enertopia Corp
Priority date: 2015-10-22
Filing date: 2016-02-02
Publication date: 2017-04-27
Anticipated expiration: 2018-04-22

Abstract

The presently disclosed subject matter is directed to viscous vaginal pharmaceutical compositions comprising a water soluble gel, methods of making such compositions, and methods of using such compositions to treat vaginal dryness in a subject in need thereof.

Description

VAGINAL GEL COMPOSITIONS AND METHODS OF USE THEREOF

CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Application No. 62/244,792 filed October 22, 2015, the disclosure of which is herein incorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The invention relates to the fields of pharmacology and medicine, and provides vaginal gel compositions and methods of use thereof.

BACKGROUND

Vaginal dryness is a frequent condition at menopausal age and is brought on by hypoestrogenism. Vaginal dryness is less common but equally unpleasant when it affects patients of childbearing age, where causes can include the use of low-dose combined estrogen- progesterone contraceptives, tampons, and stress. The vaginal mucosa is normally moistened by fluid, visible on inspection as a clear secretion consisting of plasma transudate, cervical mucus, and vestibular gland secretions. Bartolini's and Skene's glands normally produce mucus as a lubricating fluid that is useful for normal performance of sexual intercourse, but with vaginal dryness this production does not take place. The symptoms of vaginal dryness include pain, stinging, and itching, particularly during sexual intercourse.

Vaginal lubricants generally comprise mixtures of various moisturizers and

preservatives. The right personal lubricant can intensify or enhance sensation with or without a partner. Some problems with vaginal lubricating compositions to date have been that they are less than optimum for providing effective relief of vaginal dryness. Another problem exists with compositions that are not formulated to maintain normal physiological conditions of the vagina Under normal physiological conditions, the vagina is a dynamic balance of vaginal microflora modulated by closely interdependent factors such as hormone levels, pH, and immune response. The cells of the vaginal wall play an important role in maintaining this balance, particularly the surface and intermediate layers of the epithelium, whose proliferation and maturity' is hormone- related.

In view of the above, there is a need for improved vaginal lubricating compositions, particularly vaginal lubricant compositions presented in a gel formulation similar to physiological vaginal secretions that help restore and maintain the balance of the vaginal ecosystem.

SUMMARY

In one aspect, a viscous vaginal pharmaceutical composition comprising a water soluble gel is provided, wherein the water soluble gel comprises Niacin and/or L-Arginine, and wherein the water soluble gel has a pH of between about 3.8 and about 4.5. In a particular aspect, the water soluble gel has a pH of about 4.0. In a further aspect, the water soluble gel comprises less than about 0.15% by weight of Niacin, particularly about 0.14% by weight of Niacin. In yet a further aspect, the water soluble gel comprises about 1% to about 3% by weight of L-Arginine, particularly about 2% by weight of L-Arginine.

In another aspect, the water soluble gel further comprises about 5% to about 15% by weight of Glycerin, particularly about 10% by weight of Glycerin. In another aspect, the water soluble gel further comprises about 1% to about 3% by weight of Lactic acid, particularly about 2% by weight of Lactic acid. In another aspect, the water soluble gel further comprises about 1% to about 2% by weight of Hydroxyethylcellulose, particularly about 1.5% by weight of Hydroxyethylcellulose. In another aspect, the water soluble gel further comprises about 0.01% to about 0.5% by weight of Tocopheryl Acetate, particularly about 0.1% of Tocopheryl Acetate. In another aspect, the water soluble gel further comprises about 0.1% to about 1% by weight of Potassium Sorbate, particularly about 0.5% of Potassium Sorbate. In another aspect, the water soluble gel further comprises about 0.1% to about 1% Cremophor RH-40 (PEG-40

hydrogenated castor oil), particularly about 0.5% Cremophor RH-40. In another aspect, the water soluble gel further comprises about 70% to about 90% by weight of purified water, particularly about 80% by weight of purified water.

In another aspect, the water soluble gel further comprises one or more water soluble vitamins selected from the group consisting of vitamin Bl (thiamine) and vitamin C.

In another aspect, the water soluble gel further comprises one or more fat soluble vitamins selected from the group consisting of vitamins A, D, E, K, and F.

In another aspect, the water soluble gel further comprises one or more plant-derived minerals selected from the group consisting of iron, calcium, copper, cobalt, magnesium, potassium, manganese, zinc, chromium, molybdenum, vanadium, selenium, boron, iodine, and nickel, or salts or complexes thereof

In another aspect, the water soluble gel further comprises one or more plant extracts derived from a plant selected from the group consisting of wild yam (Dioscorea villosa), Ginseng (Panax quinquefolius), red raspberry (Rubus idaeus). Aloe vera, grape seed (e.g., grape seed oil), hemp (e.g., hemp oil), and Stevia rebaudiana (e.g., Stevia rebaudiana leaf powder). In another aspect, the water soluble gel provides enhanced bioavailability of the one or more water soluble vitamins, the one or more fat soluble vitamins, the one or more plant-derived minerals, and/or the one or more plant extracts as compared to the bioavailability of these agents in the subject when administered orally. In other aspects, the bioavailability of the one or more water soluble vitamins, the one or more fat soluble vitamins, the one or more plant-derived minerals, and/or the one or more plant extracts in a subject is at least about 1.5 times, 2 times, S times, or 10 times greater than the bioavailability of these agents in the subject when administered orally. In a further aspect, the bioavailability' of the one or more water soluble vitamins, the one or more fat soluble vitamins, the one or more plant-derived minerals, and/or the one or more plant extracts in a subject is greater than 20%.

