MX2007003706A - Non-absorbent and absorbent articles for inhibiting the production of exoproteins - Google Patents

Abstract

Non-absorbent and absorbent articles for inhibiting the production of exoproteins from Gram positive bacteria are disclosed. The non-absorbent and absorbent articles include an effective amount ofa precursor compound having the general formula (I):wherein R1is selected from the group consisting of formula (II) and formula (III);R7is -OCH2-;X is 0 or 1;R5is a substituted or unsubstituted aromatic ring or a monovalent saturated or unsaturated, substituted or unsubstituted, branched or straight chain hydrocarbyl moiety that may or may not be substituted with hetero atoms;R6is selected from the group consisting of an amino acid, a methyl ester of an amino acid, and an ethyl ester of an amino acid;R2, R3, and R4are independently selected from the group consisting of H, OH, COOH.

Description

ABSORBENT AND NON ABSORBENT ARTICLES TO INHIBIT THE PRODUCTION OF EXOPROTEINS BACKGROUND OF THE INVENTION The present invention relates to the inhibition of exoprotein production in and around the vagina of a woman in association with an absorbent or non-absorbent article. More particularly, the present invention relates to the incorporation of a precursor compound into or onto a non-absorbent or absorbent article so that with use, the precursor compound can be hydrolyzed by enzymatic activity in and around the vagina to produce a active species that reduces the exoprotein production of bacteria.

Disposable absorbent articles such as vaginal plugs for the absorption of vaginal exudates are widely used. These disposable articles typically have a compressed mass of absorbent formed in the desired shape which is typically dictated by the use of the intended user.In this area of a vaginal plug, the device is intended to be inserted into the vagina for the absorption of body fluids usually discharged during a woman's menstrual period.

There is a complex process in the woman's body that maintains the vagina and physiologically related areas in a healthy state. In a woman between the age of menarche and menopause, the normal vagina provides an ecosystem for a variety of microorganisms. Bacteria are the predominant type of microorganisms present in the vagina, and most women harbor about 109 bacteria per gram of vaginal fluid. The bacterial flora of the vagina is composed of both aerobic and anaerobic bacteria. The most commonly isolated bacteria are the Lactobacillus species, Corynebacteria species, Gardnerella vaginalis, Staphylococcus species, Peptococcus species, Aerobic and anaerobic Streptococcus species, and Bacteroides species. Other microorganisms that have been isolated from the vagina occasionally include fungi. { Candida albicans), protozoa (Trico onas vaginalis), mycoplasma (Mycoplasma hominis), chlamydia (Chlawydia trachomatis), and viruses (Herpes simplex). These last organisms are usually associated with vaginitis or venereal disease, even though they may be present in low numbers without causing symptoms.

The physiological, social and idiosyncratic factors affect the amount and species of bacteria present in the vagina. Physiological factors include age, menstrual cycle, and pregnancy. For example, microorganisms present in the vagina through the menstrual cycle may include lactobacilli, corynejacterium, ureaplasma, and mycoplasma.

The number of microorganisms and the types of microorganisms are unique to an individual. Social and idiosyncratic factors include method of birth control, sexual practices, systemic disease (eg, diabetes), and medications.

Bacterial proteins and metabolic products produced in the vagina can affect other microorganisms and the human host. For example, the vagina between menstrual periods is low acidic having a pH that varies from about 3.8 to about 4.5. This pH range is generally considered the most favorable condition for the maintenance of normal flora. At that pH, the vagina normally harbors the numerous species of microorganisms in a balanced ecology. These microorganisms play a beneficial role in providing protection and resistance to infection and make the vagina inhospitable to some species of bacteria such as Staphylococcus aureus. { S. aureus). The low pH is a consequence of the growth of lactobacilli and its production of acidic products. Microorganisms in the vagina can also produce antimicrobial compounds such as hydrogen peroxide and bactericides directed to other bacterial species. An example is lactocins, bacteriocin-like products of lactobacilli directed against other lactobacilli species.

Some microbial products produced in the vagina can adversely affect the human host. For example, Staphylococcus aureus can produce and secrete within its environment a variety of exoproteins including enterotoxins, Toxin-1 Toxic Shock Syndrome (TSST-1), and enzymes such as esterase and amidase. When absorbed into the bloodstream of the host, TSST-1 can lead to the development of Toxic Shock Syndrome (TSS) in non-immune humans.

Staphylococcus aureus is found in the vagina of approximately 16% of healthy women of menstrual age. Not all strains of Staphylococcus aureus can produce TSST-1. Approximately 25% of these women will harbor TSST-1 that produces Staphylococcus aureus. TSST-1 and some of the Staphylococcal enterotoxins have been identified as causing TSS in humans.

Symptoms of TSS usually include fever, diarrhea, vomiting and a rash followed by a rapid drop in blood pressure. Multiple organ failures occur in approximately 6% of those who develop the disease. Staphylococcus aureus does not initiate TSS as a result of the invasion of the microorganism inside the vaginal cavity. As Staphylococcus aureus grows and multiplies, it can produce TSST-1. Only after entering the stream The TSST-1 can act systematically and produce the symptoms attributed to the Toxic Shock Syndrome.

The menstrual fluid has a pH of around 7.3. During menstruation, the pH of the vagina moves towards neutral and can become slightly alkaline. This change allows microorganisms whose growth is inhibited by an acidic environment to proliferate. For example, Staphylococcus aureus is most frequently isolated from vaginal swabs during menstruation from cotton swabs collected between menstrual periods.

When Staphylococcus aureus is present in an area of the human body that harbors a normal microbial population such as the vagina, it can be difficult to eradicate Staphylococcus aureus bacterium without harming members of the normal microbial flora required for a healthy ecosystem. Typically, antibiotics that kill Staphylococcus aureus are not an option for use in products inserted into the vagina because of their effect on the normal vaginal microbial flora. An alternative to complete eradication is technology designed to prevent or essentially reduce the ability of bacteria to produce toxins.

There have been numerous attempts to reduce or eliminate pathogenic microorganisms and Shock Syndrome Toxic that occurs menstrually by incorporating one or more biostatic, biocidal, and / or detoxifying compounds into the vaginal products. For example, L-ascorbic acid has been applied to a menstrual plug to detoxify the toxin found in the vagina. Others have incorporated monoesters and diesters of polyhydric aliphatic alcohols, such as glycerol monolaurate, as biocidal compounds (see, for example, U.S. Patent No. 5,679,369). Still others have introduced other non-ionic surfactants, such as alkyl ethers, alkyl amines, and alkyl amides as detoxifying compounds (see, for example, U.S. Patent Nos. 5,685,872, 5,618,554, and 5,612,045).

A significant problem associated with some of the foregoing previous attempts is that the compounds used can be highly volatile during incorporation into absorbent and non-absorbent articles and during manufacturing processes. Specifically, it has been found that compounds such as aromatics, terpenes, and isoprenoids are completely volatilized out of a non-absorbent product or an absorbent during the high temperature manufacturing steps. Also, some compounds may have volatile problems during storage before use by the consumer.

As such, there remains a need for personal care products such as non-absorbent or absorbent products comprising inhibitory compounds that will effectively inhibit the production of exoproteins, such as TSST-1, from Gram-positive bacteria without being essentially damaging to the flora. natural found in the vaginal area. Additionally, these inhibitory compounds need to maintain activity even in the presence of enzymes such as lipase, esterase, and amidase, which can have adverse effects on potency and which may also be present in the vagina. It is desirable that the compounds have low volatility and remain in the product through manufacture, storage, and transportation in order to deliver an effective inhibitor to the consumer.

SYNTHESIS OF THE INVENTION The present invention is directed to non-absorbent products and absorbent articles that inhibit the exoprotein production of Gram-positive bacteria. More specifically, the present invention is directed to a vaginal plug or a non-absorbent substrate, such as a plug applicator that incorporates one or more precursor compounds that are formed by linking one or more aromatic compounds to one or more secondary compounds through of an ester or amide bond. Once introduced into the vagina, these precursor compounds can be hydrolyzed by enzymes produced by the natural vaginal flora resulting in active species that can inhibit the exoprotein production of Gram-positive bacteria without affecting essentially the flora present in the vagina. In other embodiments, the precursor compound itself can also inhibit the exoprotein production of Gram positive bacteria.

Therefore, the present invention is directed to an exoprotein inhibitor to inhibit the exoprotein production of Gram positive bacteria. The exoprotein inhibitor comprises a nonabsorbent substrate suitable for insertion into the vagina and having deposited thereon an effective amount of a precursor compound having the general formula: wherein R is selected from the group consisting of O - [R7] xCH2OCR5 and -CR6; R7 is -OCH2-; X is 0 O 1; R5 is a substituted or unsubstituted aromatic ring or a branched straight chain, substituted or unsubstituted, saturated or unsaturated monovalent ring which may or may not be substituted with heteroatoms; R6 is selected from the group which consists of an amino acid, a methyl ester of an amino acid, and an ethyl ester of an amino acid; R2, R3, and R4 are independently selected from the group consisting of H, OH, COOH, wherein with the hydrolysis of the precursor compound it is capable of producing an effective species effective to inhibit the production of exoproteins from Gram-positive bacteria.

The present invention is further directed to a plug applicator for inhibiting the exoprotein production of Gram-positive bacteria. The plug applicator comprises a non-absorbent material suitable for insertion into a vagina and having deposited thereon an effective amount of a precursor compound having the general formula: wherein R1 is selected from the group consisting of O II - [R7] xCH2OCR5 and -CR6; R7 is -OCH2-; X is 0 O 1; R5 is a substituted or unsubstituted aromatic ring or a straight or branched chain hydrocarbyl moiety, substituted or unsubstituted, saturated or unsaturated which may or may not be substituted with heteroatoms; R6 is selected from the group consisting of an amino acid, a methyl ester of an acid amino, and an ethyl ester of an amino acid; R2, R3, and R4 are independently selected from the group consisting of H, OH, COOH, wherein with the hydrolysis the precursor compound is capable of producing an effective active species to inhibit the exoprotein production of Gram-positive bacteria.

