CN1246369A - Tissue moisturizing compositions and methods - Google Patents

Abstract

The present invention relates to compositions and methods for increasing epithelial cell moisture, and in particular to methods and compositions for moisturizing comprising water, a specific bioadhesive, and preferably a thickening agent. The invention also relates to a method of preparing the moisturizing composition.

Description

Tissue moisturizing compositions and methods

The present invention relates to compositions and methods for increasing the humidity of epithelial cells, and in particular methods and compositions for moisturizing comprising water, specific bioadhesives and preferably thickeners. The present invention also relates to methods of making moisturizing compositions.

A number of environmental and pathological conditions cause desiccation or dehydration of the membrane tissues of the mammalian body. These conditions cause dry mouth (xerostomia), dry eyes (sicca condition), and dry vagina, nose, or rectal mucosa, and/or dry skin, which can be aesthetically unsightly and / or discomfort.

One method for moisturizing dry tissue uses an oily substance as the main ingredient in the form of a cream, lotion, gel, or ointment applied to diseased tissue in an attempt to prevent further dehydration of the tissue. They work by covering the tissue to be treated with an impervious, hydrophobic barrier. Petrolatum, mineral oil, lanolin and isopropyl myristate are examples of hydrophobic substances used. These articles have limited usefulness over long periods of time. Additionally, they cause an oily, sticky feel to the skin and stain clothing.

Another method for humidification uses hydrophilic molecules that absorb water. Small hydrophilic molecules such as glycerin and glycerin/water mixtures, urea, and propylene glycol are known humectants that are said to be useful in skin moisturizing.

Several synthetic hydrophilic substances that adhere to the skin and/or mucous membranes in the presence of water have been used alone or in combination with one or more active or therapeutic agents in various pathological conditions, but they have not been used as Moisturizer for dry epithelial cells such as those of the skin or mucous membranes. These hydrophilic substances are often referred to in the art as hydrogels.

Certain hydrophilic, carboxyl-functional polymers, ie, those containing carboxylic acid groups, are known for use as carriers for therapeutic agents. US 4,615,697 discloses the preferred polymer polycarbophil for use with therapeutic agents in this invention. The hydrogel polymer carrier in US Patent No. 3,074,852 is said to be the polymer of US Patent No. 2,798,053. An exemplary cross-linked polymer is said to be CARBOPOL ^(R) 934. The polymers of particular interest in US Patent No. 3,074,852 are said to be in the acid form and are described in more detail in US Patent No. 2,909,462. The polymer specifically described therein is also reported to be sold as CARBOPOL ^(R) 934 by the BF Goodrich Chemical Company.

US Patent No. 4,226,848 discloses compositions for adhering pharmaceutical products to the oral or nasal mucosa. An exemplary acrylic acid polymer disclosed therein is a lightly cross-linked acrylic acid-allyl sucrose copolymer commercially available from BF Goodrich Chemical Company under the trademark ^CARBOPOL® 934, which is said to form a highly viscous gel-like dispersion in water. .

US Patent No. 4,548,990 discloses controlled release drug delivery compositions whose crosslinked polymer moieties are prepared from monomers or mixtures comprising 55% to 99% water insoluble monoolefinic monomers. The polymer is said to swell in ethanol and water with a swelling ratio of 2:1 to 22:1.

Particularly useful polymeric carboxylic acid copolymers for therapeutic or cosmetic applications are described in European Patent Application No. 88112198.2, Publication No. 0301532 by B.F. Goodrich Company, preferably the polymers of US 4,615,697 and may include Carbopol 976. Fluffy, powdery acrylic polymers are prepared in an anhydrous, organic solvent-free polymerization medium such as carbon dioxide. The polymer is about 0.1 to 6% by weight crosslinked. The copolymer is substantially water insoluble but swellable in water. A 0.2% weight dispersion in distilled water is said to have a mucus viscosity of at least 1000 cycles per second ("cps").

Hydrophilic, carboxyl-functional water-soluble polymers have been used in cosmetic preparations. US Patent No. 4,863,725 discloses water-soluble copolymers of glycerin and methacrylic acid. German Offenlegungsschrift 24 19 046 describes linear and crosslinked polymers containing carboxyl and aldehyde groups as cosmetic compositions. Japanese Patent Publication No. 61-72706 relates to cross-linked polyacrylic acid mono- or di-hydroxypropyl acrylate polymers. PCT Application No. PCT/US89/00451, International Publication No. WO 89/06964 published August 10, 1989, relates to polycarboxylic acid ophthalmic preparations of specific pH, viscosity and osmolality for use in ophthalmic compositions .

None of the art publications discussed above teach or suggest that water-swellable but water-insoluble cross-linked bioadhesive polycarboxylate polymers such as polycarbophil or similar polymers are useful especially at acidic pH. Moisturizers in compositions for dry epithelial cells, such as skin and mucosal epithelial cells disclosed hereinafter. However PCT/US 89/00451 does refer to dry eye/tear replacement preparations comprising Carbopol 976 dissolved in water.

The present invention includes compositions and methods for increasing the moisture content of epithelial cells. According to the method, epithelial cells are contacted with an effective moisturizing amount of an aqueous moisturizing composition comprising water, a moisturizing amount of a water-swellable but water-insoluble cross-linked bioadhesive polycarboxylic acid polymer and preferably , Contains a thickening agent in a thickening and smoothing amount. Bioadhesive polymers are water-swellable but water-insoluble, particulate or fibrous cross-linked carboxy-functional polymers. The polymer is used to contact epithelial cells of mammals such as humans.

The bioadhesive polymer preferably contains (a) at least about 80%, preferably at least about 90%, of the plurality of repeating units containing at least one carboxyl functional group, and (b) substantially free of polyalkene based on the weight of unpolymerized starting material From about 0.01% to about 6%, preferably from about 0.01% to about 2%, more preferably from about 0.05% to about 1.5%, and most preferably from about 0.05% to about 1.0% of the crosslinking agent based on the polyether; and linking agents. Thickeners are water-dispersible and preferably water-soluble, nonionic or anionic polymers.

Bioadhesive polymers are water insoluble but water swellable. In contrast to water-soluble polymers, which can absorb more than 100 times their weight in water, polymers that are neither soluble in water (less than 1% soluble in water) can generally absorb about 40% to about 100% of their weight in water .

In a preferred practice, the dried bioadhesive polymer is size classified by screening through a 400 mesh screen in the US Standard Sieve series. Physiologically tolerable diluents, and in particular dispersion in liquids including water, are also preferred for the bioadhesive particles. The solution may also include other ingredients known in fluids for administration to the epithelium.

The present invention provides several advantages and benefits.

An advantage of the present invention is that its composition is not significantly irritating to the mucosa it contacts.

Another advantage of the present invention is that the bioadhesive wetting polymer has a distinctly acidic pH and a relatively high buffering capacity that facilitates maintaining the acidic pH of the surface tissue.

Due to the insolubility of the bioadhesive polymer, the moisturizing effect of the composition of the present invention lasts for a relatively long time, for example 2-3 days.

Another advantage of the present invention is that its compositions are relatively easy to formulate.

Still further benefits and advantages of the present invention will become apparent to those skilled in the art from the following detailed description, examples and claims.

In the drawings which form a part of this specification

Figure 1 shows a side view of a modified commercially available surface tensiometer for measuring the adhesion strength of bioadhesives.

Figure 2 is a graph showing an acrylic bioadhesive polymer copolymerized with 0.3% by weight of 3,4-dihydroxy-1,5-hexadiene having a density of 1.56 grams/cubic centimeter (g/cc) for resolution Force (dyne x 10 ^-2 /cm ² ) versus pH for reaction products; and

Figure 3 shows viscosity (for convenience, in cps, n shows 10,000-100,000 as 1-10×10 ⁴ ) versus shear ratio (n in rpm represents 2 separate preparations prepared as described in Example 4) Moisturizing composition) diagram. Results were obtained using a Haake ROTOVISCO model RV-12 viscometer as described in Example 6, and data for one composition are shown as filled circles and data for the other composition are shown as open circles.