In another aspect, methods of making any of the viscous vaginal pharmaceutical compositions comprising a water soluble gel described herein are provided, the method comprising the steps of: a) dissolving Niacin and/or L-Arginine in purified water to produce a water phase mixture; b) combining Glycerin and Hydroxyethylcellulose to produce a

Glycerin Hydroxyethylcellulose mixture; c) adding the Glycerin/Hydroxyethylcellulose mixture to the water phase mixture; and d) adding Tocopheryl Acetate, Potassium Sorbate, and

Cremophor RH-40 to the water phase mixture; thereby producing the viscous vaginal pharmaceutical composition comprising a water soluble gel. In another aspect, the methods further comprise adding a water soluble vitamin, fat soluble vitamin, a plant-derived mineral, and/or a plant extract to the water phase mixture.

In another aspect, a method for treating vaginal dryness in a subject in need thereof is provided, comprising vaginal administration to the subject of a therapeutically effective amount of any of the viscous vaginal pharmaceutical compositions comprising a water soluble gel described herein.

Certain aspects of the presently disclosed subject matter having been stated hereinabove, which are addressed in whole or in part by the presently disclosed subject matter, other aspects will become evident as the description proceeds when taken in connection with the

accompanying Examples as best described herein below.

DETAILED DESCRIPTION

The presently disclosed subject matter now will be described more fully hereinafter with reference to the accompanying Examples, in which some, but not all, embodiments of the inventions are shown. Like numbers refer to like elements throughout. The presently disclosed subject matter may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated Examples. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims.

I. VAGINAL PHARMACEUTICAL COMPOSITIONS

Vaginal dryness is a common condition that may affect women of all ages. The most common cause of vaginal dryness is decreased estrogen levels, which leads to thinning and drying of the vaginal wall. However, other factors such as stress, depression, and anxiety may also contribute to vaginal dryness. Vaginal dryness may make some daily activities uncomfortable, and it can also create quality of life issues for women and their partners.

Problems due to insufficient lubrication and dryness are generally addressed by vaginal compositions that provide or restore normal lubrication and hydration functions. These compositions are in the forms of creams, gels, films, liquids, solids, and foams. However, most existing compositions suffer from problems such as inconvenience, messiness, irritation, and poor lasting quality. Another problem exists with compositions that are not formulated to maintain normal physiological conditions of the vagina

In one aspect, the presently disclosed subject matter is directed to viscous vaginal pharmaceutical compositions comprising a water soluble gel, wherein the water soluble gel comprises L-Arginine, Niacin, Glycerin, Lactic acid, Hydroxyethylcellulose, Tocopheryl acetate, Potassium Sorbate, and Cremophor RH-40.

L-Arginine: L-Arginine is an amino acid; one of the "building blocks" of proteins. L- Arginine has a chemical name of (2S)-2-Amino-5-guanidinopentanoic Acid and molecular formula C₆H₁₄N₄O₂. L-Arginine is classified as a semi essential or conditionally essential amino acid because the ability of the body to synthesize sufficient quantities to meet its needs varies according to developmental age or the physical condition of the person. It is one of the more metabolically versatile amino acids, giving rise to nitric oxide (NO), urea, ornithine, citrulline, creatine, agmatine, glutamate, proline and polyamines. It can also be made synthetically in a laboratory and it is these man made versions that are usually found in medications.

Because of L-Arginine's ability to reduce anxiety and promote sexual responsiveness, it is sometimes used as a libido-enhancing ingredient in personal lubricant products. L-Arginine is generally considered a safe lubricant ingredient, but in large amounts it can worsen the symptoms of asthma and other inflammatory lung conditions. L-Arginine is also known to be a vasodilator, which increases blood flow to the area to which the product is applied. L-Arginine dilates blood vessels by causing the body to produce nitric oxide. Nitric oxide is a molecule that signals smooth muscle surrounding blood vessels (including those in the penis) to relax, which dilates blood vessels and increases blood flow - a necessity for maintaining erections. L- Arginine should be avoided by individuals who have herpes as the vasodilator has been known to cause outbreaks.

Niacin: Niacin is a water-soluble vitamin of the B complex (B3) occurring in various animal and plant tissues. Niacin is required by the body for the formation of coenzymes NAD and NADP. It has PELLAGRA-curative, vasodilating, and antilipemic properties. Niacin, also known as Nicotinic acid, has a molecular formula of C₆H₅NO₂.

Niacin causes the blood vessels to dilate or open up near the skin, which results in a hot, tingling sensation accompanied by a red flushing of the skin.

Lactic Acid: Lactic acid is a normal intermediate in the fermentation (oxidation, metabolism) of sugar. Lactic acid has a molecular formula of C₃H₆O₃. Lactic acid is an acidic compound produced in muscular areas of the human body. The vaginal canal naturally produces some lactic acid.