The present invention is further directed to a shower formulation for inhibiting the exoprotein production of Gram-positive bacteria located in and around a woman's vagina. The shower formulation comprises a vaginal cleansing formulation comprising a pharmaceutically acceptable carrier and an effective amount of a precursor compound having the general formula: where Rl is selected from the group consisting of O - [R7] xCH2OC IIR5 and -C? R6; R7 is -OCH2 -; X is 0 or 1; R5 is a substituted or unsubstituted aromatic ring or a straight or branched, saturated or unsaturated monovalent chain hydrocarbyl moiety that may or may not be substituted with heteroatoms, · R6 is selected from the group consisting of an amino acid, a methyl ester of an amino acid, and an ethyl ester of an amino acid; R2, R3, and R4 are independently selected from the group consisting of H, OH, COOH, wherein with the hydrolysis the precursor compound is capable of producing an effective active species to inhibit exoprotein production from Gram-positive bacteria, and where The vaginal cleansing formulation is suitable for use in a woman's vagina.

The present invention is also directed to an absorbent article for inhibiting the production of exoproteins from Gram-positive bacteria. The absorbent article is suitable for insertion into the vagina and comprises an absorbent structure and an effective amount of a precursor compound having the general formula where Rl is selected from the group consisting of O - [R7] xCH2OC IIR5 and -C? R6; R7 is -OCH2-; X is 0 or 1; R5 is a substituted or unsubstituted aromatic ring or a straight or branched chain hydrocarbyl, substituted or unsubstituted, saturated or unsaturated monovalent which may or may not be substituted with heteroatoms; R6 is selected from the group which consists of an acid araino, a methyl ester of an amino acid, and an ethyl ester of an amino acid; R2, R3, and R4 are independently selected from the group consisting of H, OH, COOH, wherein with the hydrolysis the precursor compound is capable of producing an active species effect in the inhibition of exoprotein production of Gram positive bacteria.

The present invention is further directed to a vaginal plug to inhibit the exoprotein production of Gram-positive bacteria. The vaginal plug comprises an absorbent plug material and an effective amount of a precursor compound having the general formula: where Rl is selected from the group consisting of - [R7] xCH2OCR5 and -CR6; R7 is -OCH2-; X is 0 or 1; R5 is a substituted or unsubstituted aromatic ring or a straight or branched chain hydrocarbyl, substituted or unsubstituted, saturated or unsaturated monovalent which may or may not be substituted with heteroatoms; R6 is selected from the group consisting of an amino acid, a methyl ester of an amino acid, and an ethyl ester of an amino acid; R2, R3, and R4 are independently selected from the group consisting of H, OH, COOH, wherein with the hydrolysis the precursor compound is capable of producing an effective active species to inhibit the exoprotein production of Gram-positive bacteria.

Other features and advantages of this invention will be evident in part and in part to be noted hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED INCORPORATIONS The present invention is generally directed to nonabsorbent or absorbent articles comprising a precursor compound which, with hydrolysis, produces an active species capable of inhibiting the production of exoproteins from Gram-positive bacteria. Specifically, the present invention relates to a non-absorbent product or an absorbent article comprising a precursor compound formed by linking an aromatic compound to a second compound by an ester or amide linkage that can be easily hydrolyzed by an enzymatic action a Once inside the vagina to produce an active species and a second compound. The active species has been found to essentially inhibit the production of exoproteins, such as TSST-1, from Gram-positive bacteria. Typically, the precursor compound itself can also inhibit the exoprotein production of Gram positive bacteria. Additionally, precursor compounds can be used in the combination with active surface agents such as, for example, mireth-3 myristate, glycerol monolaurate, and / or laureth-4, to essentially inhibit the production of exoproteins from Gram-positive bacteria.

This invention will be described herein in detail in relation to a plug applicator, but will be recognized by one skilled in the art to be applicable to other non-absorbent articles, devices, and / or products such as non-absorbent incontinent devices, devices for barrier birth control, nonabsorbent contraceptive devices and showers.

As used herein, the phrase "non-absorbent article" generally refers to substrates or devices which include an outer layer formed of an essentially hydrophobic material which repels fluids, such as menstrual fluids, blood products and the like. Suitable materials for the construction of the non-absorbent articles of the present invention include, for example, rubber, plastic, and cardboard.

Typically, a plug applicator includes an outer tube, which is preferably in the form of a hollow tube. The tube is formed of paper, cardboard, paperboard, plastic, thermoplastic film, aqueous coating or a combination thereof. If the paper, the cardboard or the cartoncillo, these can be coated with a wax or a polymer insoluble in water to make them resistant to water. Suitable plastic materials include polyolefins, such as low density polyethylene and low density polypropylene. The outer tube must have sufficient strength and rigidity to avoid collapse under normal vaginal pressures. The outer tube can also be formed into a cylindrical shape having a longitudinal seam or it can be wound convolutely or spirally. The outer tube has a relatively small diameter of around 10 millimeters to around 20 millimeters.

The outer tube has the ends spaced apart and separated first and second. The outer tube is formed of at least two distinct layers which can be constructed of an equal or different weight of cardboard. The layers may be made of different materials, for example, paperboard and film, or they may be made of a similar material having different properties, for example, a different cardboard weight. In one embodiment, the outer layer can be formed from a thin coated paperboard of about 0.06 millimeters or from a film material having a thickness of about 0.01 millimeters while one or more inner layers can be formed from a material uncoated having a higher cardboard weight. The outer layer may consist of high gloss coated paper, which is degradable in water or dispersible in water. Alternatively, The outer layer may have different finishes, such as semi-gloss or a satin finish. The coating on the outer tube can be selected from a wide variety of materials. Suitable coatings may include polyethylene, polypropylene, polyvinylidene chloride and polychloride alcohol. The outer layer can also be lubricated or contain an additive. Suitable lubricants and additives include any of the pharmaceutically accepted lubricants or additives and conventionally used in stopper applicators. Such lubricants and additives include organic compounds, aliphatic groups of each long, such as fatty acid derivatives, for example, stearamides and oleamides.

The paper used in the construction of the stopper applicator should have a cardboard weight per layer of from between about 20 pounds to about 200 pounds per ream, suitably from about 25 pounds to about 100 pounds per ream, and more appropriately, from around 30 pounds to around 50 pounds per ream. A "ream" is defined as the material having dimensions of 609.6 millimeters by 914.4 millimeters per 500 sheets. Each layer of paperboard should have a thickness of less than about 0.4 millimeters, suitably from about 0.04 millimeters to about 0.2 millimeters, and more suitably, from about 0.05 millimeters to about 0.16 millimeters. millimeters Typically, the outer layer will be thinner than the inner paperboard layer or layers.

If one of the layers is made of a thermoplastic film, it can be made of polyethylene. A suitable polyethylene film has high slip characteristics and a low density. The thermoplastic film should be thin, of less than about 0.1 millimeter, suitably from about 0.010 millimeters to about 0.050 millimeters, and more suitably from about 0.012 millimeters to about 0.040 millimeters. Other kinds of movies can also be used. Such films include cellulose ether selected from the group of aliphatic and aromatic ethers; films having ethylcellulose as the essential base constituent, or methyl cellulose films; highly plasticized and flexible cellulose acetate, formate and other similar alkyl esters; vinyl vinylidene chloride or a rubber hydrochloride, such as, for example, Pliofilm ™, or vinylite resin.

The thermoplastic film can be clear or opaque.

The film can run to the full length of the outer tube or only extend along a part of it. The film may be on the outer surface of the outer tube or be one of the inner layers.

The outer tube layers can be held together by an adhesive, such as rubber, or by heat, pressure, ultrasonic, etc. The adhesive can be either water soluble or water insoluble. A water-soluble adhesive is preferred for environmental reasons where the outer tube will break and separate quickly when submerged in water. Such immersion will occur in case the outer tube is discharged by discharging water into a toilet.

The outer tube is dimensioned and configured to house a catamenial absorbent cap. The inner diameter of the outer tube is sized to accommodate plugs of typical size. Usually, the inner diameter of the outer tube is less than about 19 millimeters and more adequately less than about 16 millimeters. Even though the outer diameter of the plugs varies, most plugs used by women have an external diameter of less than about 19 millimeters.

The outer tube must have an essentially smooth outer surface, which will facilitate the insertion of the plug applied to a woman's vagina. When the surface of the outer layer is smooth and / or slippery, the outer tube will easily slip into a woman's vagina without subjecting the internal tissues of a woman's vagina to abrasion. The outer tube can be coated to give high slip characteristics. Wax, polyethylene, a combination of wax and polyethylene, cellophane and clay are representative coatings that can be applied to the outer layer to facilitate comfortable insertion. The outer tube may be a straight elongated cylindrical tube formed on a central longitudinal axis. It is also possible to form the outer tube in an arched form. The arched or curved shape can help provide comfort when inserting the outer tube into the woman's vagina. With an arched plug applicator, it is possible to use an arched plug which again may be more comfortable for some women to use since the shape of the plug can better fit the curvature of a woman's vagina.

Formed integrally on the first end of the outer tube and extending outwardly therefrom is an insertion tip. The insertion tip is designed to facilitate the insertion of the outer tube into a woman's vagina in a comfortable way. The insertion tip should be made of a flexible and thin material or membrane which resists the rapid absorption of vaginal fluid during the period of insertion of the plug applied into a woman's vagina. The insertion tip can be constructed of paper, paperboard or film material. When the outer tube has only two layers, the insertion tip must be formed from the layer having the lowest cardboard weight. The lowest cardboard weight layer is usually the thinnest layer. A film material is preferred because it is thin, soft and flexible. Suitable materials for the insertion tip include a layer of bonded nonwoven fabric Thin coated with low density polyethylene, polyurethane or plasticized polyvinyl chloride. The insertion tip may also contain a coating or impregnation that inhibits any substantial absorption of vaginal fluids. The coating may be an oil, a wax, or an acceptable organic compound. Alternatively, the insertion tip can be self-lubricating. Such materials can be made of a polymer that inherently provides the outer surface with a low coefficient of friction. Typical polymers of this type are fluorinated, such as polytetrafluoroethylene (PTFE), fluorinated ethylene-propylene (FEP) and polyethylene oxide (PEO).

The insertion tip must have an outside diameter which is approximately equal to or less than the outer diameter of the outer tube. It should be noted that when the diameter is smaller than that of the outer tube, the difference should be small so that the end of the outer layer can not be felt by the woman during insertion. Generally, the insertion tip has a diameter that is smaller than the diameter of the outer tube. The insertion tip may be configured to be rounded, semi-spherical or frustoconical. Other nose shapes or dome types can also be used. The rounded configuration of the insertion tip works to avoid the forward end of the cap and prevent it from exerting an abrasive action on the cap. wall of the vagina as would be the case if it were discovered.