The present invention relates to compositions and methods for moisturizing epithelial cells of mucosal regions such as the mouth (oral cavity), eyes, vagina, etc., by administering the moisturizing composition to a host mammal. The composition itself is an aqueous composition comprising a moisturizing effective amount of a bioadhesive and preferably a water soluble or dispersible polymeric thickener. They differ from US Patent No. 4,615,697 and PCT/US89/00451 in that they lack therapeutic agents other than relatively inert liquids such as water, and are primarily used in dry tissue conditions.

The bioadhesives of the invention are preferably water-insoluble but water-swellable. The term water insoluble as used herein means that the bioadhesive (lacking water soluble impurities) in its acidic form at about pH 3 to 5 shows no appreciable to the viscosity. The term water-swellable means that the article, although water-insoluble, absorbs appreciable amounts of water, typically about 60 to 100 times its weight.

Moisturizing compositions designed for use on epithelial cells, that is, the skin and mucosal membranes (mucosa) of mammals, such as those of horses or humans, to which the composition adheres in the presence of a sufficient amount of water to swell the bioadhesives . Compositions thus adhered to the epithelium increase the moisture content of the contacted body part over a substantial period of time. This time is longer than the humidification time of similar compositions that do not include the bioadhesives disclosed herein. Indeed, the bioadhesive can remain in place and active from 10 to about 20 hours, ie, the renewal time of the mucosa or tissue, to about 2 to 3 days in order to moisturize the epithelial cells.

Compositions useful in the present invention are substantially nontoxic to animals to which they are administered.

For extended periods of time, the methods of the invention utilize hydrogel compositions that maintain a substantial amount of moisture in contact with the epithelial region of the host mammal. This composition additionally acts as a polyelectrolyte and limits ion flux from the contacted mucosa. This water-associated ionic efflux can cause water to flow out of the tissue. Furthermore, the moisturizing bioadhesive is itself a polyelectrolyte when swelled by an aqueous medium and produces a Donnan equilibrium effect resulting in enhanced ion influx into contacted tissue. Due to the extremely bioadhesive and mucoadhesive properties of the crosslinked polymer, the composition remains in contact with the epithelial tissue for a longer period of time.

The moisturizing method of the present invention is effective for increasing the moisture of some "dry" tissues such as dry eyes, dry skin, dry vagina, dry nasal passages, dry rectal tract and dry oral cavity.

According to the moisturizing method, there is provided as previously described comprising water, a moisturizing effective amount of a moisturizing agent and, preferably, a thickening smoothing amount of a water dispersible polymeric thickener.

Contacting is performed in the presence of sufficient water to swell the bioadhesive and cause the bioadhesive-containing composition to adhere to the contacted area. The contact is maintained for a time sufficient to increase the moisture of the contacted epithelial cells and adjacent tissues, if necessary.

The method of the present invention lowers the local pH. For example, after subjects were treated with the composition of the present invention or other commercial vaginal moisturizers without bioadhesives daily for 5 days, vaginal moistening of about 0.5 pH units or more was noted in women receiving both products. pH difference. Women using the product of the invention were observed to have a vaginal pH of about 4.8, with a lower pH than the untreated value of about 5.6, maintained for about 48 hours after treatment.

Yeast, fungi, and other microorganisms that commonly cause vaginal infections do not grow well at a pH of 5 or lower. Thus, the aforementioned method of moisturizing also provides a method of inhibiting vaginal yeast and fungal infections.

Each of the compositions described below can be administered according to this method.

The compositions of the present invention may be administered by means to provide the necessary contact between epithelial cells and the composition. For example, the composition can be applied by rubbing the composition onto the area to be moisturized. The composition may be administered by sprayer, hand, tweezers, plug, plunger, irrigator or other suitable instrument. If contact with the conjunctival epithelium is desired, the aqueous composition described hereinafter may be instilled into the pocket in the corner of the eye. If contact with the oral, nasal, anal and/or vaginal epithelium is desired, application may be by spray, hand, forceps, plug, irrigator or other suitable device.

The composition is left in place (held in contact) for a sufficient time to allow moisturization of the contacted (treated) area to occur and thus provide the mammal with its cosmetic benefit. In most cases, the administered composition is removed from the body by natural bodily mechanisms, such as by mechanically induced dispersion or erosion or by aqueous body fluids, such as vaginal discharge, or by douching. Compositions containing bioadhesive moisturizing polymers can also be lost by mechanical action at the point of contact, such as through eyelids on the eyeball or tongue action in the oral cavity. For mucous membranes, bioadhesive moisturizing polymers adhere to the mucin covering the membrane or to the membrane itself. Mucin is replaced (renewed) within about 10-20 hours, typically about every 17 hours, and the attached bioadhesive moisturizing polymer can be lost with the mucin.

The main component of the moisturizing composition of the present invention is a bioadhesive polymer.

Active moisturizers include bioadhesive polymers, water, and preferably water-dispersible thickeners. Adjuvants or diluents may be present, as well as other ingredients known for use in moisturizing compositions.

Such bioadhesive polymers include cross-linked carboxyl-functional polymers that are water-swellable, but water-insoluble, particulate or fibrous, and exhibit bioadhesive properties discussed below. The polymer preferably contains (a) at least about 80% of a plurality of repeating units containing at least one carboxyl functional group and (b) about 0.01% to 6%, preferably about 0.01% to 2%, more preferably about 0.05% to 1.5% Linking agent and substantially free of polyalkenyl polyether, the percentages are based on the weight of unpolymerized repeating units and crosslinking agent, respectively. Preferably, at least about 90% of the repeating units contain at least one carboxyl functional group, more preferably at least about 95% of the repeating units contain at least one carboxyl functional group. Also in most preferred practices, the bioadhesive contains about 0.05% to 2% by weight of polymeric crosslinker.

Bioadhesives can be broadly defined as substances that adhere to living or freshly killed biological surfaces such as mucosal or skin tissue. The "bioadhesives" used herein to define useful bioadhesive moisturizing polymers are analyzed by the method described below in Example 2 of U.S. Patent No. 4,615,697, which measures separation by adhesion. Force required to attach 2 layers of freshly resected rabbit stomach tissue together.

According to the method ^of Example 2, using the method in U.S. Patent No. 4,615,697, a bioadhesive can be defined as a substance that requires a force of at least about 50 dynes/cm to separate 2 adherent, freshly resected pieces of rabbit stomach tissue . More preferably, the force is at least about 380 dynes/ ^cm2 . The observed average force on polycarbophil was approximately 1073 dyne/cm ² . The upper limit of force required to separate freshly resected rabbit stomach tissue is not known, but is believed to be at least about 2000 dynes/ ^cm2 .

As previously stated, in order to achieve the desired amount of water-swellability in the water-insoluble polymer, it is preferred that at least about 80% of the repeating units of the preferred bioadhesives contain at least one carboxyl functional group. Monomers providing these repeating units include unsaturated monoolefins and include acrylic acid, methacrylic acid, fumaric acid, maleic acid, maleic anhydride which can be hydrolyzed to its acidic form during or after polymerization, methylenesuccinic acid, Crotonic acid etc. Each of these acids may be used alone or in combination with other such acids or with one or more pharmaceutically or cosmetically acceptable salts of these acids. Acrylic acid is a particularly preferred monomer for providing the bioadhesive polymer with carboxyl-containing repeating units.

Preferred bioadhesive polymers for use in the present invention are crosslinked by crosslinking agents known in the art. The cross-linking agent is preferably substantially free of polyalkenyl polyethers, and is particularly preferably free of polyalkenyl polyethers, such as polypropylene-based sucrose or polyacrylsucrose containing an average of at least 3 propylene groups per molecule as reported in ^CARBOPOL® 934. propenyl pentaerythritol. Examples of useful crosslinking agents are divinylbenzene, N,N-diacrylacrylamide, 3,4-dihydroxy-1,5-hexadiene, 2,5-dimethyl-1,5-hexadiene wait.

The amount of bioadhesive crosslinking is also of some importance. When less than about 0.05% by weight of a suitable cross-linking agent is present, the bioadhesive tends to become water-soluble or water-dispersible, thereby losing its desirable water-insolubility, water-swellability characteristics that are important to the present invention. For divinylbenzene or dihydroxy- or dimethyl-substituted hexadiene crosslinkers, the water-swellability of the bioadhesive when greater than about 1% or 2% crosslinker is present, depending on the polymer A perceivable decline begins. Preferably, the crosslinker is present at about 0.05% to 1% or 2%. However, the preferred range will vary with, inter alia, the nature of the polymer, the nature of the crosslinks and the degree of crosslinking. The amount of crosslinking agent refers to the percentage of those precursors, unpolymerized monomers, in the reaction mixture for bioadhesive polymerization.