Lactic acid affects the acidity (pH) of the vagina, which can in turn affect the growth of vaginal flora The lower genital tract micro biota of many women is dominated by bacteria of the genus Lactobacillus. Some studies suggest that lactic acid can promote growth of lactobacilli, and that a healthy amount of lactic acid can reduce the risk of yeast infections. Production of lactic acid by Lactobacillus acidifies the vaginal environment and forms a natural protective layer that acts as a defense against bacteria that can cause infection. The vaginal pH fluctuates between 3.8 to 4.5 in a healthy vagina. Glycerin: Glycerin is an organic compound known more formally as glycerol. Its common sources are animal fat and vegetable oil. Glycerin has the molecular formula

C₃H₅(OH)₃.

The term glycerin, introduced in 1811 by French chemist Michel-Eugene Chevrul, is ordinarily applied to commercial materials containing more than 95% glycerol. Though Chevrul gave glycerin its name, the substance was first isolated in 1783 by German Swedish chemist Carl Willem Scheele, who described it as the "sweet principle of fat."

Vegetable glycerin, or glycerol, is a clear, odourless liquid produced from plant oils, typically palm oil, soy, or coconut. Palm and coconut oils are natural triglyceride mixtures; each triglyceride is composed of three fatty acids esterified with glycerin. Vegetable glycerin has a number of valuable applications that include cosmetic products, foods and as a

replacement for alcohol in herbal and botanical tinctures.

Vegetable glycerin is produced using an extraction process called hydrolysis. During hydrolysis, oils are placed under the combined force of pressure, temperature, and water. The ester bond breaks and causes the glycerin to split from fatty acids and be absorbed by water; at which point the resultant is further isolated by distillation to increase purity. Purified vegetable glycerin has a texture similar to an oil or syrup due to its organic molecular makeup, specifically, three hydroxyl groups.

Vegetable glycerin used in food applications is USP grade or over 99% pure and has a sweet taste. It also metabolizes differently than sugar and is used in low carbohydrate foods for sweetness and moisture.

Many household products, including lotions, shampoo and toothpaste, contain vegetable glycerin. It is added to these products because it is a humectant; a substance that attracts moisture to the skin. In the cosmetic world, this has two practical applications. First, glycerin leaves your skin hydrated. Glycerin soap, for example, is popular for that very reason. Second, for cosmetic products that deliver an active ingredient, a humectant can increase the solubility of the active ingredient, making it more easily absorbed by the skin.

The safety of vegetable glycerin coupled with its functional properties has made it invaluable for various medical applications. The hydrating effect of glycerin makes it ideal as a topical remedy for burns.

Within the presently disclosed viscous vaginal pharmaceutical compositions comprising a water soluble gel, vegetable glycerin may be used that is USP grade, non-GMO, and Kosher certified. Within the presently disclosed viscous vaginal pharmaceutical compositions and methods, glycerin acts as a humectant, which helps retain moisture. Potassium Sorbate: Potassium Sorbate is a very common food preservative used in foods like cheese, wine, meats and dried fruits. Potassium Sorbate works by helping inhibit the growth of yeast and mold, thus extending shelf life. Potassium Sorbate is said to have a toxicity level similar to table salt and is generally considered safe for consumption.

Candida Albicians is yeast normally found in small amounts in the vagina When the natural pH of the vagina is upset, this yeast can multiply and irritate the vaginal walls. This then causes vaginal yeast infection, marked by a burning sensation when urinating, pain during sexual intercourse, itching around the vagina, and a white and odorless discharge that looks similar to cottage cheese.

Within the presently disclosed viscous vaginal pharmaceutical compositions comprising a water soluble gel, Potassium Sorbate acts as the preservative to extend product shelf life.

Tocophervl acetate: Tocopheryl acetate is a form of vitamin E; a natural skin- conditioning agent and antioxidant. It is the ester of acetic acid and tocopherol and is often used as an alternative to pure tocopherol (or undiluted vitamin E) because it is considered more stable and less acidic.

Tocopheryl acetate is a fat-soluble vitamin that can be isolated from vegetable oils. It is also found in dairy products, meat, eggs, cereals, nuts and leafy green and yellow vegetables. Its substantiated benefits include enhancing the efficacy of active sunscreen ingredients, reducing the formation of free radicals from exposure to UV rays, promoting the healing process, strengthening the skin's barrier function, protecting the skin barrier's lipid balance and reducing trans epidermal water loss. Attributed with antioxidant, an anti-aging, moisturizing, antiinflammatory, and enhanced SPF property, tocopherol acetate is valued both as a dietary supplement and skincare active. It is used in a variety of cosmetic and personal care products.

Vitamin E is one of the most well researched antioxidants. It is available in eight different forms, which can be extracted from nature or synthetically produced. Though all members of the vitamin E family are fat-soluble, tocopherol is the most bioavailable, and thus the most readily absorbed by the body.

The strong moisturizing properties of vitamin E might help relieve symptoms of vaginal dryness. A fat-soluble antioxidant, vitamin E helps to protect the body from environmental free radicals and maintain the immune system Vitamin E is a common component of commercial moisturizers because of its effectiveness in helping to repair damaged skin cells and in promoting skin cell moisture.