The insertion tip is formed of at least one of the layers, which forms the outer tube and can be formed of more than one layer if desired, provided it has less thickness. The insertion tip can be formed of at least one layer less than the number of layers of which the outer tube is constructed. The insertion tip has a thickness that is less than the thickness of the outer tube to assume that it is soft and flexible. The thickness of the insertion tip should be less than about 50% of the thickness of the outer tube, suitably less than about 75% of the thickness of the outer tube, and more suitably, less than about 80% of the thickness of the outer tube .

The insertion tip may have a plurality of soft and flexible petals, which are arranged to form a domed nose. The petals are separated by narrow slots. The petals are capable of radially flexing or bending outwards to provide an amplified opening through which the plug can exit when it is pushed forward by the inner tube. Either an even number or an uneven number of petals can be used but preferably, there is an uneven number of petals, such as 3, 5, 7, etc. because the uneven number of petals will prevent the outer tube from bending or flattening after the plug is ejected. By preventing the outer tube from collapsing, one can ensure that the vaginal tissue will not be pinched when the tampon applicator is removed from the wearer's vagina. For example, the insertion tip will contain five petals, each having an approximately truncated and elongated shape with a rounded end and each being about 11.1 millimeters in length.

As indicated above, the plug applicator includes an inner tube. The inner tube, like the outer tube, can be spirally wound, coiled convolutely or sewn longitudinally, a hollow tube constructed of paper, paperboard, cardboard, plastic, film, aqueous coating or a combination thereof . The inner tube can also be formed in a hollow tube by overlapping the material on itself. The inner tube can be constructed of the same material as the outer tube or it can be made of a different material. In addition, the inner tube can be constructed as a laminate having two or more layers which are then wound spirally, coiled convolutely or sewn longitudinally into a cylindrical tube. Either a rolled tube or a longitudinally stitched tube is preferred because the finished tube will have a wall of constant thickness. However, some manufacturers may prefer to build the inner tube as a solid stick or use some other unique shape. The inner tube also has a distant or free end on which the finger The user's index can rest to facilitate movement of the inner tube inside the outer tube. The far end therefore functions as a seat for the index finger. It is also possible to form an amplified ring or flange on the distal end of the inner tube to provide a larger contact surface.

The inner tube works by moving the outer tube telescopically inside. When the inner tube is pushed inside the outer tube, the plug is forced forward against the insertion tip. The contact with the plug causes the petals to open radially to a diameter, which is sufficient to allow the plug to be expelled from the outer tube. With the plug properly placed in the woman's vagina, the plug applicator is removed and discarded.

The weight of a plug applicator will depend on the size and absorbency of the plug. For example, a more absorbent and longer plug will be heavier than a shorter shorter absorbent plug. Typically, a suitable applicator for use in the present invention with a regular absorbency plug will weigh about 3.62 grams; A suitable applicator for use with a much larger absorbent or super absorbency plug will weigh around 4.12 grams.

Other non-absorbent articles suitable for the present invention include, for example, non-absorbent incontinent devices, nonabsorbent contraceptive devices, such as barrier birth control devices, and showers. As used herein, the device, "for non-absorbent incontinent" refers to a device designed to be inserted into a woman's vagina and expanded to relieve or eliminate the involuntary passage of urine through the urethra from the bladder . The expansion of the nonabsorbent urinary incontinent device provides a stable background to the musculature and body tissue located near the urethro-vaginal myofacial area and causes the urethra to be compressed on itself during episodes of increased intra-abdominal pressure. In addition, the expansion of the incontinent device in the vagina will help the urinary sphincter muscle to maintain the configuration in circular cross section. An example of a suitable non-absorbent incontinent device is described in U.S. Patent No. 6,679,831 issued to Zunker, et al. (January 20, 2004).

Suitable non-absorbing contraceptive devices, such as barrier birth control devices, for the present invention are known in the art. For example, U.S. Patent No. 4,711,235 issued to Willis (December 8, 1987) describes a device comprising a ring having a central sheet of flexible waterproof material placed between two layers of foam rubber. Foam rubber traps sperm and bacteria in a vaginal recess for a sufficient time to be destroyed by the normal acidic pH of vaginal secretions. The ring defines the sheet material in a cup shape with four sides, a pair of opposite sides including a wire core bent inward and another pair of sides with one rounded outward and the other having a fork configuration. The waterproof and flexible material is typically a nonabsorbent neoprene rubber material.

This invention also relates to absorbent articles and will also be described herein in detail in connection with a vaginal plug, but will be understood by those skilled in the art to be applicable to other disposable absorbent articles such as sanitary napkins, panty liners, adult incontinence garments, absorbent contraceptive sponges, diapers, wound dressings, medical bandages and other absorbent plugs such as those intended for medical, dental, surgical and / or nasal use wherein the inhibition of exoproteins from Gram-positive bacteria would be beneficial.

As used herein, the phrase "absorbent plug" generally refers to vaginal plugs, medical plugs, dental plugs, surgical plugs and nasal plugs. The phrase "absorbent article" generally refers to devices which absorb and contain the fluids of the body, and more specifically, refer to devices that are placed against or close to the skin, or within the body cavity, to absorb and contain the various fluids discharged from the body. The term "disposable" is used herein to describe absorbent articles that are not intended to be washed or otherwise restored or reused as an absorbent article after a single use. Examples of such disposable absorbent articles include, but are not limited to, health care-related products including bandages and tampons such as those intended for medical, dental, surgical and / or nasal uses; absorbent personal care products such as women's hygiene products (e.g., sanitary napkins, pant lining, and vaginal plugs), diapers, training underpants, incontinence products and the like, wherein the inhibition of Exoprotein production of Gram-positive bacteria would be beneficial.

Vaginal closures suitable for use with the present invention are typically made of absorbent materials such as absorbent fibers, including natural and synthetic fibers, compressed into a unitary body of a size that can be easily inserted into the vaginal cavity. Suitable fibers include, for example, cellulosic fibers such as cotton and rayon. The fibers can be 100% cotton, 100% rayon, a mixture of cotton and rayon or other materials known to be suitable for the use of stoppers.

The vaginal plugs are typically made in an elongated cylindrical shape so that they can have a body of material long enough to provide the required absorbent capacity, but they can be made in a variety of ways. The plug may or may not be compressed, although compressed types are generally preferred. The plug can be made of various fiber blends including both the absorbent and non-absorbent fibers which may or may not be wrapped in a cover or wrap. Typically, the cover or sheath can be formed of a nonwoven material such as a polyolefin, particularly polypropylene or polyethylene. A suitable material is a yarn bonded material. The cover or wrap is beneficial to assume that the fibers of the plug do not directly contact the inner walls of a woman's vagina. This ensures that no fibers will remain in the vagina after the plug has been removed. The cover can be tucked into spaced apart ends of the plug as to completely enclose and enclose the fibers. The cover or wrap can also be constructed of a material that can be heat sealed to help bind the fiber to the fibers, such as by heat and / or pressure. Suitable methods and materials for the production of stoppers are well known to those skilled in the art.

In one embodiment, a plug suitable for use in the present invention has a cover or wrap. Typically, the weight of the plug having a cover or shell will depend on the absorbency level of the plug. For example, a more absorbent plug will be heavier than a less absorbent plug. Typically, a regular absorbency plug with a cover or wrapping will weigh from about 1.77 grams to about 2.67 grams, suitably about 2.22 grams; a super absorbency plug with a cover or wrap will weigh from about 2.67 grams to about 3.57 grams, suitably about 3.12 grams; A plus super absorbency plug with a cover or wrap will weigh from around 3.67 grams to around 4.97 grams, appropriately around 4.32 grams.

The plugs come in a variety of sizes. In another embodiment, a plug for use in the present invention does not have a cover or wrap. Typically, a regular absorbency plug without a cover or wrap suitable for the present invention will weigh from about 1.60 grams to about 2.50 grams, suitably about 2.05 grams; a super absorbency plug without a cover or wrap will weigh from about 2.49 grams to about 3.39 grams, suitably around 2.94 grams; a super-plus absorbency plug without a cover or wrap will weigh from about 3.49 grams to about 4.79 grams, suitably about 4.14 grams.

As indicated above, the absorbent and non-absorbent articles of the present invention comprise an effective amount of a precursor compound which, upon hydrolysis, produces an active species that can essentially inhibit the production of exoproteins by Gram-positive bacteria and specifically the production of TSST-1 of bacteria Staphylococcus aureus. As used herein, the term "precursor compound" means a compound that is introduced into and / or onto a non-absorbent article or an absorbent that is capable of undergoing hydrolysis within and / or to one side of the vagina to produce an active species able to inhibit the exoprotein production of Gram positive bacteria. The precursor compounds are formed by linking an aromatic compound to a second compound with an ester or amide bond. The ester or amide bond contained in the precursor compound is hydrolyzed by enzymes, such as lipase, esterase, and / or amidase, which are produced by bacteria found in the natural vaginal flora, resulting in an active species that can inhibit the production of exoprotein from Gram-positive bacteria. Together with the active species produced, the hydrolysis reaction produces a second compound that is not critical to the function of the active species. In some embodiments, the second compound will be identical or similar to compounds that occur naturally in the human body. Even though as noted above, the second compound is not critical, the parent compound must be designed so that With hydrolysis the second compound formed is not essentially harmful to the vagina or to the bacteria located there.

During the hydrolysis process, the precursor compound is slowly broken down into the active species and the secondary compound; and, as noted above, both the precursor compound and the active species can inhibit the production of dexoproteins from Gram-positive bacteria. This is suitably advantageous since it allows a long-term continuous inhibition of dexoprotein production by Gram-positive bacteria. The precursor compounds of the present invention can inhibit deoxoprotein production prior to hydrolysis; and then, when the precursor compounds are hydrolyzed, the active species are produced, which further inhibit the production of dexoprotein.

The precursor compounds described herein and suitable for introduction into and / or onto a non-absorbent or absorbent article are both essentially stable in and / or on non-absorbent or absorbent articles both through the manufacturing processes and during storage in the shelf. In other words, the precursor compounds are not easily volatilized from or out of the absorbent or non-absorbent article during high temperature manufacturing processes or during shipment and storage. This property of the precursor compounds is highly desirable since it is important for the precursor compound to remain in or on the non-absorbent or absorbent article product in an amount effective for ultimate use by the consumer. As noted above, the volatility of the active compounds of non-absorbent or absorbent articles has been problematic in the past and may result in a non-absorbent product or in an absorbent article devoid of active compound.

Without wishing to be bound by a particular theory, it is believed that the precursor compounds of the present invention can remain in or on the non-absorbent or absorbent articles in an increased amount as compared to the above ingredients due to their increased molecular weight. Even though the precursor compounds of the present invention have a generally higher molecular weight compared to some active ingredients used in the past, they are suitably hydrolyzed in the body to produce highly desirable active species, such as benzyl alcohol and benzoic acid. , which are highly effective in inhibiting exoprotein production by Gram positive bacteria.