Thus, as used herein, a bioadhesive polymer can be defined in part as a copolymerization of at least about 80% by weight of an unsaturated monoethylenic carboxyl functional monomer and about 0.01% to 2.0% by weight of a polyalkenyl-free polyether crosslinking agent reaction product. Other monomers which may be present to make up 100% by weight of the monomers are described below.

In addition to the above 2 components, the bioadhesive polymer may also include polymerized unsaturated monoethylenic repeat units such as C ₁ -C ₆ alkyl esters of one or more of the above acids, such as hexyl acrylate, butyl isobutylene Esters and methyl crotonates; hydroxyalkenyl-functional esters of the above acids containing an average of about 1 to 4 oxyalkenyl groups containing 2 to 3 carbon atoms per molecule such as hydroxyethyl methacrylate, hydroxypropyl Acrylates and 5 tetraethylene glycol monoacrylates; methacrylamides, acrylamides and their C ₁ -C ₄ mono- and di-alkyl derivatives such as N-methacrylamide, N-butylmethacrylamide and N, N-dimethylacrylamide; styrene; etc., which are known in the art, can be copolymerized with the above-mentioned carboxyl functional group-containing monomer and crosslinking agent. The bioadhesive polymer is most preferably prepared only from unsaturated monoalkenyl carboxyl functional monomers and a crosslinker.

The bioadhesive polymers used herein can be prepared by conventional polymerization techniques described in the literature. Exemplary preparations of useful bioadhesives are provided below and can also be found in US Patent No. 2,810,716 and Patent No. 3,202,577.

The polymers of the invention can also be prepared as described in European Patent Application No. 88112198.2, published February 1, 1989 as 0 301 532 A2. According to its specification, the acrylic acid and the cross-linked product are mixed in carbon dioxide as solvent at 45-65°C and a pressure above the critical point of the mixture, such as about 1250 pounds per square inch at 45°C, in the presence of a suitable free radical initiator. Medium reaction to provide fine, fluffy polymers.

The bioadhesives used herein are granular or fibrous, swellable but not soluble in water. To say that the bioadhesive polymers of the present invention are characterized as being swellable and insoluble in water means that the polymer can absorb typically about 1 to 100 times its weight in water but is sufficiently insoluble that it can absorb water at pH 6 .5 Provides measurable viscosity at a concentration of 0.2% by weight in water.

The bioadhesive polymers of the present invention are swellable in water, ie the polymer particles absorb moisture in the presence of water and thus become larger in volume. Moisture for this swelling is typically provided by the aqueous composition of the present invention or it may be provided in part by the body of the treated animal, such as through transpiration or secretion of moisture from the skin, transpiration from mucous membranes during secretion, such as from saliva or vaginal mucus. Secretion, or through the secretion of tears in the eye. It has however been noted that the latter bodily secretions are generally absent or present in relatively small amounts leading to the need for the present composition.

The size of the bioadhesive particles has an effect on the compositions of the invention. Obviously the bioadhesive particles should not be too large to apply the composition without undue difficulty. Likewise, particles larger than the sizes discussed below can sometimes cause pain and irritation when applied to the eye, oral cavity, or vagina. Furthermore, particles of the same size as discussed below appear to provide improved functionality to the moisturizer composition compared to larger particles in size, ie, in the longest dimension.

Generally, the largest useful bioadhesive polymer size will pass through a 400 mesh screen (US Molecular Sieve System); ie, 38 micron openings. Preferably, the bioadhesive polymer particles are smaller such that the longest dimension is about 20 microns. Most preferably, the particles have an average size in the longest dimension of about 2-5 microns. Particles of the desired size can be obtained, for example, by grinding, crushing or otherwise comminuting larger particles, and by direct polymerization.

Particles with a relatively small size have a greater surface area per unit weight, swell faster and exhibit better adhesion than particles with a comparable size. For convenience, the bioadhesive measurements discussed above and in Example 2 below were performed with bioadhesives screened through a 30 mesh molecular sieve and retained on a 40 mesh molecular sieve (US Standard Molecular Sieve series), ie, a 30/40 mesh size.

Bioadhesion was found not to be a function of bioadhesive molecular weight. Thus, the bioadhesive can have essentially any molecular weight as long as it adheres at least about 50 dynes/ ^cm2 and preferably about 380 dynes/ ^cm2 in the adhesion test described below.

As previously mentioned, bioadhesives can be prepared by polymerization in aqueous media. In preferred practice, the aqueous medium is a saturated solution of an alkaline earth metal salt such as magnesium sulfate. Alkaline earth metal salts have at least 2 functions. First, it increases the density of the polymerization medium so that the polymerized bioadhesives float on the surface of the aqueous medium and can be easily removed therefrom. Second, the use of magnesium sulfate inter alia reduces the swelling of the bioadhesive in aqueous media to facilitate polymerization and recovery.

Bioadhesives thus prepared typically contain about 0.5% to 1% alkaline earth metal ions after some water washing of the polymer. These polymers are therefore different from those in which alkaline earth metal hydroxides such as calcium or magnesium polycarbophil are used to neutralize the carboxyl groups.

A particularly preferred bioadhesive commercially available is the material sold under the name Polycarbophil by AH Robins Company of Richmond, Virginia, and CARBOPOL® ⁹³⁴ by BF Goodrich Chemical Company of Cleveland, Ohio, also discussed herein. ^CARBOPOL® "EX55", also known as ^CARBOPOL® 976, is sold by the manufacturer. United States Pharmacopoeia (USP) 1980 Ed., USP Congress, Inc., Rockville, Maryland, on page 638 describes polycarbophil as a polyacrylic acid cross-linked with diethylene glycol, which has less than 4.0% flammability residue and absorbs about 60 times its original weight in Test B. The 1985 edition of USP lists only calcium polycarbophil containing 18-22% calcium and is different from the substance described in the 1980 edition.

The above-mentioned substance named "EX55" by BF Goodrich has a specific gravity of about 1.4 and absorbs (absorbs and adsorbs) about 60 to 100 times its weight in water. This absorption value is similar to that of natural mucin. In contrast, CARBOPOL ^(R) 934 is reported to absorb hundreds of times its weight in water. Useful bioadhesives are also polyanionic polymers with charge densities similar to mucins.

The density of bioadhesives useful in the present invention is measured and generally ranges from about 1.30 to 1.70 grams per cubic centimeter (g/cc), or a specific gravity of about 1.30 to 1.70. As shown in the table below, the percentage of crosslinking was found to have a minor effect on the resulting density of the exemplary synthetic polymers. Also shown in column 11 of the table is the content of US Patent No. 4,615,917.

The bioadhesive moisturizing agent is present in the compositions of the present invention in an amount sufficient to provide moisturization for a desired period of time to the individual to whom the compositions are applied, and such an amount is referred to herein as an "effective moisturizing amount". As is well known, an effective amount of an agent will vary with the particular agent employed, the condition being treated and the rate at which compositions containing the agent are eliminated from the body, and with the animal to which it is administered. Therefore, the effective amount of moisturizing agent cannot be limited for each agent.

Thus, an effective moisturizing amount is that which provides a sufficient amount of moisturizing agent in the compositions of the present invention to provide the desired moisturizing effect on the body of the mammal being treated for the desired period of time. An effective amount can therefore also be defined as a moisturizing amount.

Moisturizing compositions for use in the methods of the present invention are designed to provide about 0.25 to 15 grams (g) of bioadhesive per 100 milliliters of composition (about 0.25 to 15% by weight). More preferably, the bioadhesive polymer is present in about 2-5 grams per 100 milliliters of the composition (about 2-5% by weight).

Humidifying moisture may be provided by the composition or the contacted epithelium or both. Thus, the bioadhesive wetting agent may be dispersed or pre-swelled in an aqueous medium prior to use, or used dry and anhydrous or dispersed in a vehicle containing sufficient moisture to partially hydrate the bioadhesive wetting agent particles.