Within the presently disclosed viscous vaginal pharmaceutical compositions comprising a water soluble gel, vitamin E acetate is used to help relieve symptoms of vaginal dryness. Hvdroxvetfavlcellulose: Hydroxyethylcellulose (HEC), a non-ionic water-soluble polymer, is a white, free-flowing granular powder. It is insoluble in organic solvents, yet it is easily dispersed in cold and hot water to give solutions of varying viscosities. Chemically, it is cellulose that has been etherified with Hydroxyethyl groups to give the desired properties. It is used as a thickener, protective colloid, binder, stabilizer and suspending agent, particularly in application where non-ionic material is desired.

Hydroxyethylcellulose form films, exhibit pseudo plastic solution behaviour, tolerate salts and retain water. Within the presently disclosed viscous vaginal pharmaceutical compositions comprising a water soluble gel, Hydroxyethylcellulose is used as a thickener to achieve a gel form product that is easy to apply.

Cremophor RH-40: Cremophor RH-40 is a non-ionic solubilizer and emulsifying agent obtained by reacting hydrogenated castor oil with ethylene oxide. Cremophor RH-40 is used to solubilize vitamins and hydrophobic active substances in aqueous solutions.

In one aspect of the presently disclosed subject matter, a viscous vaginal pharmaceutical composition comprising a water soluble gel is provided, wherein the water soluble gel comprises Niacin and/or L-Arginine, and wherein the water soluble gel has a pH of between about 3.8 and about 4.5. In a particular aspect, the water soluble gel has a pH of about 4.0. In a further aspect, the water soluble gel comprises less than about 0.15% by weight of Niacin, particularly about 0.14% by weight of Niacin. In yet a further aspect, the water soluble gel comprises about 1% to about 3% by weight of L-Arginine, particularly about 2% by weight of L-Arginine.

hydrogenated castor oil), particularly about 0.5% Cremophor RH-40. In another aspect, the water soluble gel further comprises about 70% to about 90% by weight of purified water, particularly about 80% by weight of purified water. In another aspect, the water soluble gel further comprises one or more water soluble vitamins selected from the group consisting of vitamin Bl (thiamine) and vitamin C. For example, where the water soluble gel further comprises vitamin Bl, the water soluble gel may comprise less man about 0.015% by weight of vitamin Bl, particularly about 0.011% by weight of vitamin B 1. In another example, where the water soluble gel further comprises vitamin C, the water soluble gel may comprise less than about 0.08% by weight of vitamin C, particularly about 0.075% by weight of vitamin C. In addition, the vitamin C may be provided in the form of Ascorbic Acid.

In another aspect, the water soluble gel further comprises one or more fat soluble vitamins selected from the group consisting of vitamins A, D, E, K, and F. For example, where the water soluble gel further comprises vitamin A, the water soluble gel may comprise less than about 0.015% by weight of vitamin A, particularly about 0.012% by weight of vitamin A. In another example, where the water soluble gel further comprises vitamin D, the water soluble gel may comprise less than about 0.005% by weight of vitamin D, particularly about 0.003% or about 0.0025% by weight of vitamin D. In another example, where the water soluble gel further comprises vitamin E, the water soluble gel may comprise less than about 0.15% by weight of vitamin E, particularly about 0.1% by weight of vitamin E.

In another aspect, the water soluble gel further comprises one or more plant-derived minerals selected from the group consisting of iron, calcium, copper, cobalt, magnesium, potassium, manganese, zinc, chromium, molybdenum, vanadium, selenium, boron, iodine, and nickel, or salts or complexes thereof. For example, iron may be in the form of ferric pyrophosphate, ferric chloride, ferrous sulfate, iron succinate, ferrous sodium succinate, etc., while calcium may be in the form of calcium chloride, calcium lactate, calcium gluconate, etc.

In another aspect, the water soluble gel further comprises one or more plant extracts derived from a plant selected from the group consisting of wild yam (Dioscorea villosa),

Ginseng (Panax quinquefolius), red raspberry (Rubus idaeus), Aloe vera, grape seed (e.g., grape seed oil), hemp (e.g., hemp oil), and Stevia rebaudiana (e.g., Stevia rebaudiana leaf powder). For example, where the water soluble gel further comprises wild yam extract, the water soluble gel may comprise less than about 2.0% by weight of wild yam extract, particularly about 1.0% by weight of wild yam extract. In another example, where the water soluble gel further comprises Ginseng extract, the water soluble gel may comprise less than about 2.0% by weight of Ginseng extract, particularly about 1.0% by weight of Ginseng extract. In another example, where the water soluble gel further comprises Red raspberry extract, the water soluble gel may comprise less than about 2.0% by weight of Red raspberry extract, particularly about 1.0% by weight of Red raspberry extract. In another example, where the water soluble gel further comprises Grape seed extract, the water soluble gel may comprise less than about 2.0% by weight of Grape seed extract, particularly about 1.0% by weight of Grape seed extract. In another example, where the water soluble gel further comprises Aloe vera extract, the water soluble gel may comprise less than about 2.0% by weight of Aloe vera extract, particularly about 1.0% by weight of Aloe vera extract. In another example, where the water soluble gel further comprises hemp oil, the water soluble gel may comprise less than about 0.1% by weight of hemp oil, particularly about 0.05% by weight of hemp oil. In another example, where the water soluble gel further comprises Stevia rebaudiana leaf powder, the water soluble gel may comprise less than about 0.030% by weight of Stevia rebaudiana leaf powder, particularly about 0.020% by weight of Stevia rebaudiana leaf powder.