In addition to having reduced volatility and being able to remain in and / or on a non-absorbent or an absorbent product through manufacturing, shipping and storage, the precursor compounds described herein, together with the hydrolyzed active species and the latter compounds produced in the body, do not kill a substantial amount of naturally occurring bacteria found in the vagina. This property is significant since the specific complete or non-complete destruction of the bacteria located in and around the vagina can be very harmful to the host since natural flora is required to maintain a healthy vagina. In contrast to agents such as antibacterials or antivirals that do not specifically kill all the microorganisms in the vagina, the precursor compounds and hydrolyzed compounds produced in and around the vaginal cavity do not have a substantial destruction effect on the bacteria in the vagina. concentration incorporated in the product, but the active species produced by hydrolysis can essentially inhibit the production of exotoxins from Gram-positive bacteria. an embodiment of the present invention the precursor compounds have the general chemical structure: OR wherein R1 is - [R7] xCH2OCR5; R7 is -OCH2-; X is 0 or 1; R5 is a substituted or unsubstituted aromatic ring or a straight or branched, substituted or unsubstituted saturated or unsaturated monovalent hydrocarbyl moiety which may or may not be substituted with heteroatoms; and R2, R3, and R4 are independently selected from the group consisting of H, OH, COOH.

As noted above, the hydrocarbyl moieties described herein include both straight-chain and branched chain hydrocarbyl moieties which may or may not be substituted with various substituents such as, for example, hydroxyl groups. Additionally, the hydrocarbyl moiety may or may not be interrupted with hetero. The hetero atoms that can interrupt the hydrocarbyl moiety include, for example, oxygen, nitrogen, and sulfur. In one embodiment, R5 is one half straight chain hydrocarbyl or. branched, substituted or unsubstituted, monovalent saturated having from 1 to 15 carbon atoms, more suitably from 1 to 12 carbon atoms.

Some specific precursor compounds having a linking ester and suitably for the above-described incorporation of the present invention can be found in Table 1 given below.

Table 1 The above compounds can be used alone or in combinations thereof.

As noted above, enzymes such as esterase produced by bacteria such as Staphylococcus aureus found in the vaginal flora together with enzymes that naturally occur in menstrual fluid, can hydrolyse the precursor compounds described herein to produce an active species and a second compound. For example, the enzyme esterase can react with the ester linkage of the precursor compounds described above to form the benzyl alcohol of active species and a hydrocarbon. Benzyl alcohol has been found to inhibit essentially the exoproteins of the Gram-positive bacteria without essentially eliminating the bacteria.

In another embodiment, the precursor compounds have the general chemical structure: or where R is -CR °; R is selected from the group consisting of an amino acid, a methyl ester of an amino acid, and an ethyl ester of an amino acid; R2, R3, and R4 are independently selected from the group consisting of H, OH, COOH.

Amino acids are organic compounds that contain an amino group and a carboxylic acid group. The appropriate amino acids that can be used for R6 are any of the twenty amino acids found naturally in the human body. More particularly, amino acids for use in the present invention suitably include, for example, valine, leucine, cysteine, and combinations thereof.

Suitable compounds for this incorporation can be found in Table 2 given below.

Table 2 The above compounds described herein may be used alone or in combination thereof.

As described above, enzymes such as the amidase produced by the bacterium such as Staphylococcus aureus found in the vaginal flora along with the enzymes that occur naturally in the menstrual fluid they can hydrolyze the precursor compounds containing the amino acid. For example, the amidase enzyme can react with the parent compound and break the amide bonds of said compounds in this embodiment to release the benzoic acid and an amino acid. Like the benzyl alcohol discussed above, benzoic acid has been found to essentially inhibit the exoproteins of Gram-positive bacteria without essentially eliminating naturally occurring flora.

According to the present invention, the non-absorbent article or absorbent comprises an effective amount of the precursor compound which upon hydrolysis of the precursor compound, there is a sufficient amount of active agent produced to essentially inhibit the formation of exoproteins such as TSST-1 when The non-absorbent or absorbent article is exposed to Staphylococcus aureus bacteria. Several methods are known in the art to test the effectiveness of potential inhibitory agents, such as benzyl alcohol or benzoic acid on the inhibition of TSST-1 production in the presence of Staphylococcus aureus. One of such preferred method is set forth in Example 1. When tested in accordance with the methodology set forth herein, preferably, the active species produced from the hydrolysis of the parent compound reduces the formation of TSST-1 by Staphylococcus aureus at least about 40%, more preferably at least about 50%, even more preferably at least about 60%, even more preferably at least about 70%, still more preferably at least about 80%, even more preferably at least about 90% and even more preferably at least about 95%. Additionally, as noted above, the precursor compound can also inhibit the exoprotein production of Gram positive bacteria in some embodiments. The test procedure set forth in Example 1 can also be used to measure the amount of inhibition by the precursor compound. In some embodiments, the precursor compound can reduce the formation of TSST-1 by at least about 50%, preferably at least about 80%.

According to the present invention, the non-absorbent products or absorbers comprise a suitable amount of the precursor compound such that, with use, the precursor compound and / or the active species produced therefrom in or around the vagina as discussed here can essentially inhibit the exoprotein production of a Gram positive bacterium. Generally, the non-absorbent products will comprise from about 0.15% (by weight of the non-absorbent substrate) to about 2.0% (by weight of the non-absorbent substrate) of the parent compound, and the absorbent articles will comprise from about 0.15% ( by weight of the absorbent structure) to about 2.0% (by weight of the absorbent structure) of the parent compound. These percentages are commonly referred to as "aggregate over weight percentages. "In a desirable embodiment, the non-absorbent products will comprise from about 0.17% (by weight of the non-absorbent substrate) to about 1.7% (by weight of the non-absorbent substrate) of the parent compound, and the absorbent products. they will comprise from about 0.17% (by weight of the absorbent structure) to about 1.7% (by weight of the absorbent structure) of the parent compound.

In a specific embodiment, a plug applicator as described herein comprises a suitable amount of precursor compound such that, with use, the precursor compound and / or the active species produced therefrom in or around the vagina as discussed Here you can essentially inhibit the exoprotein production of Gram positive bacteria. Generally, the plug applicator will comprise from about 0.15% (by weight of the non-absorbent substrate) to about 2.0% (by weight of the non-absorbent substrate) of the parent compound. In a desirable embodiment, the plug applicator will comprise from about 0.17% (by weight of the non-absorbent substrate) to about 1.7% (by weight of the non-absorbent substrate) of the parent compound.

In another specific embodiment, a vaginal plug as described herein without a cover or wrapping material comprises a suitable amount of a precursor compound such that, with use, the precursor compound and / or the active species produced thereof in or around of the vagina as it discussed here can essentially inhibit the exoprotein production of Gram-positive bacteria. Generally, the vaginal plug without a sheath cover will comprise from about 0.15% (by weight of the absorbent plug material) to about 2.0% (by weight of the absorbent plug material) of the precursor compound. In the desirable embodiment, the plug will comprise from about 0.17% (by weight of the absorbent plug material) to about 1.7% (by weight of the absorbent plug material) of the parent compound.

In another specific embodiment, a vaginal plug as described herein is provided having a cover or wrapping material comprising a suitable amount of the precursor compound such that, with use, the parent compound and / or the active species produced thereof in or around the vagina as discussed here can essentially inhibit the exoprotein production of Gram positive bacteria. The precursor compound is introduced directly into or onto the cover or wrapping material as opposed to being introduced into or onto the absorbent substrate of the vaginal plug. In a desired embodiment, the cover or wrapping material of the vaginal plug will comprise from about 2.6% (by weight of the cover or wrapping material) to about 35.0% (by weight of the cover or wrapping material) of the precursor compound. More desirably, the cover or wrapping material of the vaginal plug will comprise from about 2.95% (by weight of the cover or wrapping material) to about 29.5% (by weight of the cover or wrapping material) of the parent compound.

In a preferred embodiment of the present invention, the precursor compounds described herein can be introduced into and / or onto the non-absorbent article or the absorbent product in combination with one or more surfactants to further reduce the production of exoproteins such as TSST-1. without significantly eliminating the beneficial bacterial flora. The active surface agents used in combination with the precursor compounds can also act as lubricants and / or emollients to further improve product performance. When used in combination with the vaginal plug, the surfactants can also help in the removal of a "dry plug". In one embodiment including a plug applicator or a vaginal plug, a suitable surface active agent is mireth-3-myristate, which is a product commercially sold by CETIOL 1414 by Kraft Chemical Corporation (of Melrose Park, Illinois). Other surface active agents suitable for the present invention include, for example, glycerol monolaurate and laureth-4.

According to the present invention, the non-absorbent or absorbent products may comprise a suitable amount of surfactants so that, with use, the surfactants can further inhibit the exoprotein production of Gram positive bacteria. Generally, the non-absorbent products will comprise from about 0.4% (by weight of the non-absorbent substrate) to about 1.1% (by weight of the non-absorbent substrate) of the active surface agent. In one embodiment, the non-absorbent product is a plug applicator comprising about 0.75% (by weight of the non-absorbent substrate) of the active surface agent. Generally, the absorbent articles will comprise from about 0.4% (by weight of the absorbent structure) to about 1.1% (by weight of the absorbent structure) of the active surface agent. In a specific embodiment, the absorbent product is a vaginal plug that has a cover and will comprise about 0.75% (by weight of the total plug including a cover) of the active surface agent.

In another embodiment, the active surface ingredient may be introduced directly into or onto the cover or wrapping material as opposed to being introduced into or onto the absorbent substrate of the vaginal plug. Typically, the cover or wrapping material of the vaginal plug will comprise about 13% (by weight of the cover material) of the active surface agent.

Additionally, the precursor compounds described herein may be introduced into and / or onto the absorbent or non-absorbent product in combination with one or more secondary agents to further reduce the production of exoproteins such as TSST-1 without significantly eliminating the beneficial bacterial flora. Suitable examples of the secondary agents useful in the present invention include agents selected from the group consisting of: compounds with an ester, ether, amide, glycosidic, or amine bond bonding a C8-Ci8 fatty acid with an aliphatic alcohol.