In addition to water and the aforementioned bioadhesive polymers, the compositions of the present invention preferably contain a thickening and smoothing amount of a thickener, which is a water-soluble or water-dispersible polymer.

Thickeners for use herein have sufficient water solubility or water dispersibility to substantially modify the viscosity of aqueous compositions even in relatively small amounts. Such substances can exhibit bioadhesive effects, but due to their solubility or dispersibility in aqueous media, they tend to be lost from the composition relatively quickly and thus cannot provide the adhesive properties provided by the aforementioned bioadhesive polymers. long-term humidification effect.

For ease of expression, thickeners will generally be referred to herein as water-dispersible.

Whether the thickener is dispersed or truly dissolved, compositions of the thickener present at up to about 10% in deionized or distilled water form a single phase visually at 20°C, and once formed, when maintained at 20°C for 24 hours Still no separation occurs. When the thickener is an acid, cations such as sodium, potassium and ammonium ions for dispersing or dissolving the consistency regulator may also be present in the composition.

Examples of thickeners include anionic (carboxyl group-containing) and nonionic polymers such as polymers containing multiple carboxyl groups and polymers containing multiple C ₂ -C ₃ hydroxyalkyl groups. Particularly preferred thickening polymer agents include carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl starch derivatives, hydroxyethyl cellulose, gums such as tragacanth, hydroxyethyl acrylates or methacrylates, poly Acrylamides, and lightly crosslinked polyacrylic acid polymers, such as ^CARBOPOL® 934 described above, are particularly preferred. ^CARBOPOL® 934 is reported to be a polymer of acrylic acid crosslinked with polypropylene sucrose (polyalkenyl sucrose) containing an average of at least 3 propylene groups per molecule. Preferred thickener polymers are therefore considered to be derivatized polysaccharides and polyacrylic acids; ie amides and hydroxyethyl esters. Other thickening polymer agents include polyvinylpyrrolidone, polyvinyl alcohol and polyethylene oxide.

Thickeners function in the compositions described herein as their name implies; namely, to increase the thickness of the composition. This enhancement is manifested in 2 aspects: viscosity and texture.

As already stated, the thickeners used herein are water-dispersible and relatively small amounts of such substances can greatly increase the viscosity or thicken an aqueous composition. Since bioadhesives impart only a rather weakly controlled viscosity-building effect to aqueous compositions, compositions containing only bioadhesive moisturizing polymerization agents may be too watery and too soft or too hard for specific purposes such as vaginal products.

The bioadhesive moisturizing polymer and thickening polymer combine to provide a suitably thickened aqueous moisturizing composition when mixed in the amounts and conditions described below.

A particularly unexpected effect of mixing useful bioadhesive wetting polymers and thickening polymer agents is that the texture of the resulting thickened composition becomes creamier than when the bioadhesive wetting polymer is used alone. Thus, aqueous polymers containing only bioadhesive moisturizing polymers may exhibit a rigid and almost gritty feel, so they may be uncomfortable in vaginal products, especially during intercourse.

On the other hand, the presence of the thickening polymer agent unexpectedly makes the aqueous polymer creamier so that it does not exhibit a substantially rigid or gritty feel. The creamy texture also provides better lubricity to the composition.

One serving of thickening polymer agent provides the desired thickening and increased creaminess. Therefore, the amount of this material used is described as a thickening smoothing amount. The thickener can be a single polymer or a mixture of polymers such as those previously described.

The thickening polymer agent is present in a thickening and smoothing amount, preferably together with other ingredients that may be present in the aqueous composition, to provide a gel-like viscosity, the product having a viscosity at 25°C of about 4,000～40,000cps. As discussed in detail below, composition viscosity is a function of several variables, each of which can be varied to alter or maintain a desired viscosity.

Typical compositions may contain from about 0.25 to 10 percent by weight thickening polymer. More specifically about 0.5-5 weight percent is used.

Larger amounts of thickener are generally used with smaller amounts of bioadhesive polymer, and vice versa. For example, a pH 2.2-2.5 composition containing 0.25 weight percent polycarbophil as a bioadhesive requires about 8-10 weight percent CARBOPOL( ^R) 934 to achieve a viscosity suitable for mechanical placement in the vagina.

Moisturizing moisture may be provided by the composition or the contacted epithelial cells or both, although generally the moisture will be provided by the composition. Thus, the bioadhesive wetting agent and preferably the present thickener can be mixed and pre-swelled in an aqueous medium prior to use, or can be pre-swelled in a medium containing sufficient moisture to partially hydrate the bioadhesive wetting agent particles and thickener. Mix in an aqueous carrier.

Useful aqueous compositions can have room temperature viscosities from nearly non-pourable liquids to gels, the latter being preferred, with a viscosity that is about that of water, bioadhesive wetting polymers, thickening polymer agents (when present) The relative amount is a function of the osmolarity and pH of the formed composition. A relatively small amount of polymer in a given amount of water produces a relatively dilute composition in which the pH remains stable at both concentrations compared to a larger amount of polymer.

Useful bioadhesive wetting polymers have a pK _a of about 3-4. As a result, if the pH of the composition is about 5-6 or higher, substantially all of the acidic protons are neutralized and the polymer-containing composition exhibits the thickest viscosity at that concentration. On the other hand, at pH values such as 2, below the _pKa value of the polymer, the composition is relatively dilute for a given concentration.

Carboxylic acid-containing thickeners such as the particularly preferred CARBOPOL( ^R) ₉₃₄ have pK _a values similar to those of bioadhesive polymers. As a result, for a given concentration of thickener and all other ingredients held constant, use of the composition at a pH of about 5 or higher provides the most viscous composition, while use at a pH of about 2 provides the most viscous composition. the thinnest composition. Non-ionic thickeners change their viscosity and the viscosity of the composition less over the pH range than anionic materials.

Furthermore, the permeability of the composition also plays a role in the viscosity of the composition. In general, higher solute concentrations reduce the viscosity of the composition while the bioadhesive polymer, thickening polymer agent (when present), water, and pH are held constant. Thus, the viscosity of the aforementioned compositions having a pH value greater than 5 can be reduced from a strong gel to a pourable liquid by increasing the osmolarity of the composition.

Isotonic products have an osmolarity of about 280-320 mOsM, and are useful herein. The osmolarity of the moisturizing composition can be as high as 450-500 mOsM.

Pharmaceutically acceptable electrolytes and nonelectrolytes (collectively referred to as solutes) are used to adjust the permeability and viscosity of useful compositions. Exemplary pharmaceutically acceptable electrolytes include sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, sodium and potassium sulfates, sodium bicarbonate and potassium. Exemplary pharmaceutically acceptable non-electrolytes include glycerol, sugars such as glucose and sucrose, sorbitol and urea. Thus, those solutes that are well known for adjusting osmolality or osmolality are useful herein.

The permeability of a given composition is a measurement obtained with a gas phase osmometer.

Accordingly, compositions comprising bioadhesive wetting polymers exhibited more coagulation with or without carboxyl-containing thickening polymer agents at or near the aforementioned upper concentration limits and at pH values of about 5 or higher. Glue-like properties. However, such compositions can be extruded in droplets from an eye dropper, particularly when sufficient electrolytes or other solutes are present to increase the osmolarity to approximately 450 mOsM. In contrast, compositions at or near the aforementioned lower concentration limit and with a pH below about 3 generally behave like nearly non-pourable liquids unless significant amounts of bioadhesive polymer are present.

In a specific example, a composition for vaginal moisturizing may exhibit a viscosity of about 4,000-40,000 cps at 25°C, while a composition for oral moisturizing exhibits a viscosity of about 1-4,000 cps at 25°C. More viscous compositions generally exhibit non-Newtonian flow characteristics. The viscosity of the solution is therefore measured with a viscometer designed especially for the composition. The viscometer used for viscosity measurements discussed herein is the commercially available Haake ROTOVISCO Model RV-12, and is available from Haake, Inc., 244 Saddle Brook Road, Saddle Brook, New Jersey 07662. The machine uses an SV cup and SVII spindle for measuring viscosity in centipoise (cps) at a shear rate of 1-8 revolutions per minute (rpm) and 25°C.