As used herein, the terms "plant-derived", "plant extract", and '¾erbal extract" are used interchangeably to refer to substances that are produced in plant tissues and that can be obtained from plants or herbs by isolating at least a part of the plant away from its natural state, such as by removing water {e.g. , extracting the juice and/or pulp), or by extracting one or more components chemically, mechanically, thermally, by size, or otherwise separating the components using polar, non-polar, mineral, petroleum or other solvents. The isolation of the active agent from the plant will depend on the nature of the active agent, such as water solubility and the like, and sensitivity to decomposition (e.g., denaturation by heat, pH, oxygen, light, etc.). Plant extracts also include dehydrated plant materials in which the bulk liquid is removed to concentrate the bioavailable solids in the plant or herb.

In another aspect, the water soluble gel provides enhanced bioavailability of the one or more water soluble vitamins, the one or more fat soluble vitamins, the one or more plant-derived minerals, and/or the one or more plant extracts as compared to the bioavailability of these agents in the subject when administered orally. Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. Bioavailability for a given formulation provides an estimate of the relative fraction of the orally administered dose that is absorbed into the systemic circulation. Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs.

Insufficient time for absorption in the gastrointestinal tract is a common cause of low bioavailability. If the drug does not dissolve readily or cannot penetrate the epithelial membrane (e.g., if it is highly ionized and polar), time at the absorption site may be insufficient. Orally administered drugs must pass through the intestinal wall and then the portal circulation to the liver, both of which are common sites of first-pass metabolism (metabolism that occurs before a drug reaches systemic circulation). Thus, many drugs may be metabolized before adequate plasma concentrations are reached.

Bioavailability is usually assessed by determining the area under the plasma

concentration-time curve (AUC). AUC is directly proportional to the total amount of unchanged drug that reaches systemic circulation. Plasma drug concentration increases with extent of absorption; the maximum (peak) plasma concentration is reached when drug elimination rate equals absorption rate. Peak time is the most widely used general index of absorption rate; the slower the absorption, the later the peak time.

Accordingly, in some aspects, the bioavailability of the one or more water soluble vitamins, the one or more fat soluble vitamins, the one or more plant-derived minerals, and/or the one or more plant extracts in a subject is at least about 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 9 times, 9.5 times, or 10 times greater than the bioavailability of these agents in the subject when administered orally.

In a further aspect, the bioavailability of the one or more water soluble vitamins, the one or more fat soluble vitamins, the one or more plant-derived minerals, and/or the one or more plant extracts in a subject is greater than 20% or at least about 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, or greater.

Assays and methods for measuring bioavailability of vitamins and minerals are well known in the art (see, e.g., Etcheverry et al. (2012) Frontiers in Physiology 3: 1-22; Perales et al. (2005) J. Agric. Food. Cnem. 53:3721-6; Wienk et al. (1999) Eur. J. Nutr. 38:51-75; Shargel & Yu (2015) Applied biopharmaceutics & pharmacokinetics (7th ed.). New York: McGraw-Hill; Hu & Li (2011) Oral Bioavailability: Basic Principles, Advanced Concepts, and Applications, John Wiley & Sons Ltd.).

Glycerin Hydroxyethylcellulose mixture; c) adding the Qycerin/Hydroxyethylcellulose mixture to the water phase mixture; and d) adding Tocopherol Acetate and Potassium Sorbate to the water phase mixture; thereby producing the viscous vaginal pharmaceutical composition comprising a water soluble gel. In another aspect, the methods further comprise adding a water soluble vitamin, a fat soluble vitamin, a plant-derived mineral, and/or a plant extract to the water phase mixture.

II. METHODS OF TREATING VAGINAL DRYNESS

In another aspect, a method for treating vaginal dryness in a subj ect in need thereof is provided, comprising vaginal administration to the subject of a therapeutically effective amount of any of the viscous vaginal pharmaceutical compositions comprising a water soluble gel as described herein.

The term ''administering" as used herein refers to contacting at least a cell with a viscous vaginal pharmaceutical composition comprising a water soluble gel as described herein.

The subject treated by the presently disclosed methods in their many embodiments is desirably a human subject. Accordingly, a "subject" can include a human subject for medical purposes, such as for the treatment of an existing disease, disorder, condition or the prophylactic treatment for preventing the onset of a disease, disorder, or condition. Further, a "subject" can include a patient afflicted with or suspected of being afflicted with a disease, disorder, or condition. Thus, the terms "subject" and "patient" are used interchangeably herein.

In particular aspects, the subject is suffering from or susceptible to a disease, disorder, or condition associated with vaginal dryness.

As used herein, the terms "treat," treating," "treatment," and the like, are meant to decrease, suppress, attenuate, diminish, arrest, the underlying cause of a disease, disorder, or condition, or to stabilize the development or progression of a disease, disorder, condition, and/or symptoms associated therewith. The terms "treat," "treating," "treatment," and the like, as used herein can refer to curative therapy, prophylactic therapy, and preventative therapy. Treatment according to the presently disclosed methods can result in complete relief or cure from a disease, disorder, or condition, or partial amelioration of one or more symptoms of the disease, disease, or condition, and can be temporary or permanent. The term "treatment" also is intended to encompass prophylaxis, therapy and cure.