In one embodiment, the precursor compound described herein can be used in combination with the ester compounds having the general formula: O R27 C O 28 wherein R27 is a straight or branched alkyl or a straight or branched alkenyl having from 8 to about 18 carbon atoms and R28 is selected from the group consisting of an alcohol, a polyhydric alcohol, and an ethoxylated alcohol. As used herein, the term "polyhydric" refers to the presence in a chemical compound of at least two hydroxyl (OH) groups. Suitable compounds include glyceryl monolaurate, glyceryl dilaurate, mireth-3-myristate, and mixtures thereof.

In another embodiment, the precursor compound described herein can be used in combination with the ether compounds having the general formula: Rio or R11 wherein R10 is straight branched alkyl or straight branched alkenyl having from 8 to about 18 carbon atoms and R11 is selected from the group consisting of an alcohol, an ethoxylated alcohol, a polyalkoxylated sulfate salt and a sulfosuccinate salt polyalkoxylated. Suitable compounds include laureth-3, laureth-4, laureth-5, PPG-5 lauryl ether, 1-0-dodecyl-rac-glycerol, sodium laureth sulfate, potassium laureth sulfate, sulfosuccinate (3) laureth disodium, sulfosuccinate (3) dipotassium laureth, and polyethylene oxide (2) sorbital ether.

In another embodiment, the precursor compounds described herein can be used in combination with an alkyl polyglycoside compound. Suitable alkyl polyglycosides for use in combination with the precursor compounds include alkyl polyglycosides having the general formula: H (Zn) O R14 wherein Z is a saccharide having 5 or 6 carbon atoms, n is a complete number from 1 to 6, and R 14 is a linear or branched alkyl group having from about 8 to about 18 carbon atoms. Glucopon 220, 225, 425, 600, and 625 (all commercially available from Henkel Corporation, of Ambler, Pennsylvania) and TL 2141 (commercially available from ICI Surfactants, of Wilmington, Delaware) are suitable alkyl polyglycosides for use in combination with the precursor compounds of the present invention.

In another embodiment, the precursor compounds described herein can be used in combination with an amide-containing compound having the general formula: R 17 CN -R 18 R18 wherein R, inclusive of the carbonyl carbon, is an alkyl group having 8 to 18 carbon atoms, and R18 and R19 are independently selected from hydrogen or an alkyl group having from 1 to about 12 carbon atoms the which may or may not be substituted with selected groups of ester groups, ether groups, amine groups, hydroxyl groups, carboxyl groups, carboxyl salts, sulfonate groups, sulfonate salts, and mixtures thereof. Preferred amide compounds for use in combination with the precursor compounds described herein include sodium lauryl sarcosinate, lauramide monoethanolamide, diethanolamide lauramide, lauramidopropyl dimethylamine, lauramido monoethanolamide disodium sulfosuccinate, and disodium lauroamphodiacetate.

In another embodiment, the precursor compounds described herein can be used in combination with the amine compounds having the general formula: wherein R20 is an alkyl group having from 8 to about 18 carbon atoms and R21 and R22 are independently selected from the group consisting of hydrogen and alkyl groups having from 1 to about 18 carbon atoms and which they may have one or more substitutional moieties selected from the group consisting of hydroxyl, carboxyl, carboxyl salts, and imidazoline. Preferred amine compounds for use with the precursor compounds described herein include laureth triethanolamide sulfate, lauramine, lauramino propionic acid, sodium lauriminodipropionic acid, lauryl hydroxyethyl imidazoline, and mixtures thereof.

In another embodiment, the amine compound may be an amine salt having the general formula: R24 23 R25 R26 wherein R23 is an anionic moiety associated with the amine and is derived from an alkyl group having from 8 to about 18 carbon atoms and R24, R25, and R26 are independently selected from the group consisting of hydrogen and group of alkyl having from 1 to about 18 carbon atoms and which may have one or more substitution moieties selected from the group consisting of hydroxyl, carboxyl, carboxyl salts, and imidazoline. R24, R25, and R26 can be saturated or unsaturated. A preferred illustrative compound of an amine salt is laureth sulfate TEA.

The amounts of the secondary compounds described herein to be added to the non-absorbent products to further reduce the production of TSST-1 have been found to be from about 0.15% (by weight of the non-absorbent substrate) to about 2.0% ( by weight of the non-absorbent substrate) of the secondary compound. More suitably, the non-absorbent products comprise from about 0.17% (by weight of the non-absorbent substrate) to about 1.7% (by weight of the non-absorbent substrate) of the secondary compound.

The amounts of the secondary compounds described herein to be added to the absorbent articles to further reduce the production of TSST-1 have been found to be from about 0.15% (by weight of the absorbent structure) to about 2.0% (by weight of the absorbent structure) of the secondary compound. More suitably, the absorbent products comprise from about 0.17% (by weight of the absorbent structure) to about 1.7% (by weight of the absorbent structure) of the secondary compound.

The precursor compounds can be applied to the non-absorbent substrate using conventional methods to apply a chemical agent to the desired nonabsorbent substrate. For example, non-absorbent articles can be immersed directly in a liquid bath containing the precursor compound and then can be air dried, if required to remove any volatile solvents. Alternatively, the non-absorbent articles of the present invention may be sprayed or otherwise coated with the inhibitor compounds of the present invention.

The precursor compounds may additionally employ one or more conventional pharmaceutically acceptable and compatible carrier materials useful for the desired application, such as to facilitate absorption into the absorbent product. The carrier may be able to dissolving or suspending the precursor compound used in the non-absorbent article or the absorbent. Carrier materials suitable for use in the present invention include those known to be used in the cosmetic and medical arts as a base for ointments, lotions, creams, salvias, aerosols, suppositories, gels, and the like. For example, a suitable carrier is Cetiol. Additionally, as discussed above, Cetiol can also act as both a lubricant and an emollient. Other suitable carrier materials include water, various alcohols, and other organic solvents.

In another embodiment, the precursor compounds of this invention can be formulated in a variety of formulations such as those in current commercial shower formulations, or in higher viscosity showers. For example, the precursor compounds of the present invention can be incorporated into formulations used to irrigate and clean the vagina and prevent vaginal infections. Additionally, the precursor compounds can be formulated with surfactants, desirably nonionic surfactants, such as Cremophos RH60, Tween 20 or the like. The formulations of this invention may also contain preservatives. Compounds that can impart higher viscosity such as propylene glycol can be added to the formulations of this invention. Generally, higher viscosity formulations are preferred in order to create formulations that tend to remain in the vagina for a relatively long period of time after administration.

When the precursor compounds are incorporated into a formulation, which includes a pharmaceutically acceptable carrier, the formulation typically contains at least about 0.01% (w / v) and desirably at least about 0.4% (w / v) of compound precursor (based on the total weight of the formulation). Generally, the formulations do not contain more than about 0.3% (weight / volume) of precursor compound. Formulations particularly suitable for use in vaginal cleansing applications can contain from at least about 0.2 millimoles / liter to about 50 millimoles / liter, suitably from about 0.3 millimoles / liter to about 30 millimoles / liter and , more suitably, from about 1.0 millimoles / liter to about 15 millimoles / liter of the parent compound.

The precursor compounds of the present invention can be prepared and applied to the absorbent article in any suitable form, but are preferably prepared in forms including, without limitation, aqueous solutions, lotions, balms, gels, salvias, ointments, boluses, suppositories, and Similar.

The precursor compounds can be applied to the absorbent article using conventional methods to apply a chemical agent to the desired absorbent article. For example, unitary plugs without separate wrapping can be sprayed with a solution containing the desired concentration of the precursor compound and then air dried, if necessary, to remove any volatile solvents. For compressed plugs, it is generally preferable to impregnate the plug with any chemical compounds prior to compression. The precursor compounds when incorporated into and / or into the plug materials can be fugitives, loose adhered, bonded, or any combination thereof. As used herein, the term "fugitive" means that the composition is capable of migrating through the plug materials.

Generally, it is not necessary to impregnate the entire absorbent body of the plug with the precursor compound. Optimum results both economically and functionally can be obtained by concentrating the precursor compound on or near the outer surface of the stopper or other absorbent product where it can be most effective during use.

The precursor compounds of the present invention can, in some embodiments, be used in combinations with conventionally attached components found in the pharmaceutical compositions in their established form in the art and at concentrations that will not alter the normal vaginal flora. For example, the compositions may contain additional compatible pharmaceutically active materials for the combination therapy, such as selectively complementary antibacterials, antioxidants, anti-parasite agents, antipruritics, astringents, local anesthetics, or agents against inflammation.

In one embodiment, the precursor compounds can be microencapsulated in a shell type material that will dissolve as it will disintegrate, rupture, or otherwise disintegrate upon contact with natural fluids or other vaginal secretions to release the component. With this incorporation, the encapsulating material retards the volatilization of the precursor compound until it is wetted with a body secretion, which results in a release of the parent compound. Such encapsulation can significantly increase the amount of the parent compound present in the product after manufacture and storage. Suitable microencapsulated cover materials are known in the art and include cellulose-based polymeric materials (e.g., ethyl cellulose), carbohydrate-based materials (e.g., starches and cationic sugars) and materials derived therefrom (e.g. , dextrins and cyclodextrins) as well as other materials compatible with human weaves.

The thickness of the microencapsulation cover can vary and is generally fabricated to allow the encapsulated precursor compound to be covered by a thin layer of encapsulation material, which can be a thicker or monolayer laminate layer or can be a composite layer. The microencapsulation layer must be thick enough to resist cracking or breaking the cover during handling or shipping of the product. The microencapsulation layer must be constructed so that the humidity of the atmospheric conditions during storage, shipping, or use will not cause a breakdown of the microencapsulation layer and result in a release of the parent compound.

The microencapsulated components or formulations applied directly to the non-absorbent articles or to the absorbers should be of a size such that the user can not feel the encapsulated cover on the skin or mucosa during use. Typically, the capsules have a diameter of no more than about 25 microns, and desirably no more than about 10 microns. These sizes, there is no "gritty" or "scratchy" feeling when the formulation makes contact with the skin.

The present invention is illustrated by the following examples which are merely for the purpose of illustration and should not be seen as limiting, of the scope of the invention or the manner in which it may be practiced.

Example 1 In this Example, the effect of several test compounds on the growth of Staphylococcus aureus and the production of TSST-1 was determined. The test compound, in the desired concentration (expressed in% by weight (w / v)) was placed in 10 mL of the growth medium in a sterile, conical 50 mL polypropylene tube (Sarstedt, Inc., of Newton, North Carolina) .