Keeping these viscosity limits in mind, the skilled artisan can readily formulate a moisturizing composition having the desired viscosity. It should also be understood that the pH of the moisturizing composition will change once the composition is in contact with the epithelial tissue due to the local pH of the area where the composition is applied.

The moisturizing composition is applied to the epithelium in an amount sufficient to form a substantially continuous layer of hydrated bioadhesive particles on the application surface. Generally, this layer is several grains thick. For dry bioadhesive wetting agents, the bioadhesive wetting agent is applied in an amount of about 1 to 50 milligrams (mg) per square centimeter ( ^cm2 ) of contacted epithelial cells. Administration to the epithelium can, and preferably does, exceed the amount necessary to provide moisturization.

The amount administered is also a function of the site of administration. For example, relatively small amounts of the total moisturizing composition are required for ocular application because of the potential for discomfort when any foreign material enters the eye. Conversely, application to the skin and vaginal epithelium may exceed the amount necessary to provide moisturization.

For example, about 0.025 to 1.0 mg/ ^cm of moisturizing polymer (about 25 to 50 microliters of a composition containing about 1 to 3 percent by weight polymer) is used for eye moisturizing compositions, and about 10 to 50 mg / ^cm2 of moisturizing polymer is used to moisturize the skin.

For oral, nasal, rectal and vaginal epithelial administration, it is more convenient to refer to the amount of bioadhesive moisturizing polymer administered in terms of the total weight of polymer applied. Thus, for the oral epithelium, a composition comprising about 0.25 to 5 percent by weight bioadhesive moisturizing polymer is applied. Particularly for the vaginal epithelium, the amount of the composition is about 1 to 5 grams of the composition containing about 0.25 to 3 percent by weight of the bioadhesive polymer. The latter amount is in excess of that required for moisturization, but the excess is useful in providing lubrication during intercourse. Broadly speaking, then, the liquid composition contains from about 0.25 to about 5 percent by weight of the bioadhesive polymer or wetting agent.

In addition to bioadhesive polymeric wetting and thickening agents, compositions useful in the present invention may also contain one or more pharmaceutically or cosmetically acceptable additives referred to herein as adjuvants , they help meet the shelf life or customer tolerance of the humidification product. Exemplary adjuvants include antiseptics, astringents, skin toners, skin conditioners, skin feel enhancers, emollients, lubricating oils, emulsifiers, humectants, colorants, and odor-providing agents (odours) agent).

Typical preservatives known to be used in moisturizers include alcohol, ascorbyl palmitate, benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, ethylenediamine, ethylparaben Ethylparaben, Ethylvanillin, Glycerin, Methylparaben, Monothioglycerol, Phenol, Phenylethylalcohol, Phenylmercuric Nitrate, Propylparaben Propylparaben, sassafras oil, sodium benzoate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sorbic acid, sulfur dioxide, maleic acid, and propyl gallic acid. Obviously, any of the aforementioned preservatives is irritating to sensitive tissues to a certain extent, so less irritating preservatives should be selected.

Typical astringents known to be used in moisturizers are (1) aluminum, zinc, manganese, iron and bismuth salts, (2) some other salts containing these metals (such as permanganate) and (3) tannic acid or related polyphenolic compounds.

Typical emollients known for use in moisturizers are less irritating fatty or oily substances used for softening, making the skin more pliable by penetrating the emollient into the superficial layer. Typical emollients known to be used include castor oil, sulfated castor oil, cocoa butter, cold cream, corn oil, cottonseed oil, rosewater ointment (also known as cold cream), a mixture of white wax and white petrolatum, ten Sodium Dialkyl Sulfonate, Mixture Of Propylene Glycol And Stearyl Alcohol, Sesame Oil, Cocoa Bean Butter, Myristyl Alcohol And Shark Liver Oil.

Typical lubricants or lubricating oils known for use in moisturizers are petrolatum, white or yellow wax, cocoa butter, oleic acid, olive oil, jojoba oil, paraffin, starch glycerin, lanolin, paraffin, hydrophilic petrolatum, Mineral oil, cetyl alcohol, glyceryl monostearate, lanolin, stearic acid, polyethylene glycol, polyoxytetrastearate, polysorbate, cholesterol and high molecular weight lipids.

Emollients and lubricants provide skin care products with desirable smooth feel and rub-in properties to enhance ease of use and encourage consumers to use the product more casually and frequently. A certain number of compounds allow substances such as petrolatum to be mixed with glycerin and used in non-sticky personal care products. A petrolatum-glycerin mixture is especially effective in lightening dry skin.

Typical emulsifiers known to be used in moisturizers are sodium alginate, carbopol, sodium carboxymethylcellulose, carrageenan, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl Methylcellulose, octoxynol9, oleyl alcohol, polyethylene glycol, polyvinylpyrrolidone, sodium laurylsulfonate, sorbitan esters, alcohol stearate, tragacanth, and xanthan gum. Emulsifiers are used in the preparation of oil-in-water emulsions and can be classified into 3 types: single-molecular, multi-molecular, and solid particles. Known monomolecular emulsifiers include potassium laurate, polyoxyethylene sorbitan monooleate. Polyemulsifiers include acacia gum and gelatin. Solid particle emulsifiers include bentonite, graphite and magnesium hydroxide. Emulsifiers can also be chemically classified as anionic, cationic, and nonionic.

Typical humectants known for use in moisturizers are glycerin, propylene glycol, pyrrolidone carboxylic acid, sodium lactate, urea, and certain natural lipid mixtures. Other known humectants include certain proteins, gelatin, hyaluronic acid, vitamins and some natural ingredients. Some of the proteins used are collagen, hyaluronic acid, elastin, placental proteins and proteins from mammalian epithelial tissue are also used. In general, humectants work by penetrating the stratum corneum and increasing the amount of water held in close association with stratum corneum lipids or proteins.

The articles of manufacture are rendered sterile by autoclaving at increased temperature and pressure at a level and for a time sufficient to kill all bacterial contaminants or they are prepared under sterile conditions.

This product was made pyrogen-free by using pyrogen-free water available from commercial laboratories.

Phrases such as "pharmaceutically acceptable", "cosmetically acceptable" or "physiologically tolerable" as used herein mean that the substance in question can be used in the treatment of humans or other mammals without causing Pathogenic effects, such as toxicity, blistering or bleaching of mucous membrane or skin tissue, and these substances are not themselves bioadhesive wetting agents, as those terms are used herein. Exemplary adjuvants can be found in Chapter 67 of Remington's Pharmaceutical Sciences, 16th Edition, edited by Osol et al., Mack Publishing Company, Easton, PA (1980) and Chapter 84 of its 17th Edition.

It has been noted that the adjuvants mentioned above can be present in amounts greater than the bioadhesive polymer. Even if this is the case, the adjuvant does not provide the moisturizing effect of the composition, but provides emulsification or lubrication, etc., and generally facilitates the administration of the composition. This is the case if compounds such as glycerin or sorbitol, which are known as humectants, are present, since these substances are water soluble, non-bioadhesive agents which are generally lost with perspiration and the like. Lubricating oils and emulsifiers provide lubrication to the sexual composition.

Moisturizing compositions useful herein can be applied to contact the skin as dry powders, aqueous suspensions, or non-aqueous suspensions. The composition can be applied as a powder or suspension sprayed, or dripped, into a form having a cream or gel-like consistency.

In one embodiment, the dry bioadhesive wetting polymer is swollen in an aqueous medium at the desired pH and then used to contact the desired tissue, such as the eye. The word "dry" as used herein in relation to a bioadhesive wetting polymer means that it does not adhere and does not substantially swell when touched with a finger in a rubber glove.

Bioadhesives are also available as suppositories for rectal or vaginal administration, in which the bioadhesive polymer is dispersed. Dilute aqueous dispersions of bioadhesive moisturizing particles are also useful as vaginal or rectal douches. A gel-like consistency is preferred for vaginal moisturizers, and the composition is administered with a plunger-shaped applicator well known for administering vaginal products.

In another illustrative embodiment, the bioadhesive wetting agent is uniformly mixed with a pharmaceutically acceptable aqueous carrier as a diluent for application to the eye. The bioadhesive is preferably ground or otherwise sized to average about 2-5 microns in the longest dimension for application to the eye. The composition thus prepared can then be instilled as liquid droplets into the precorneal pocket of the eye to contact the conjunctiva and thus provide a moisturizing composition in contact with the mucosa.