As used herein, the terms "prevent," "preventing," "prevention," "prophylactic treatment" and the like refer to reducing the probability of developing a disease, disorder, or condition in a subject, who does not have, but is at risk of or susceptible to developing a disease, disorder, or condition. Thus, in some embodiments, a viscous vaginal pharmaceutical composition comprising a water soluble gel as described herein can be administered

prophylactically to prevent the onset of a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition. The term "effective amount," as in "a therapeutically effective amount," of a therapeutic agent refers to the amount of the agent necessary to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of an agent may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue or cell, and the like. More particularly, the term "effective amount" refers to an amount sufficient to produce the desired effect, e.g., to reduce or ameliorate the severity, duration, progression, or onset of a disease, disorder, or condition, or one or more symptoms thereof; prevent the advancement of a disease, disorder, or condition, cause the regression of a disease, disorder, or condition; prevent the recurrence, development, onset or progression of a symptom associated with a disease, disorder, or condition, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.

In any of the above-described methods, administration of a viscous vaginal

pharmaceutical composition comprising a water soluble gel as described herein can result in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 100% decrease in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8. 9, or 10) symptoms of a disease, disorder, or condition associated with vaginal dryness.

In any of the above-described methods, administration of a viscous vaginal

pharmaceutical composition comprising a water soluble gel as described herein as described herein results in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 100% decrease in the likelihood of developing a disease, disorder, or condition associated with vaginal dryness compared to a control population of subjects that are not administered a viscous vaginal pharmaceutical composition comprising a water soluble gel as described herein. Alternatively, in any of the above-described methods, administration of a viscous vaginal pharmaceutical composition comprising a water soluble gel as described herein results in at least about a 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8- fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55- fold, 60-fold, 65-fold, 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, or 100-fold decrease in the likelihood of developing a disease, disorder, or condition associated with vaginal dryness compared to a control population of subj ects that are not administered a viscous vaginal pharmaceutical composition comprising a water soluble gel as described herein.

Actual dosage levels of the agents described herein can be varied so as to obtain an amount of the agent that is effective to achieve the desired therapeutic response for a particular subject, composition, route of administration, and disease, disorder, or condition without being toxic to the subject. The selected dosage level will depend on a variety of factors including the activity of the particular agent employed, or salt thereof, the route of administration, the time of administration, the rate of excretion of the particular agent being employed, the duration of the treatment, other drugs, agents and/or materials used in combination with the particular agent employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

III. GENERAL DEFINITIONS

Following long-standing patent law convention, the terms "a," "an," and "the" refer to

"one or more" when used in this application, including the claims. Thus, for example, reference to "a subject" includes a plurality of subjects, unless the context clearly is to the contrary (e.g., a plurality of subjects), and so forth.

Throughout this specification and the claims, the terms "comprise," "comprises," and "comprising" are used in a non-exclusive sense, except where the context requires otherwise. Likewise, the term "include" and its grammatical variants are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items.

For the purposes of this specification and appended claims, unless otherwise indicated, all numbers expressing amounts, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, parameters, quantities, characteristics, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term "about" even though the term "about" may not expressly appear with the value, amount or range. Accordingly, unless indicated to the contrar ', the numerical parameters set forth in the following specification and attached claims are not and need not be exact, but may be approximate and/or larger or smaller as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art depending on the desired properties sought to be obtained by the presently disclosed subject matter. For example, the term "about," when referring to a value can be meant to encompass variations of, in some embodiments, ± 100% in some embodiments ± 50%, in some

embodiments ± 20%, in some embodiments ± 10%, in some embodiments ± 5%, in some embodiments ±1%, in some embodiments ± 0.5%, and in some embodiments ± 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions. Further, the term "about" when used in connection with one or more numbers or numerical ranges, should be understood to refer to all such numbers, including all numbers in a range and modifies that range by extending the boundaries above and below the numerical values set forth. The recitation of numerical ranges by endpoints includes all numbers, e.g., whole integers, including fractions thereof, subsumed within that range (for example, the recitation of 1 to 5 includes 1, 2, 3, 4, and 5, as well as fractions thereof, e.g., 1.5, 2.25, 3.75, 4.1, and the like) and any range within that range.

EXAMPLES

The following Examples have been included to provide guidance to one of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill can appreciate that the following examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter. The synthetic descriptions and specific examples that follow are only intended for the purposes of illustration, and are not to be construed as limiting in any manner to make compounds of the disclosure by other methods.

EXAMPLE 1

Many people use personal lubricant to enhance their sexual pleasure. Lubricants improve sexual intercourse by making genital tissues moist, which decreases friction and makes intimate contact more pleasurable. Friction can cause small tears in the fragile vaginal lining through which disease-causing microorganisms can enter. Using lubricant may prevent these tears from forming. Lubricant should be applied before sexual intercourse and can easily be integrated into foreplay. It can also be useful during sexual activity- after menopause. Estrogen levels dip quite a bit during menopause and a woman's natural lubrication may decrease.

Consequently, intercourse can become painful. Lubricants can help ease vaginal dryness and improve sexual intercourse.