The growth medium was prepared by dissolving 37 grams of heart and brain infusion broth (BHI) (Disco Laboratories, Cockeysville, Maryland) in 880 mL of distilled water and sterilizing the broth according to the manufacturer's instructions. Heart Brain Infusion broth was supplemented with 100 mL of fetal bovine serum (FBS) (from Sigma Chemical Company, of St. Louis, Missouri). Ten mL of a 0.021 M sterile solution of magnesium chloride hexahydrate (from Sigma Chemical Company, St. Louis, Missouri) were added to the Fetal Bovine Heart-Serum Bovine Infusion Broth mixture. Ten mL of a 0.027 M sterile solution of L-glutamine (Sigma Chemical Company of St. Louis, Missouri) were also added to the Fetal Bovine Heart-Serum Bovine Infusion Broth mixture.

The compounds that are going to be tested included N-benzoyl-DL-leucine (Sigma B-1504) and N-benzoyl-DL-valine (Sigma B-6500). The test compounds were received as solids. The solids were dissolved in the Heart Brain Infusion broth prepared as described above. The test compounds were added to the growth medium and the amount necessary to obtain the desired final concentration. Cetiol 1414E (mireth-3-myristate) (from Kraft Chemical Corporation, Melrose Park, Illinois) was included in the growth medium in some assays at a concentration of 10 mM.

In preparation for inoculation of the growth medium tubes containing the test compounds, an inoculation broth was prepared as follows: Staphylococcus aureus MN8 was streaked onto a tryptic soy agar plate (TSA, from Disco Laboratories, Inc.). Cockeysville, Maryland) and incubated at 35 ° Celsius. The test organism in this example was obtained from Dr. Pat Schlievert, Department of Miiology, University of Minnesota School of Medicine, Minneapolis, Minnesota. After 24 hours of incubation, three to five individual colonies were taken with a sterile inoculation loop and used to inoculate 10 mL of growth medium. The tube of growth medium inoculated was incubated at 35 ° Centigrade in an atmospheric air. After 24 hours of incubation, the culture was removed from the incubator and mixed well on a S / P brand vertex mixer. A second tube containing 10 mL of the growth medium was inoculated with 0.5 mL of the 24-hour old culture described above and incubated at 35 ° Centigrade in atmospheric air. After 24 hours of incubation the culture was removed from the incubator and mixed well on an S / P brand swirl mixer. The optical density of the culture fluid was determined in a milate reader (from Bio-Tek Instruments, Model EL309, Winooski, Vermont). The amount of inoculum needed to give 5 x 106 CFU / mL in 10 mL of growth medium was determined using a previously prepared standard curve.

This example includes the growth medium tubes with varying concentrations of the test compounds, varying the concentrations of the test and Cetiol 1414E compounds, and the growth medium tubes without the test compounds (control). Each tube was inoculated with the amount of inoculum determined as described above. The tubes were capped with foam plugs (IDENTI-PLUG plastic foam plugs, from Jaece Industries, purchased from VWR Scientific Products, of South Plainfield, New Jersey). The tubes were incubated at 35 ° Centigrade in atmospheric air containing 5% by volume of Co2. After 24 hours of incubation the tubes were removed from the incubator, the The culture fluid was examined for the number of colony forming units of Staphylococcus aureus, and the culture fluid was prepared for the TSST-1 analysis as described below.

The number of colony forming units per mL after incubation was determined using the standard plate count procedures. In preparation for the TSST-1 analysis, the culture fluid broth was centrifuged at 2500 revolutions per minute at 2-10 ° C for 15 minutes and the supernatant was subsequently filtered and sterilized through a FISHERBRAND filter of 0.45. μ? MCE, with a pore size of 0.2 / M. The resulting fluid was frozen at -70 ° C in a FISHERBRAND 12 x 75 mm polystyrene culture tube (Fisher Scientific, of Pittsburgh, Pennsylvania).

The amount of TSST-1 per mL was determined by a non-competitive enzyme-linked immunosorbent assay (ELISA). The method used was as follows: four reagents, TSST-1 (# TT-606), polyclonal rabbit anti-TSST-1 IgG (LTI-101), rabbit polyclonal anti-TSST-1 IgG conjugated to strong root peroxidase (# LTC-101), and free rabbit serum (NRS) anti-TSST-1 certified free (# NRS-10) were purchased from Toxin Technology, Inc. (of Sarasota, Florida). A solution of 10 // g / mL of the polyclonal rabbit anti-TSST-1 IgG was prepared in salt water buffered with phosphate (PBS) (pH 7.4). The PBS was prepared from 0.016 M NaH2P04, 0.004 M NaH2P04-H20, 0.003 M KCl and 0.137 M NaCl, all available from Sigma Chemical Company (of St. Louis, Missouri). One hundred microliters of the polyclonal rabbit anti-TSST-1 IgG solution was pipetted into the internal wells of the polystyrene microplates, (Nunc-Denmark, Catalog Number # 439454). The plates were converted and incubated at room temperature overnight. The unbound toxin was removed by draining until it was dried.

TSST-1 was diluted to 10 ng / mL with phosphate-buffered salt water (PBS) (pH 7.4) containing 0.05% (volume / volume) Tween-20 (PBS-Tween) (Sigma Chemical Company, St. Louis, Missouri ) and 1% (volume / volume) NRS and incubated at 4o Celsius overnight. The test samples were combined with 1% NRS (volume / volume) and incubated at 4 o Celsius overnight. Samples of the culture fluid and reference standard TSST-1 were examined in triplicate.

One hundred microliters of a 1% (w / v) solution of the casein sodium salt (Sigma Chemical Company, St. Louis, Missouri) in PBS was pipetted into the inner wells of polystyrene microplates. The plates were covered and incubated at 35 ° C for one hour. The unbound BSA was removed by 3 washed with PBS-Tween. The reference standard TSST-1 (10 ng / mL) treated with NRS, the test samples treated with NRS, and the reagent controls were pipetted in volumes of 200 μL to their respective walls on the first and seventh columns of the plate. One hundred microliters of PBS-Tween were added to the remaining wells. The reference standard TSST-1 and the test samples were then serially diluted 5 times in the PBS-Tween by transferring 100 microliters from well to well. The samples were mixed before transferring by repeated aspiration and expression. The samples of said test samples and of the TSST-1 reference standard were tested in triplicate. This was followed by incubation for 1.5 hours at 35 ° C and five washes with PBST-T and three washes with distilled water to remove the unbound toxin. The rabbit polyclonal anti-TSST-1 conjugated to strong root peroxidase IgG was diluted according to the manufacturer's instructions and 50 microliters were added to each well, except well A-1, the conjugate control well. The plates were covered and incubated at 35 ° C for one hour.

After incubation the plates were washed five times in PBS-Tween and three times with distilled water. After the washings, the walls were treated with 100 microliters of a strong root peroxidase substrate buffer consisting of 5 mg of o-phenylenediamine and 5 μL of % hydrogen peroxide (both available from Sigma Chemical Company, St. Louis, Missouri) in 11 mL of citrate buffer (pH 5.5). The citrate buffer was prepared from 0.012 M anhydrous acrylic acid and 0.026 M dibasic sodium phosphate both available from Sigma Chemical Company (St. Louis, Missouri). The plates were incubated for 15 minutes at 35 ° C. The reaction was stopped by the addition of 50 microliters of 5% of a sulfuric acid solution. The intensity of the color reaction in each well was assessed using the Bio-Tek EL309 Model of the microplate reader (OD 490 nm). The TSST-1 concentrations in the test samples were determined from the derived reference toxin regression equation during each test procedure. The effectiveness of the compound for inhibiting the production of TSST-1 is shown in Table 3 given below.

Table 3 N / A = Not Applicable According to the present invention, the data in Table 3 show that Staphylococcus aureus MN8, when compared to the control, produced less TSST-1 in the presence of test compounds containing amino acid. At the concentrations tested, these compounds reduced the amount of toxin produced by 79% to 93%. The data also showed that Staphylococcus aureus MN8, when compared to the control, produced less TSST-1 in the presence of amino acid-containing test compounds when combined with Cetiol 1414E. At the concentrations tested, these compounds, when combined with Cetiol 1414E, reduced the amount of toxin produced by 93% to 95%. However, even when the amount of the toxin produced was significantly reduced, there was minimal, if any, effect on the growth of Staphylococcus aureus.

EXAMPLE 2 In this Example, the effect of benzyl alcohol (Aldrich 40,283-4) and benzyl ethyl malonate (Aldrich 30,069-1) (Sigma Chemical Corporation, St. Louis, Missouri) on the growth of Staphylococcus aureus and the production of TSST -1 was determined. The effect of the test compounds tested in Example 2 was determined by placing the desired concentration, expressed in% (v / v), in 10 mL of the growth medium as described in Example 1. The test compounds were then tested and evaluated as in Example 1, except that each test was carried out in quadruplicate. The results shown represent an average of the four values. The effect of the test compounds on the growth of Staphylococcus aureus MN8 and the production of TSST-1 is shown in Table 4 given below.

Table 4 N A = Not Applicable At the concentrations tested, both the benzyl ethyl malonate compound, and the active species, benzyl alcohol, reduced the amount of toxin produced by 85% to 94%. The data also show that Staphylococcus aureus MN8, when compared to the control, produced less TSST-1 in the presence of benzyl alcohol or benzyl ethyl malonate when combined with Cetiol 1414E (mireth-3-myristate). At the concentrations tested, these compounds, when combined with Cetiol 1414E, reduced the amount of toxin produced by 98% to 99%.

The statistical analyzes of the treatments were carried out using a pairwise comparison on Least Squares Means in a context analysis of Valencia. The pairwise comparisons were equivalent to Standard T Tests. The results of the comparisons showed that the growth in the presence of Cetiol only resulted in a significantly greater inhibition of growth of Staphylococcus aureus than growth in its absence or growth in the presence of benzyl alcohol alone or of benzyl ethyl malonate with or without Cetiol. Growth in the presence of benzyl ethyl malonate and combinations of Cetiol with benzyl alcohol or benzyl ethyl malonate resulted in a significant decrease in toxin production when compared to growth in the presence of Cetiol alone or without additives. However, even when the amount of toxin produced was significantly reduced under these conditions, there was a minimal effect, if any, on the growth of Staphylococcus aureus.

EXAMPLE 3 In this Example, the effect of benzyl (s) - (-) - lactate (Aldrich 42,484-6) (Sigma Chemical Corporation, St. Louis, Missouri) on the growth of Staphylococcus aureus and the production of TSST-1 was determined. The effect of the test compounds was determined by placing the desired concentration, expressed in% (v / v), in 10 mL of growth medium as in Example 1, the compounds were then tested and evaluated as in Example 1 , except that each test was carried out in quadruplicate. The results shown represent an average of four values. The effect of the test compounds on the growth of Staphylococcus aureus MN8 and on the production of TSST-1 is shown in Table 5 given below.