Best Mode for Carrying Out the Invention

Example 1: Preparation of Bioadhesive Polymers

The bioadhesive polymers used herein are prepared according to the general synthetic methods discussed immediately below. Specific bioadhesive polymers prepared following general synthetic procedures are described in Table 1 below.

A solution containing 100 ml of distilled water and 800 g of magnesium sulfate (MgSO ₄ -7H ₂ O) was stirred and heated to reflux. A mixture of 1 gram of starter dissolved in 100 grams of monomeric carboxyl functional repeating units and the amount of crosslinker shown in Table 1 was added to the continuously stirring refluxing aqueous solution. The polymeric compositions thus prepared were stirred and heated to the temperatures shown in Table 1 for the initiation of polymerization and during hardening after polymerization.

At the end of the hardening time, the polymerized composition was diluted with 150 ml of distilled water heated to about 95°C and filtered through a 40 mesh stainless steel sieve (US Standard Sieve Series). The filtered bioadhesive retained on the sieve was washed with 1 liter of water heated to about 80° C. and then washed 5 times with 1 liter of warm water respectively. The washed bioadhesive thus prepared was then dried in a forced air oven at 90°C for 48 hours.

The bioadhesive thus prepared is then used directly or ground and sieved to provide the desired particle size.

Table 1

Bioadhesive Carboxyl Functional Group Polymerization Conditions Repeat Unit ¹ Crosslinker ² Initiator ³ Polymerization Time ⁴ T ⁵ Time ⁶ Yield ⁷ (A) (a) 0.2 (1) 15 95 2 83 (A) (b) 1.0 ( 1) 25 95 18 67(B) (a)1.0 (1) 30 95 48 53(B) (b)1.0 (1) 30 95 48 87(C) ⁸ (a)1.0 (1) -- 65 24 11 (D) ⁸ (a)0.2 (2) 20 95 72 10(A) (c)0.2 (1) 10 95 4 98(B) (c)0.2 (1) 10 95 20 93

1 Use 100 grams each of the following carboxyl functional repeat units: (A) = acrylic acid; (B) = methacrylic acid; (C) = methylenesuccinic acid; and (D) = maleic anhydride.

2 Numbers in the table indicate the grams of specific crosslinker used. Specific crosslinking agents are: (a) = 3,4 dihydroxy-1,5-hexadiene; (b) = divinylbenzene; and (c) = 2,5 dimethyl-1,5-hexadiene alkene.

3 1 gram of the following starting materials was used: (1) = benzoyl peroxide; and (2) = azobisisobutylate.

4 Minutes of initial polymerization time.

5 Temperature of initial polymerization and hardening after polymerization (°C)

6 Hours of hardening time after polymerization.

7 Yield of dry bioadhesive calculated from weight of starting material and recovered bioadhesive.

8 A nitrogen sparge was used during the polymerization and air-free distilled water was prepared by boiling the distilled water for 10 minutes.

Although optimization of polymerization conditions is not reflected in the data in Table 1, it can be seen from these data that useful amounts of bioadhesives useful herein can be readily prepared. It should be noted that the first bioadhesive listed in Table 1 has substantially the same properties as the commercially available material named polycarbophil sold by A.H. Robins Company of Richmond, Virginia, and by Cleveland, Ohio Bioadhesion and other physicochemical properties of a substance marketed by B.F. Goodrich Chemical Company as EX55.

Example 2: Determination of Adhesion

As previously noted, the bioadhesive moisturizing polymers of the present invention are water-insoluble, water-swellable, particulate, fibrous, cross-linked carboxyl-functional polymers containing specified amounts of carboxyl-functional groups and cross-linking agents. . Furthermore, with regard to its chemical definition, a useful bioadhesive by definition must also exhibit at least about 50 Viscosity in dyne/cm ² .

Exemplary results obtained using the above measurement technique for four useful bioadhesives are shown in Table 2 below. Bioadhesives were prepared as described in Example 1 except that 0.3 weight percent crosslinker was used. After preparation, the bioadhesives were screened and dry particles with a 30/40 mesh size (US Standard Sieve Series) were used for these assays.

Table 2

Bioadhesion assay Polymer ¹ Weight of tissue to be separated ² Force to separate tissue ³ Number of determinations

1 855±55 1061±68 13

2 864±56 1072±68 12

3 876±57 1086±71 13

4 306±45 380±56 8

1 polymer 1 = polyacrylic acid crosslinked with 3,4 dihydroxy-1,5-hexadiene; polymer 2 = polyacrylic acid crosslinked with 2,5 dimethyl-1,5-hexadiene; Polymer 3 = polyacrylic acid crosslinked with divinylbenzene; and Polymer 4 = polymethacrylic acid crosslinked with divinylbenzene.

2 Weight expressed in milligrams ± standard error of the mean (S.E.M)

3 Force expressed in dynes/cm ² ±SEM.

Using the assay technique described above, p-HEMA, commercially available from Aldrich Chemical Company of Milwaukee, Wisconsin, required a force ^of 29 dynes/cm to detach tissue, while AMBERLITE®, available from Rohm and Haas Company of Philadelphia, Pennsylvania 200 Cation Exchange Resins require little force to separate tissue.

Example 3: Adhesion as a function of pH

The measured force for the separation of the bioadhesive polymer is shown in Figure 2. The bioadhesive polymer is polyacrylic acid with 0.3 weight percent of 3,4-dihydroxy-1,5-hexanedi The reaction product of olefin polymerization and has a density of 1.56 g/cc. As shown, the greatest adhesion was observed at a pH of about 5-6. This maximum is more than twice the adhesion force required for separation at pH 0.46, 1.42 or 2.0. It can also be seen that the adhesion provided by the bioadhesive polymer is greatly reduced at pH 7. This reduction was statistically significant in a Student's t-test with p less than 0.01. Bioadhesion was determined as described in Example 2 above.

Example 4: Method of Moistening and Drying the Vagina

Prepared as an emulsion by stirring and mixing, containing polycarbophil (20 g, BFGoodrich Ex55) of a size capable of passing through a 400 mesh molecular sieve (U.S. Standard Sieve series) having an average longest one-dimensional value not exceeding about 20 microns, ^CARBOPOL® 934 (10 g, BFGoodrich), Hydrogenated Palm Glyceride Dispersion [10 g, MYVEROL 18-04K (Eastman)], Heavy Mineral Oil (USP Heavy Mineral Oil; 50 ml, Purepac), USP Glycerin (100 ml, Purepac), methyl paraben (1.0 g) and add distilled deionized water to 1000 g of moisturizing composition. The pH was adjusted to 2.4 with sodium citrate solution in HCl.

About 4 g of the above composition is placed in a plunger type applicator. The applicator and its contents are placed in the vagina of a postmenopausal woman exhibiting vaginal dryness and vaginitis, and the plunger is squeezed to force the composition into the subject's vaginal cavity to contact the vaginal mucosa. The composition thus applied increases the moisture of the mucous membranes and also provides lubrication for sexual intercourse.

Example 5: Comparative Viscosity Study

Three aqueous vaginal moisturizing compositions essentially the same as those in Example 4 were prepared except that the amount of polycarbophil as the bioadhesive moisturizing polymer was varied and CARBOPOL® ⁹³⁴ as the thickener The amount is kept constant, using more or less moisture replenishing composition.

All three compositions contained 1 weight percent ^CARBOPOL® 934. Composition 1 contained 1 weight percent polycarbophil. Composition 2, as in Example 4, contained 2 weight percent polycarbophil, while composition 3 contained 3 weight percent polycarbophil. Composition 1 was considered too thin to use despite its creamy consistency. Composition 3 was too thick for dispersion. Composition 2 had a suitable viscosity for dispensing with a plunger type applicator and showed a good feel when rubbed on the skin.

Embodiment 6: the mensuration of viscosity

The moisturizing composition of the present invention is viscous, preferably having a gel-like consistency slightly thicker or more viscous than mayonnaise. Such compositions exhibit non-Newtonian fluid characteristics that can be described as thixotropic; i.e., fluids characterized by 1) a plastic deformation point, 2) pseudoelastic behavior, and 3) a visible drop in viscosity with sustained shear over a limited period of time , and 4) the tendency to rebuild viscosity and/or plastic point at rest.