V-Love™ Gel is a water-based personal lubricant. It is formulated with ingredients that will not cause latex to deteriorate and rinses off easily in plain water.

V-Love™ Gel is a water-based personal lubricant that contains L-Arginine, Niacin, Glycerin, Lactic acid, Hydroxyethylcellulose, Tocopheryl acetate and Potassium Sorbate. In particular, V-Love™ Gel contains the following ingredients and quantities in weight percent:

• L-Arginine 2.5% • Niacin 2.0%

• Glycerin 10%

• Lactic acid 2.0%

• Hydroxyethylcellulose 1.5%

· Tocopheryl Acetate 0.10%

• Potassium Sorbaie 0.50%

• Purified water 81.9%

An alternative formulation for V-Love™ Gel contains L-Arginine, Niacin, Glycerin, Lactic acid, Hydroxyethylcellulose, Tocopheryl acetate, Potassium Sorbate, and Cremophor RH-40, along with various vitamins, plant-derived minerals, and/or plant extracts. In particular, mis alternative formulation for V-Love™ Gel contains the following ingredients and quantities in weight percent:

• L-Arginine 2.0%

• Niacin 0.14%

· Glycerin 10%

• Lactic acid 2.0%

• Hydroxyethylcellulose 1.5%

• Tocopheryl Acetate 0.10%

• Potassium Sorbate 0.50%

· Cremophor RH-40 0.50%

• Ascorbic Acid (Vitamin C) 0.075%

• Thiamine (Vitamin Bl) 0.011%

• Stevia Rebaudiana Leaf Powder 0.020%

• Vitamin A Palmitate 0.012%

· Cholecalciferol (Vitamin D) 0.003%

• Wild Yam Extract 1.0%

• Ginseng Extract 1.0%

• Red Raspberry Extract 1.0%

• Grapeseed Extract 1.0%

· Aloe vera Extract 1.0%

• Hemp Oil 0.05%

• Purified Water 78.089% Use For: Relief of vaginal dryness, effective lubrication, intimacy enhancement. V- Love™ Gel is pH balanced for women (pH of between about 3.8 and about 4.5, particularly 4.0). V-Love™ Gel provides a moisturizing feeling for vaginal dryness as well as a lubricant effect that enhances sexual pleasure with a partner or for individual intimate moments. V- Love™ Gel can be used daily, is silky smooth, is fragrance free, and is free of DEA, gluten, parebens, and sorbitol. V-Love™ Gel is water based and latex condom friendly.

Directions: Apply desired amount of V-Love™ Gel to intimate areas. This product is not a contraceptive and does not contain spermicide. Store at room temperature 15-30° Celsius. EXAMPLE 2

V-Love™ Gel as described in Example 1 may be made as follows. Into a mixing tank, add the purified water and dissolve L-arginine and niacin. Glycerin and Hydroxyethylcellulose are mixed together and added into the water phase mixture. Potassium Sorbate and Tocopherol acetate are then added and mixed. The end product is a translucent gel.

REFERENCES

All publications, patent applications, patents, and other references mentioned in the specification are indicative of the level of those skilled in the art to which the presently disclosed subject matter pertains. All publications, patent applications, patents, and other references are herein incorporated by reference to the same extent as if each individual publication, patent application, patent, and other reference was specifically and individually indicated to be incorporated by reference. It will be understood that, although a number of patent applications, patents, and other references are referred to herein, such reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art.

Although the foregoing subject matter has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood by those skilled in the art mat certain changes and modifications can be practiced within the scope of the appended claims.

Claims

THAT WHICH IS CLAIMED:

1. A viscous vaginal pharmaceutical composition, wherein the vaginal pharmaceutical composition comprises a water soluble gel, wherein the water soluble gel comprises Niacin and/or L-Arginine, and wherein the water soluble gel has a pH of between about 3.8 and about 4.5.

2. The viscous vaginal pharmaceutical composition of claim 1, wherein the water soluble gel has a pH of about 4.0.

3. The viscous vaginal pharmaceutical composition of any one of claims 1 to 2, wherein the water soluble gel comprises less than about 0.15% by weight of Niacin.

4. The viscous vaginal pharmaceutical composition of claim 3, wherein the water soluble gel comprises about 0.14% by weight of Niacin.

5. The viscous vaginal pharmaceutical composition of any one of claims 1 to 4, wherein the water soluble gel comprises about 1% to about 3% by weight of L-Arginine.

6. The viscous vaginal pharmaceutical composition of claim 5, wherein the water soluble gel comprises about 2% by weight of L-Arginine.

7. The viscous vaginal pharmaceutical composition of any one of claims 1 to 6, wherein the water soluble gel comprises about 5% to about 15% by weight of Glycerin.

8. The viscous vaginal pharmaceutical composition of claim 7, wherein the water soluble gel comprises about 10% by weight of Glycerin.

9. The viscous vaginal pharmaceutical composition of any one of claims 1 to 8, wherein the water soluble gel comprises about 1% to about 3% by weight of Lactic acid.

10. The viscous vaginal pharmaceutical composition of claim 9, wherein the water soluble gel comprises about 2% by weight of Lactic acid.