Table 5 N / A = Not Applicable At the concentration tested, benzyl (s) - (-) - lactate reduced the amount of toxin produced by 97%. Also, the data show that Staphylococcus aureus MN8, when compared to the control, produced less TSST-1 in the presence of benzyl (s) - (-) -lactate when combined with Cetiol 1414E (mireth-3-myristate) . At the tested concentration, benzyl (s) - (-) -lactate, when combined with Cetiol 1414E, reduced the amount of toxin produced by 99%.

Statistical comparisons of the treatments were carried out by the method discussed in Example 2. The results of the comparisons showed that the growth in the presence of Cetiol alone or Cetiol and benzyl (s) - (-) -lactate resulted in significantly greater inhibition of growth of Staphylococcus aureus than growth in the absence of Cetiol or growth in the presence of benzyl (s) - (-) - lactate alone. Growth in the presence of benzyl (s) - (-) -lactate and combinations of Cetiol with benzyl (s) - (-) - lactate resulted in significantly decreased toxin production when compared to growth in the presence of Cetiol alone or without additives.

EXAMPLE 4 In this Example, the effect of benzyl (s) - (-) -lactate in combination with the surface active agent Cetiol 1414E (mireth-3-myristate) was tested using an experimental 5 x 4 checker board design. allowed the evaluation of the interaction of the two test compounds on the growth of Staphylococcus aureus and the production of TSST-1.

Five concentrations of benzyl (s) - (-) -lactate (0.00, 0.06%, 0.13%, 0.25%, and 0.50%) were combined with four concentrations of Cetiol 1414E (10 mM, 5 mM, 2.5 mM, and 0. 0 mM) in an array of twenty tubes. For example, tube # 1 contained 0.0 mM of Cetiol 1414E and 0.0% of benzyl (s) - (-) -lactate (w / v) in 10 mL of growth medium (as prepared in Example 1). Each of the # l- # 20 tubes contained a unique combination of benzyl (s) - (-) - lactate and Cetiol. The solutions were tested and evaluated as in Example 1. The effect of the test compounds on the growth of Staphylococcus aureus M 8 and on the production of TSST-1 is shown in Table 6 below.

Table 6 N A = Not Applicable At each concentration of Cetiol 1414E, benzyl (s) - (-) -lactate increases the inhibition of TSST-1 production. The effect appears to be additive.

EXAMPLE 5 In this Example, the effect of benzyl laurate (from Penta Manufacturing, of Fairfield, New Jersey) on the growth of Staphylococcus aureus MN8 and the production of TSST-1 was determined. The effect of the test compound was determined by placing the desired concentration, expressed in% (v / v), in 10 mL of a growth medium as in Example 1. The compounds were then tested and evaluated as in Example 1 The effect of benzyl laurate on the growth of Staphylococcus aureus MN8 and on the production of TSST-1 is shown in Table 7 given below.

Table 7 N A = Not Applicable At the concentrations tested the benzyl laurate reduced the amount of toxin produced by 62% to 91%. At the concentrations tested, benzyl laurate, when combined with Cetiol 1414E (mireth-3-myristate), reduced the amount of toxin produced by 86% to 90%.

EXAMPLE 6 In this Example, commercial stoppers (KOTEX Super Absorbency from Kimberly-Clark Worldwide, Inc., of Neenah, Wisconsin) were treated with benzyl alcohol for determine the effect of the treated plug on the growth of Staphylococcus aureus 8 and the production of TSST-1. As stated above, the commercial stopper will contain about 0.75% (by weight of the total stopper having a cover) Cetiol 1414E (mireth-3-myristate). In preparation for the experiment, the stopper cord was cut and the stopper was placed in a 50 mL test tube of capped and sterile polystyrene with the rope end down.

The plug applicators were inoculated with 5 mL of five concentrations (0.0, 0.3%, 0.15%, 0.075%, and 0.03%) of dissolved benzyl alcohol in a Heart Brain Infusion Broth (BHI). The plug applicators were allowed to settle at room temperature for one hour.

Each plug applicator was then inoculated with 5.5 mL of an inoculation broth containing 5 x 106 + 1 X 106 CFU / mL of Staphylococcus aureus MN8 to achieve a final volume of 10.5 mL. The tubes were capped with foam plugs (IDENTI-PLUG plastic foam plugs, from Jaece Industries, purchased from VWR Scientific Products, South Plainfield, New Jersey) and inoculated at 37 ° C for 24 hours. The plug applicators were removed from the incubator and placed individually in sterile STOMACHER bags (Seward Limited of Norfolk, United Kingdom), which contained 50 mL of Sterile Heart Brain Infusion Broth. The plug and fluid applicators were then mixed in the bags. The Aliquots of the fluid were removed from the STOMACHER bags and placed in sterile tubes for testing.

The plate count samples were prepared by swirling the sample, 5 mL of the sample was removed and 5 mL was placed in a new 50 mL sterile centrifuge tube. The sample was then sonicated using a Virsonic 600 Ultrasonic Cell Switch (from the Virtis Company, of Gardiner, New York) for 15 seconds at an output force of 8%. When all samples had been sonicated, the number of colony forming units (CFU) per mL was determined using standard plate count procedures.

In the preparation for the TSST-1 analysis, the culture fluid broth was centrifuged at 9000 rpm at 4o Celsius for 5 minutes and the supernatant was subsequently filtered and sterilized through a 0.45 μ filter. MCE, with a pore size of 0.2 / M. The resulting fluid was frozen at -70 ° C in two 1 mL aliquots in 1.5 mL polypropylene screw cap freezer containers.

The amount of TSST-1 per mL was determined by a non-competitive sandwich enzyme-linked immunosorbent assay (ELISA). The method used was as follows: four reagents, TSST-1 (# 606), anti-TSST-1 IgG polyclonal rabbit (LTI-101), anti-TSST-1 rabbit polyclonal IgG conjugated to strong root peroxidase (# LTC-101), and normal rabbit serum (NRS) anti-TSST-1 certified free (# NRS- 10) were purchased from Toxin Technology, Inc. (of Sarasota, Florida). Sixty-two microliters of # LTI-101 were diluted so that the 1: 100 dilution gave an absorbance of 0.4 to 205 nm and subsequently they were added to 6.5 mL of Na2C03 buffer, a pH of 7.2, 0.5 M buffer. carbonate, pH 9.6, and 100 μL of the solution were pipd into each of the inner wells of the polystyrene microplates (available from Nunc-Denmark, Catalog Number # 439454). The plates were covered and incubated at 37 ° C overnight.

The unbound toxin was removed by four washes in an automatic phosphate-buffered saltwater dishwashing machine (0.016 M Na2HP04, available from Sigma Chemical Company, St. Louis, Missouri), pH 7.2, and 0.9% (w / v) NaCl (VWR Scientific Products, of South Plainfield, New Jersey) containing 0.5% (v / v) Tween 20 (Sigma Chemical Company of St. Louis, Missouri). The plates were treated with 100 μL of 1% solution (w / v) of bovine serum albumin (BSA) fraction V (Sigma Chemical Company, St. Louis, Missouri), in the Na2C03 plus NaHC03 buffer described above. The plates were again covered and incubated at 37 ° Celsius for one hour. The unbound BSA was removed by six washes of 250 juL of PBS-Tween.

The test samples were then treated with normal rabbit serum (10% (v / v) concentration) for 15 minutes at room temperature. The reference standard TSST-1 (serially diluted 2-20 ng / mL in PBS-Tween) and the test samples treated with NRS (serially diluted in PBS-Tween so that the resulting TSST-1 concentration is between 2-20 ng), they were pipd in 100 juL volumes to their respective wells. The samples were then incubated for two hours at 37 ° C and the unbound toxins were then removed with four 250 μL washes of PBS-Tween. Anti-TSST-1 rabbit polyclonal IgG conjugated to strong root peroxidase was diluted according to the manufacturer's instructions. The final use dilution of the conjugate was determined by running the standard curves of the reference standard TSST-1 with the conjugate at dilutions of 1: 2, and 1: 4 undiluted. The dilution that gave the most comparable results to the previous lots of conjugate was selected. One hundred / L volumes of this dilution were added to each microconcentration well. The plates were covered and incubated at 37 ° C for one hour.

After incubation, the plates were washed six times in 250 juL PBS-Tween. After the washings,the wells were treated with 100 μL of a strong root peroxidase substrate solution consisting of 0.015 M sodium citrate, a pH of 4.0, 0.6 mM of 2, 2'-Azino-bis- (3-ethylbenzethiazoline-6). sulfonic acid) diammonium salt and 0.009% (v / v /) hydrogen peroxide (all available from Sigma Chemical Company of St. Louis, Missouri). The intensity of the color reaction in each well was assessed over time using a Molecular VersaMax Device Microplate reader (OD 405 nm) and SoftMax Pro software (both available from Molecular Devices, Inc.). The TSST-1 concentrations in the test samples were delivered from the reference toxin regression equations for each test procedure.

The efficiency of the benzyl alcohol to inhibit the production of TSST-1 by Staphylococcus aureus is shown in Table 8 given below.

Table 8 N / A = Not Applicable * As stated above, this Example uses commercial plugs. As such, this example contains about 0. 75% (by weight of cap with cover) Cetiol 1414E (mireth-3-myristate).

According to the present invention, the data show that Staphylococcus aureus MN8 produced less TSST-1 in the presence of plugs containing both benzyl alcohol and Cetiol 1414E (mireth-3-myristate) compared to control plugs containing only Cetiol 1414E. At the concentrations tested, the benzyl alcohol reduced the amount of toxin produced by 8% to 50%.

EXAMPLE 7 In this Example, the effect of the growth of Staphylococcus aureus M 8 on the integrity of several test compounds was determined by measuring the amount of breakage of the test compounds caused by the enzymes produced by Staphylococcus aureus M 8 bacteria. of test in the desired concentrations, were placed in 100 mL of a culture medium in a sterile 500 mL Corning Fleaker (Fisher Scientific, of Pittsburg, Pennsylvania). Growth medium and inoculum were prepared as in Example 1.

Compounds to be tested included 0.2% (v / v) benzyl alcohol (Aldrich 40,283-4), 0.5% (w / v) sodium benzoate, 0.3% (v / v) benzyl (s) - ( -) -lactate (Aldrich 42,484-6), 0 - 8% (v / v) benzyl ethyl malonate (Aldrich .069-1), and 0.3% (weight / v) N-benzoyl-DL-leucine (Sigma B-1504). The test compounds were added to the growth medium in the amount necessary to obtain the desired final concentration.