Due to the expected non-Newtonian fluid characteristics of the moisturizing composition, viscosity measurements were made with a viscometer specifically designed for this fluid. Therefore, with the specified viscometer, the viscosity values are reported at the indicated temperature and shear rate.

The viscometer used for viscosity measurements discussed herein is the commercially available Haake ROTOVISCO Model RV-12, available from Haake, Inc., 244 Saddle Brook Road, Saddle Brook, New Jersey 07662. The machine uses an SV cup and SVII spindle for measuring viscosity in centipoise (cps) at a shear rate of 1-8 revolutions per minute (rpm) and 25°C.

Two exemplary moisturizing compositions prepared as described in Example 4 were prepared separately by different persons. The viscosities of the 2 compositions were measured at shear rates of 1, 2, 4 and 8 rpm respectively and then compared.

The results of this comparison are shown in Figure 3, where the viscosity n (cps x ¹⁰⁴ ) is plotted against the shear ratio n (rpm). Data points for 2 different compositions are shown with open and filled circles.

Example 7: Comparison of Vaginal Humidification

A double-blind study of vaginal moisturization was performed under the supervision of a qualified physician using a moisturizing composition and method of the present invention (Example 4) and a commercially available vaginal lubricating product, wherein the lubricating product was Described by the manufacturer as a non-greasy, water-soluble lyogel, it is clear, spreads easily and is non-irritating. A total of 89 premenopausal or postmenopausal women were enrolled in the study. A total of 8 subjects withdrew from the study for various reasons.

A thorough medical history and physical examination was performed on each enrollee prior to study initiation. A vaginal examination was performed and a PAP smear was taken for vaginal cytology. Determination of indicators of vaginal dryness, including pH measurement, was performed.

A fixed dose of 2.5 grams of either of the two compositions was inserted into the enrollee's vagina at night for 5 consecutive days. No composition was administered on days 6-8.

Vaginal dryness index, vaginal pH value and PAP smear were measured on the 5th-8th day. Enrollees used the other composition on days 9-13 and again recorded the above data on days 13-16. Subjects were also asked to keep a diary during the study and told to maintain their normal sexual intercourse habits during the study and were advised not to use vaginal medications, including douches, during the study.

Most subjects (57.5%) had previously used vaginal lubricants, and most (71.4%) reported vaginal pain as the reason for use. 37.6% of subjects reported recurrent vaginal dryness, 31.8% intermittent, and 30.6% initial intermittent and now regular. The results were determined by statistical methods.

The findings of the study can be summarized as follows:

(1). There was a statistically significant drop in vaginal pH (at the level of 0.01) when using the composition of the present invention, whereas there was no drop in pH when using a commercially available lyogel. The vaginal pH is maintained at about pH 5 or lower about 48 hours after the last application of the composition.

(2). The moisturizing effect of the gel composition of the present invention tends to last longer than that of commercial products (p<0.001). More subjects using the gel of the invention reported a moisturizing effect lasting longer than 12 hours, while the commercial product lyogel was more frequently reported as lasting less than 6 hours.

(3) When asked which composition they prefer, 61.5% favor the composition of the present invention, while 25.6% favor the commercial lyogel.

(4) Most of the women who received the gel composition of the present invention had vulvar moisturizing effect or partially. Leakage was reported by more subjects using the commercial lubricating fluid gel compared to using the composition of the present invention. None of the subjects using the gel of the present invention reported excessive vulvar moisture, while 40% of the subjects using the commercial lubricating fluid gel reported excessive vulvar moisture.

(5) Ten women reported exacerbations when using the commercial lubricating fluid gel compared to only one woman who reported exacerbations when using the gel of the present invention. At the same time, 5 women reported that their condition was exacerbated by using both compositions. The women who used the water-soluble commercial lubricating fluid gel reported no residue compared to 7.8% of the women who used the gel of the present invention reported residue.

(6) Using the gel of the present invention has better (rank higher) mucous membrane quality than commercial gels. Although there was a statistically significant difference between the use of the gel composition and the pretreated control value, there was no statistically significant difference between the use of the two compositions.

(7) Moisture levels were statistically significantly higher with the gel composition of the invention compared to control values and values using commercially available lubricating fluid gels.

The vaginal dryness index is evaluated as 5 parameters, each of which is assumed to have a numerical score from 1 to 5, with 5 being the best. Thus, the lower the score, the greater the lack of vaginal lubrication.

The 5 parameters and their scores (in brackets) are as follows:

1. Overall vaginal elasticity

(1) None, (2) Weak, (3) Average, (4) Good, (5) Excellent;

2. Type and viscosity of vaginal discharge

(1) none, (2) a small amount of thin and yellow, (3) thin and white thin layer, (4) thin and white layer of medium thickness, (5) normal [white

color flocculent];

3. pH value

(1) 6.1 or higher, (2) 5.6-6.0, (3) 5.1-5.5, (4) 4.7-5.0, (5) 4.6 or lower;

4. Vaginal mucosa

(1) ecchymosis noted before exposure, (2) bleeding from high exposure 10 samples, (3) bleeding from rubbing, (4) non-breakable thin

Mucous membranes, (5) normal mucous membranes that are not friable; and

5. Vaginal Moisture

(1) None, mucosal inflammation, (2) None, 15 samples had no mucosal inflammation, (3) little, (4) moderate, (5) normal.

Example 8: Method of increasing moisture in dry skin

Prepared by stirring and mixing dry polycarbophil (5 g, B.F. Goodrich Ex55), microsilicate particles of a size capable of passing through a 400-mesh molecular sieve (U.S. Standard Sieve series) and having an average longest dimension of less than about 20 microns (3.75 g Syloid 244 FP, Davison Chemical Division, W.R. Grace & Co., Baltimore, Maryland), light mineral oil (50 ml), 95% ethanol (250 ml) and water (distilled deionized )Compositions.

The composition thus prepared is applied to the dry skin surface in an amount of about 0.5-1 g per 20-30 ^cm2 of the skin to be moisturized and allowed to adhere. The polymer composition adheres to the contact area and retains moisture in contact with the dry skin surface.

Example 9: Method of increasing moisture in dry skin

Dry polycarbophil (5.00 g; BFGoodrich Ex55) and ^CARBOPOL® 934P (2.50 g) having an average particle size of about 2-5 microns were mixed by stirring, Syloid 244 FP (3.75 g) containing light mineral oil (50.00 ml) , 95% ethanol (250.00 ml), urea (100.00 g), methyl paraben (1 g), propyl paraben (0.5 g) and dilute to 1000 with distilled deionized water ml to prepare the composition. The resulting composition has a creamy texture.

The composition is used to treat dry skin as described in Example 4 above. The presence of mineral oil and ^CARBOPOL® 934 in the composition improves its texture and makes the composition smoother when applied to the skin.

Example 10: Method of increasing moisture in a dry vagina

A composition prepared from dry polycarbophil (3 g) in Example 8, methylparaben (0.2 g), propylparaben (0.03 g) and water (100 ml) were mixed and stirred and the pH was adjusted to 2.4 with sodium citrate solution in HCl. The composition thus prepared has a gel-like consistency.

About 4 g of the above composition is placed in a plunger-type applicator. The applicator and its contents are placed in the vagina of a postmenopausal woman exhibiting vaginal dryness and vaginitis, and the plunger is squeezed to force the composition into the subject's vaginal cavity to contact the vaginal epithelium. The composition thus applied increases the moisture of the mucous membranes and also provides lubrication for intercourse.

Example 11: Method of increasing dry mouth moisture

Dry polycarbophil (2.0 g), sorbitol [NEOSORB ^® P100T (10 g, Roquette Company)], aspartame (0.06 g, NUTRASWEET ^® ), lemon-vanilla flavoring from Example 8 (1.0 g), methyl paraben (0.20 mg), propyl paraben (0.03 g) and water (100 ml) were mixed and stirred to prepare the composition, and the lemon in HCl NaOH solution to adjust the pH to 2.3.

The composition is applied to the mouth to moisturize dry or dehydrated tissues therein. Similar compositions can be administered in various administration forms, such as aqueous sprays, gels, chewable tablets, dry powders, sachets, pastilles, lozenges and emulsions. Other application forms are prepared by well-known techniques and need only contain the bioadhesive moisturizing polymer among the ingredients listed above.