11. The viscous vaginal pharmaceutical composition of any one of claims 1 to 10, wherein the water soluble gel comprises about 1% to about 2% by weight of

Hydroxy ethylcell ulose.

12. The viscous vaginal pharmaceutical composition of claim 11, wherein the water soluble gel comprises about 1.5% by weight of Hydroxyethylcellulose.

13. The viscous vaginal pharmaceutical composition of any one of claims 1 to 12, wherein the water soluble gel comprises about 0.01% to about 0.5% by weight of Tocopherol Acetate.

14. The viscous vaginal pharmaceutical composition of claim 13, wherein the water soluble gel comprises 0.1% by weight of Tocopheryl Acetate.

15. The viscous vaginal pharmaceutical composition of any one of claims 1 to 14, wherein the water soluble gel comprises about 0.1% to about 1% by weight of Potassium Sorbate.

16. The viscous vaginal pharmaceutical composition of claim 15, wherein the water soluble gel comprises about 0.5% by weight of Potassium Sorbate.

17. The viscous vaginal pharmaceutical composition of any one of claims 1 to 16, wherein the water soluble gel comprises about 0.1% to about 1% by weight of Cremophor RH- 40.

18. The viscous vaginal pharmaceutical composition of claim 17, wherein the water soluble gel comprises about 0.5% by weight of Cremophor RH-40.

19. The viscous vaginal pharmaceutical composition of any one of claims 1 to 18, wherein the water soluble gel comprises about 70% to about 90% by weight of purified water.

20. The viscous vaginal pharmaceutical composition of claim 19, wherein the water soluble gel comprises about 80% by weight of purified water.

21. The viscous vaginal pharmaceutical composition of any one of claims 1 to 20, wherein the water soluble gel further comprises one or more water soluble vitamins selected from the group consisting of vitamin Bl (thiamine) and vitamin C.

22. The viscous vaginal pharmaceutical composition of claim 21, wherein the bioavailability of the one or more water soluble vitamins in a subject is at least about 1.5 times greater man the bioavailability of the one or more water soluble vitamins in the subject when administered orally.

23. The viscous vaginal pharmaceutical composition of claim 21 , wherein the bioavailability of the one or more water soluble vitamins in a subject is greater than 20%.

24. The viscous vaginal pharmaceutical composition of any one of claims 1 to 20, wherein the water soluble gel further comprises one or more fat soluble vitamins selected from the group consisting of vitamins A, D, E, K, and F.

25. The viscous vaginal pharmaceutical composition of claim 24, wherein the bioavailability of the one or more fat soluble vitamins in a subject is at least about 1.5 times greater than the bioavailability of the one or more fat soluble vitamins in the subject when administered orally.

26. The viscous vaginal pharmaceutical composition of claim 25, wherein the bioavailability of the one or more fat soluble vitamins in a subject is greater than 20%.

27. The viscous vaginal pharmaceutical composition of any one of claims 1 to 20, wherein the water soluble gel further comprises one or more plant-derived minerals selected from the group consisting of iron, calcium, copper, cobalt, magnesium, potassium, manganese, zinc, chromium, molybdenum, vanadium, selenium, boron, iodine, and nickel, or salts or complexes thereof.

28. The viscous vaginal pharmaceutical composition of claim 27, wherein the bioavailability of the one or more plant-derived minerals in a subject is at least about 1.5 times greater than the bioavailability of the one or more plant-derived minerals in the subject when administered orally.

29. The viscous vaginal pharmaceutical composition of claim 27, wherein the bioavailability of the one or more plant-derived minerals in a subject is greater than 20%.

30. The viscous vaginal pharmaceutical composition of any one of claims 1 to 20, wherein the water soluble gel further comprises one or more plant extracts derived from a plant selected from the group consisting of wild yam (Dioscorea villosa), Ginseng (Panax

quinquefolius), red raspberry (Rubus idaeus), Aloe vera, grape seed, hemp, and Stevia rebaudiana.

31. The viscous vaginal pharmaceutical composition of claim 30, wherein the bioavailability of the one or more plant extracts in a subject is at least about 1.5 times greater than the bioavailability of the one or more plant extracts in the subject when administered orally.

32. The viscous vaginal pharmaceutical composition of claim 30, wherein the bioavailability of the one or more plant extracts in a subject is greater than 20%.

33. A method of making a viscous vaginal pharmaceutical composition of any one of claims 1 to 32, comprising the steps of:

a) dissolving Niacin and/or L-Arginine in purified water to produce a water phase mixture;

b) combining Glycerin and Hydroxyethylcellulose to produce a

Glycerin/Hydroxyethylcellulose mixture;

c) adding the Glycerin/Hydroxyethylcellulose mixture to the water phase mixture; and

d) adding Tocopheryl Acetate, Potassium Sorbate, and Cremophor RH-40 to the water phase mixture;

thereby producing the viscous vaginal pharmaceutical composition comprising a water soluble gel.

34. The method of claim 33, further comprising the step of adding a water soluble vitamin, a fat soluble vitamin, a plant-derived mineral, and/or a plant extract to the water phase mixture.

35. A method for treating vaginal dryness in a subject in need thereof is provided, comprising vaginal administration to the subject of a therapeutically effective amount of a viscous vaginal pharmaceutical composition comprising a water soluble gel according to any one of claims 1 to 32.