Each fleaker was inoculated with the amount of inoculum determined as described above. The fleakers were capped with a sterile aluminum foil and incubated at 35 ° Centigrade in atmospheric air in a Lab-Line orbital water bath (available from VWR Scientific Products, McGaw Park, Illinois) at 180 revolutions per minute. Fifteen milliliter samples were removed at 3, 6, 9, and 24 hours. The optical density (595 nm) of the culture fluid was determined and the culture fluid collected in 24 hours was examined for the number of colony forming units of Staphylococcus aureus M 8 using standard plate count procedures. The test compounds, at the concentrations tested, did not inhibit the growth of Staphylococcus aureus.

In preparation for the integrity analysis of the test compounds, the culture fluid was centrifuged at 3000 revolutions per minute at 2-10 ° C for 15 minutes. The supernatant was filtered and sterilized through an AUTOVIAL 5 syringeless filter, a pore size of 0.45 [M (available from Hatman, Inc., of Clifton, New Jersey).

The resulting fluid was frozen at -70 ° C in a FISHERBRAND polystyrene culture tube (12 millimeters x 75 millimeters) (from Fisher Scientific, Pittsburgh, Pennsylvania) until chemical analysis could be carried out.

Using the Agilent 5973N GC / MS Technologies, the analysis was carried out on solutions not diluted to 3, 6, 9, and 24 hours to evaluate the availability of Staphylococcus aureus M 8 to break the test compounds. Based on the analysis, the control sample, which had no aggregate test compounds, comprised mainly acetic acid at all time intervals. Samples containing benzoic acid and benzyl alcohol were found to have benzoic acid and benzyl alcohol respectively, as the dominant compound, but benzoic acid and benzyl alcohol concentrations decreased over time. The sample comprised N-benzoyl-DL-leucine as the test compound was found to contain benzoic oil as the dominant compound, having a decreased concentration with time. The sample comprised benzyl (s) - (-) -lactate as the test compound was found to contain benzyl alcohol as the dominant compound. In addition, it was found that the concentration of benzyl alcohol increased over time. Finally, the sample comprising benzyl ethyl malonate as the test compound was found to contain benzyl alcohol as the dominant compound. In addition, it was found that the concentration of benzyl alcohol increased over time.

In accordance with the present invention, the GC / MS analysis above showed that the precursor compounds were broken by the enzymes produced by Staphylococcus aureus M 8 to produce the active species. It can further be seen that the precursor compounds were allowed to slowly break over time to allow a continuous long-term inhibition of exoprotein production by the active species.

Additional analysis of the 6-hour and 24-hour samples was carried out by liquid chromatography. In preparation for chromatography, the samples were diluted 10 times with water. The dilutions were then analyzed using an ion exclusion column to achieve separation. The detection of the compounds was achieved through the ultraviolet absorbance at 230 nm.

In accordance with the present invention, liquid chromatography analysis of the test compounds showed that the compounds were broken in the active species, benzoic acid and benzyl alcohol, over a period of 24 hours. Specifically, the 6 hour and 24 hour samples containing 0.3% N-benzoyl-DL-leucine showed evidence of the compound breaking in benzoic acid. Additionally, the 6-hour and 24-hour samples containing benzyl (s) - (-) - lactate and benzyl ethyl malonate showed evidence of the breakdown of the compounds in benzyl alcohol. How can furthermore, the 24 hour samples containing benzyl (s) - (-) - lactate and benzyl ethyl malonate showed evidence of a high level of benzyl alcohol compared to the 6 hour samples.

In view of the foregoing, it will be seen that several objects of the invention are achieved and advantageous results are obtained.

When introducing the elements of the present invention or preferred embodiments thereof, the articles "a", "an", "the" and "said" are intended to mean that there is one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there are more additional elements than the listed elements.

As various changes may be made in the foregoing without departing from the scope of the invention, it is intended that all of the material contained in the foregoing description and shown in the accompanying drawings be construed as illustrative and not in a limiting sense.

Claims (20)

RE IVI ND I CAC I ONE S

1. An exoprotein inhibitor for inhibiting the exoprotein production of Gram positive bacteria comprising a nonabsorbent substrate suitable for insertion into the vagina, the nonabsorbent substrate having deposited thereon an effective amount of a precursor compound having the general formula: wherein R1 is selected from the group consisting of O - [R7] xCH2OC IIR5 and -? CR6; R7 is -OCH2-; X is 0 O 1; R5 is a straight or branched chain hydrocarbyl, substituted or unsubstituted, saturated or unsaturated, monovalent or unsubstituted aromatic ring that may or may not be substituted with hetero atoms; R6 is selected from the group consisting of an amino acid, a methyl ester of an amino acid and an ethyl ester of an amino acid; R2, R3, and R4 are independently selected from the group consisting of H, OH, COOH, wherein with the hydrolysis the precursor compound is capable of producing an effective active species to inhibit the exoprotein production of the Gram positive bacteria.

2. The exoprotein inhibitor as claimed in clause 1, characterized in that R5 is a monovalent saturated substituted or unsubstituted branched straight chain hydrocarbyl moiety which may or may not be substituted with hetero atoms having from 1 to 15 carbon atoms. carbon

3. The exoprotein inhibitor as claimed in clause 1, characterized in that R2 is selected from the group consisting of H and OH, and R3 and R4 are independently 1 and H.

4. The exoprotein inhibitor as claimed in clause 1, characterized in that it further comprises an active surface agent selected from the group consisting of mireth-3-myristate, glycerol monolaurate, and laureth-4.

5. The exoprotein inhibitor as claimed in clause 1, characterized in that the precursor compound is selected from the group consisting of benzyl (s) - (-) - lactate, benzyl ethyl malonate, benzyl laurate, benzyl benzoate, benzyl paraben , benzyl salicylate, and phenoxyethyl paraben.

6. The exoprotein inhibitor as claimed in clause 1, characterized in that the precursor compound is present in an amount of from about 0.15% (by weight of the non-absorbent substrate) to about 2.0% (by weight of the non-absorbent substrate ).

7. The exoprotein inhibitor as claimed in clause 1, characterized in that R6 is an amino acid, wherein the amino acid is selected from the group consisting of valine, leucine, and cysteine.

8. The exoprotein inhibitor as claimed in clause 1, characterized in that the precursor compound is selected from the group consisting of n-benzoyl-dl-valine, n-benzoyl-dl-leucine, and n-benzoyl-dl-cysteine .

9. The exoprotein inhibitor as claimed in clause 1, characterized in that the non-absorbent substrate is selected from the group consisting of a non-absorbent incontinence device, a barrier birth control device, a nonabsorbent contraceptive device, a plug applicator, and a shower.

10. The exoprotein inhibitor as claimed in clause 9, characterized in that the exoprotein inhibitor is a shower comprising a formulation of vaginal cleansing, and wherein the precursor compound is present in the vaginal cleansing formulation in an amount of from about 0.2 millimoles / liter to about 50 millimoles / liter.

11. An absorbent article for inhibiting the exoprotein production of Gram-positive bacteria comprising an absorbent structure and an effective amount of a precursor compound having the general formula: wherein R1 is selected from the group consisting of O - [R7] xCH2OCR5 and -CR6; R7 is -OCH2-; X is 0 or 1; R5 is a straight or branched chain hydrocarbyl, substituted or unsubstituted, saturated or unsaturated, monovalent or unsubstituted aromatic ring that may or may not be substituted with hetero atoms; R6 is selected from the group consisting of an amino acid, a methyl ester of an amino acid and an ethyl ester of an amino acid; R2, R3, and R4 are independently selected from the group consisting of H, OH, COOH, wherein with the hydrolysis the precursor compound is able to produce an effective active species to inhibit exoprotein production of Gram positive bacteria.

12. The absorbent article as claimed in clause 11, characterized in that R5 is a monovalent saturated or straight-chain or branched, substituted or unsubstituted hydrocarbyl moiety that may or may not be substituted with hetero atoms having from 1 to 15 atoms of carbon.

13. The absorbent article as claimed in clause 11, characterized in that R2 is selected from the group consisting of H and OH, and R3 and R4 are independently H.

14. The absorbent article as claimed in clause 11, characterized in that it also comprises an active surface agent selected from the group consisting of mireth-3-myristate, glycerol monolaurate, and laureth-4.

15. The absorbent article as claimed in clause 11, characterized in that the precursor compound is selected from the group consisting of benzyl (s) - (-) - lactate, benzyl ethyl malonate, benzyl laurate, benzyl benzoate, benzyl paraben, benzyl salicylate, and phenoxyethyl paraben.

16. The absorbent article as claimed in clause 11, characterized in that the precursor compound is present in an amount of from about 0.15% (by weight of the absorbent structure) to about 2.0% (by weight of the absorbent structure) .

17. The absorbent article as claimed in clause 11, characterized in that R6 is an amino acid, wherein the amino acid is selected from the group consisting of valine, leucine, and cysteine.

18. The absorbent article as claimed in clause 11, characterized in that the precursor compound is selected from the group consisting of n-benzoyl-dl-valine, n-benzoyl-dl-leucine, and n-benzoyl-dl-cysteine.

19. The absorbent article as claimed in clause 11, characterized in that the absorbent article is selected from the group consisting of a vaginal plug, a sanitary napkin, a panty liner, an incontinent undergarment, a contraceptive sponge, a diaper , a wound dressing, a dental plug, a medical plug, a surgical plug, and a nasal plug.

20. The absorbent article as claimed in clause 19, characterized in that the article The absorbent comprises a vaginal plug, the vaginal plug comprises an absorbent plug material and a cover material, and wherein the precursor compound is present on the cover material in an amount of at least about 2.6% (by weight of the roofing material) to around 35% (by weight of roofing material). SUMMARIZES Absorbent and non-absorbent articles are described to inhibit the production of exoproteins of Grara positive bacteria. The non-absorbent and absorbent articles include an effective amount of a precursor compound having the general formula (I): wherein R 1 is selected from the group consisting of formula (II) and of formula (III); R7 is -OCH2-; X is 0 or 1; R5 is a straight or branched chain, substituted or unsubstituted, saturated or unsaturated, monovalent or substituted or unsubstituted aromatic ring that may or may not be substituted with hetero atoms; R6 is selected from the group consisting of amino acid, a methyl ester of an amino acid and an ethyl ester of an amino acid; R2, R3, and R4 are independently selected from the group consisting of H, OH, COOH.