Regardless of the form in which the composition is used, the bioadhesive polymer contacts the oral membrane tissue and retains moisture within the oral mucosa.

Example 12: Ways to Increase Moisture in Dry Eyes

Polycarbophil (B.F. Goodrich Ex55) was dried, crushed and sieved to provide particles which passed through a 400 mesh molecular sieve (US Standard Sieve series) and which had an average longest dimension of about 2-5 microns. Compositions of these polycarbophil particles (3.0 g) and water (100 ml) were prepared by mixing with stirring and adjusting the pH to about 5.5. Electrolyte was added with further stirring to provide a more viscous liquid. The liquid is applied to the eye epithelium with an eye dropper in an amount of about 0.025-0.05 ml. Contact with the ocular mucosa is maintained until the subject is prompted to require additional treatment due to eye itching.

The foregoing is intended to illustrate the invention, not to limit it. Numerous changes or modifications can be made without departing from the spirit and scope of the novel concept of the present invention.

Claims (41)

1. A method for moisturizing mammalian epithelial cells, comprising: Contacting a mammalian epithelial cell to be humidified with an effective wetting amount of an aqueous composition comprising water and a wetting amount of a bioadhesive agent having an adhesion force of at least about 380 dynes per square centimeter. wherein the bioadhesive wetting polymer comprises a water-swellable, but water-insoluble, cross-linked carboxyl-functional polymer; and The contact is maintained for a sufficient time to moisturize the contacted epithelial cells. 2. The method according to claim 1, wherein said bioadhesive moisturizing polymer comprises a plurality of repeating units, wherein said repeating units contain at least 80% carboxyl functional groups. 3. The method according to claim 2, wherein said bioadhesive polymer contains about 0.01-6% crosslinking agent. 4. The method according to claim 3, wherein said crosslinking agent is substantially free of polyalkenyl polyethers. 5. The method according to claim 3, wherein said aqueous composition further comprises a thickening smoothing amount of a thickener. 6. A method of moisturizing mammalian epithelial cells, comprising: Mammalian epithelial cells to be humidified are contacted with an effective humidifying amount of an aqueous composition comprising water, a humidifying amount of a bioadhesive having an adhesion force of at least about 380 dynes per square centimeter to wet polymerize Thickeners and thickening smoothing amounts, said bioadhesive moisturizing polymers comprising water-swellable but water-insoluble, particulate cross-linked carboxyl functional polymers comprising: (a) A plurality of repeating units, wherein at least about 80% of the repeating units contain at least one carboxyl functional group and (b) from about 0.01% to about 6% respectively of a cross-linking agent and a cross-linking agent, said thickener being water-dispersible nonionic or anionic polymers; and The contact is maintained for a time sufficient to moisturize the contacted vaginal epithelium. 7. The method of claim 6, wherein said bioadhesive polymer particles are sized to pass through a 400 mesh US Standard Sieve series when dry. 8. The method according to claim 7, wherein said thickener is an anionic polymer having a plurality of carboxyl groups. 9. The method according to claim 7, wherein said thickener is present in said composition at about 0.25-10 weight percent. 10. The method of claim 7, wherein said bioadhesive polymer particles are dispersed in a physiologically tolerable diluent prior to said contacting. 11. The method according to claim 7, wherein the contacted epithelium is selected from the group consisting of skin, vaginal mucosa, oral mucosa, nasal mucosa, anal mucosa and conjunctival mucosa. 12. An epithelial tissue moisturizing composition comprising water, a moisturizing amount of a bioadhesive moisturizing polymer having an adhesion force of at least about 380 dynes per square centimeter, and a thickening and smoothing amount of a thickener, wherein The bioadhesive moisturizing polymers include water-swellable but water-insoluble, cross-linked carboxyl-functional polymers, and the thickeners are water-dispersible nonionic or anionic polymers. 13. The composition according to claim 12, wherein said bioadhesive moisturizing polymer comprises a plurality of repeating units, wherein at least about 80% of the repeating units contain at least one carboxyl functional group. 14. The composition according to claim 13, wherein said bioadhesive polymer comprises from about 0.01% to about 6% of a crosslinking agent. 15. The composition according to claim 14, wherein said crosslinking agent is substantially free of polyalkenyl polyethers. 16. A vaginal moisturizing polymer comprising water, a moisturizing amount of a bioadhesive moisturizing polymer having an adhesion force of at least about 380 dynes per square centimeter and a thickening and smoothing amount of a thickener, The described bioadhesive moisturizing polymer consists essentially of a water-swellable but water-insoluble, particulate cross-linked carboxy-functional polymer comprising (1) a plurality of repeating units, of which at least about 80% repeating units containing at least one carboxyl functional group and (b) about 0.01% to 6% of a crosslinking agent, said percentages being based on the weight of unpolymerized repeating units and crosslinking agent, respectively, said thickening agent being water Dispersed nonionic or anionic polymers. 17. The composition of claim 16, wherein said bioadhesive polymer particles are sized to pass through a 400 mesh US Standard Sieve series when dry. 18. The composition according to claim 16, wherein said thickener is present in said composition at about 0.25-10 weight percent. 19. A moisturizing composition comprising water and a moisturizing amount of a bioadhesive moisturizing polymer having an adhesion force of at least about 380 dynes per square centimeter and an adjuvant known for use in moisturizing compositions The bioadhesive moisturizing polymer comprises a water-swellable but water-insoluble, particulate cross-linked carboxyl-functional polymer. 20. The composition according to claim 19, wherein said bioadhesive moisturizing polymer comprises a plurality of repeating units, wherein at least about 80% of the repeating units contain at least one carboxyl functional group. 21. The composition according to claim 20, wherein said bioadhesive polymer comprises from about 0.01% to about 6% of a crosslinking agent. 22. The composition according to claim 19, wherein said crosslinking agent is substantially free of polyalkenyl polyethers. 23. The composition according to claim 21, in a substantially sterile formulation. 24. A composition according to claim 21 which is substantially pyrogen-free. 25. A composition according to claim 21 which contains one or more preservatives. 26. A composition according to claim 21 which contains a lubricant. 27. A composition according to claim 21 which contains one or more preservatives, a lubricant and a thickener. 28. A method of producing a moisturizing composition comprising mixing water and a moisturizing amount of a bioadhesive moisturizing polymer having an adhesion force of at least about 380 dynes per square centimeter and known to be used in moisturizing compositions Adjuvants, said bioadhesive polymers include water-swellable but water-insoluble, particulate cross-linked carboxy-functional polymers. 29. The method of claim 28, wherein said bioadhesive wetting polymer contains a plurality of repeat units, wherein at least about 80% of the repeat units contain at least one carboxyl functional group. 30. The method of claim 29, wherein said bioadhesive polymer contains from about 0.01% to about 6% crosslinking agent. 31. The method of claim 29, wherein said crosslinking agent is substantially free of polyalkenyl polyethers. 32. A method according to claim 28, followed by sterilizing the mixture. 33. The method according to claim 28, followed by testing for pyrogen free. 34. The method of claim 28, which includes adding one or more preservatives. 35. The method of claim 28, including adding one or more lubricants. 36. The method of claim 28 including adding thickeners and lubricants. 37. A method according to claim 36 which is free of irritating substances. 38. A method of preparing a vaginal moisturizing composition comprising mixing a moisturizing amount of a bioadhesive moisturizing polymer having an adhesion force of at least about 380 dynes per square centimeter and a thickening and smoothing amount of a thickener, said The bioadhesive polymers include water-swellable but water-insoluble, cross-linked carboxyl-functional polymers comprising (1) a plurality of repeating units, wherein at least about 80% of the repeating units contain at least one carboxyl-functional group and (b) About 0.01% to 6% of cross-linking agent, the thickener is water-dispersible non-ionic or anionic polymer. 39. The composition of claim 38, wherein said bioadhesive polymer particles are sized to pass through a 400 mesh US Standard Sieve series when dry. 40. The composition according to claim 38, wherein said bioadhesive polymer particles have an average longest dimension of about 2 to 5 microns. 41. The composition according to claim 38, wherein said thickener is present in said composition at about 0.25-10 weight percent.

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