EP1432459A1 - Inhibition de la production d'exoproteines a l'aide de compositions aromatiques - Google Patents

Inhibition de la production d'exoproteines a l'aide de compositions aromatiques

Info

Publication number
EP1432459A1
EP1432459A1 EP02773321A EP02773321A EP1432459A1 EP 1432459 A1 EP1432459 A1 EP 1432459A1 EP 02773321 A EP02773321 A EP 02773321A EP 02773321 A EP02773321 A EP 02773321A EP 1432459 A1 EP1432459 A1 EP 1432459A1
Authority
EP
European Patent Office
Prior art keywords
active ingredient
absorbent article
set forth
group
cooh
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02773321A
Other languages
German (de)
English (en)
Inventor
Rae Ellen Syverson
Richard A. Proctor
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kimberly Clark Worldwide Inc
Kimberly Clark Corp
Original Assignee
Kimberly Clark Worldwide Inc
Kimberly Clark Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/969,299 external-priority patent/US20030135173A1/en
Priority claimed from US09/969,218 external-priority patent/US7026354B2/en
Priority claimed from US09/969,391 external-priority patent/US7022333B2/en
Application filed by Kimberly Clark Worldwide Inc, Kimberly Clark Corp filed Critical Kimberly Clark Worldwide Inc
Publication of EP1432459A1 publication Critical patent/EP1432459A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants

Definitions

  • the present invention relates to the inhibition of exoprotein production in association with an absorbent article such as a catamenial tampon, or a non- absorbent substrate or article. More particularly, the present invention relates to the incorporation of certain aromatic compositions into absorbent articles or non- absorbent substrates and the effects of these compounds on Gram positive bacteria. Also, the present invention relates to methods of using the aromatic compositions.
  • Disposable absorbent devices such as catamenial tampons, for the absorption of human exudates are widely used. These disposable devices typically have a compressed mass of absorbent formed into the desired shape, which is typically dictated by the intended consumer use. In the area of a menstrual tampon, the device is intended to be inserted in a body cavity for absorption of the body fluids generally discharged during a woman's menstrual period.
  • vaginal fluid The bacterial flora of the vagina is comprised of both aerobic and anaerobic bacteria.
  • the more commonly isolated bacteria are Lactobacillus species, Corynebacteria, Gardnerella vaginalis, Staphylococcus species, Peptococcus species, aerobic and anaerobic Streptococcus species, and Bacteroides species.
  • yeast Candida albicans
  • protozoa Trichomonas vaginalis
  • mycoplasma ⁇ Mycoplasma hominis mycoplasma ⁇ Mycoplasma hominis
  • chlamydia Chlamydia trachomatis
  • viruses Herpes simplex
  • vaginal flora present in the vagina throughout the menstrual cycle can include lactobacilli, corynebacterium, ureaplasma, and mycoplasma.
  • Social and idiosyncratic factors include method of birth control, sexual practices, systemic disease (e.g., diabetes), and medications.
  • Bacterial proteins and metabolic products produced in the vagina can effect other microorganisms and the human host.
  • the vagina between menstrual periods is mildly acidic having a pH ranging from about 3.8 to about 4.5. This pH range is generally considered the most favorable condition for the maintenance of normal flora.
  • the vagina normally harbors the numerous species of microorganisms in a balanced ecology, playing a beneficial role in providing protection and resistance to infection and makes 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 their production of acidic products.
  • Microorganisms in the vagina can also produce antimicrobial compounds such as hydrogen peroxide and bactericides directed at other bacterial species.
  • One example is the lactocins, bacteriocin-like products of lactobacilli directed against other species of lactobacilli.
  • Some microbial products produced in the vagina may negatively affect the human host. For example, S.
  • aureus can produce and excrete into its environment a variety of exoproteins including enterotoxins, Toxic Shock Syndrome Toxin-1 (TSST-1 ), and enzymes such as proteases and lipase. When absorbed into the bloodstream of the host, TSST-1 may produce Toxic Shock Syndrome (TSS) in non-immune humans.
  • TSS Toxic Shock Syndrome
  • S. aureus is found in the vagina of approximately 16% of healthy women of menstrual age. Approximately 25% of the S. aureus isolated from the vagina are found to produce TSST-1. TSST-1 and some of the staphylococcal enterotoxins have been identified as causing TSS in humans. Symptoms of Toxic Shock Syndrome generally include fever, diarrhea, vomiting and a rash followed by a rapid drop in blood pressure. Multiple organ failure occurs in approximately 6% of those who contract the disease. S. aureus does not initiate Toxic Shock Syndrome as a result of the invasion of the microorganism into the vaginal cavity. Instead as S. aureus grows and multiplies, it can produce TSST-1. Only after entering the bloodstream does TSST-1 toxin act systemically and produce the symptoms attributed to Toxic Shock Syndrome.
  • Menstrual fluid has a pH of about 7.3.
  • the pH of the vagina moves toward neutral and can become slightly alkaline. This change permits microorganisms whose growth is inhibited by an acidic environment the opportunity to proliferate.
  • S. aureus is more frequently isolated from vaginal swabs during menstruation than from swabs collected between menstrual periods.
  • S. aureus is present in an area of the human body that harbors a normal microbial population such as the vagina, it may be difficult to eradicate the S. aureus bacterium without harming members of the normal microbial flora required for a healthy vagina.
  • antibiotics that kill S.
  • aureus are not an option for use in catamenial products because of their effect on the normal vaginal microbial flora and their propensity to stimulate toxin production if all of the S. aureus are not killed.
  • An alternative to eradication is technology designed to prevent or substantially reduce the bacterium's ability to produce toxins.
  • non-ionic surfactants such as alkyl ethers, alkyl amines, and alkyl amides as detoxifying compounds (see, e.g., U.S. Patent Nos. 5,685,872, 5,618,554, and 5,612,045).
  • the present invention is based on the discovery that when one or more aromatic compounds, or compositions comprising the aromatic compounds, having the general structure:
  • R 1 is selected from the group consisting of H, COR 5
  • R is a monovalent saturated or unsaturated aliphatic hydrocarbyl moiety
  • R 6 is a divalent saturated or unsaturated aliphatic hydrocarbyl moiety
  • R 7 is a trivalent saturated or unsaturated aliphatic hydrocarbyl moiety
  • R 8 is a monovalent substituted or unsubstituted saturated or unsaturated aliphatic hydrocarbyl moiety which may or may not be interrupted with hetero atoms
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of H, OH, COOH, and -C(0)R 9
  • R 9 is hydrogen or a monovalent saturated or unsaturated aliphatic hydrocarbyl moiety, are incorporated into an absorbent article, such as a catamenial tampon, or a non-absorbent substrate, the production of exoprotein in Gram positive bacterium is substantially inhibited.
  • a more specific object of the present invention is to provide a catamenial tampon incorporating one or more aromatic compounds which act to substantially inhibit the production of TSST-1 and Enterotoxin B by S. aureus.
  • Another object of the present invention is to provide a catamenial tampon incorporating one or more aromatic compounds in combination with one or more other inhibitory ingredients such as, but not limited to, for example, laureth-4, PPG- 5 lauryl ether, 1-0-dodecyl-rac-glycerol, disodium laureth sulfosuccinate, glycerol monolaurate, alkylpolyglycosides, polyethylene oxide (2) sorbital ether or myreth- 3-myristate which in combination act to substantially inhibit the production of TSST-1 and Enterotoxin B by S. aureus.
  • inhibitory ingredients such as, but not limited to, for example, laureth-4, PPG- 5 lauryl ether, 1-0-dodecyl-rac-glycerol, disodium laureth sulfosuccinate, glycerol monolaurate, alkylpolyglycosides, polyethylene oxide (2) sorbital
  • a further object of the present invention is to provide a catamenial tampon that has incorporated therewith one or more compounds that will inhibit the production of exoproteins from Gram positive bacterium without significantly imbalancing the natural flora present in the vaginal tract.
  • the present invention also relates to non-absorbent substrates or articles which inhibit the production of exoproteins from Gram-positive bacteria.
  • the substrates are particularly useful for inhibiting the production of TSST-1 from S. aureus bacteria in the vaginal area.
  • suitable non-absorbent substrates which can have the aromatic compounds of the present invention incorporated thereon include non-absorbent incontinence devices, barrier birth control devices, douches, contraceptive sponges, and tampon applicators.
  • non-absorbent incontinence device is a female barrier incontinence device, such as an incontinence pledget formed from a resilient material like rubber.
  • a non-absorbent substrate is the applicator used with a tampon.
  • the tampon applicator may have the aromatic compound coated on an outer surface, such that when the applicator is used to introduce a tampon into a women's vagina the aromatic compound (typically in the form of a cream, wax, gel or other suitable form) is transferred from the applicator onto the wall of the vagina. It is a general object of the present invention to provide a non-absorbent article which inhibits the production of exoprotein from Gram positive bacterium.
  • a more specific object of the present invention is to provide a non-absorbent incontinence device, a barrier birth control device, a contraceptive sponge, tampon applicator, or a douche incorporating one or more aromatic compounds which act to substantially inhibit the production of TSST-1 and Enterotoxin B by S. aureus.
  • Another object of the present invention is to provide a non-absorbent substrate incorporating one or more aromatic compounds in combination with one or more other inhibitory ingredients such as, but not limited to, for example, laureth-4, PPG-5 lauryl ether, 1-0-dodecyl-rac-glycerol, disodium laureth sulfosuccinate, glycerol monolaurate, alkylpolyglycosides, polyethylene oxide (2) sorbital ether or myreth-3-myristate which in combination act to substantially inhibit the production of TSST-1 and Enterotoxin B by S. aureus.
  • inhibitory ingredients such as, but not limited to, for example, laureth-4, PPG-5 lauryl ether, 1-0-dodecyl-rac-glycerol, disodium laureth sulfosuccinate, glycerol monolaurate, alkylpolyglycosides, polyethylene oxide (2) sorbital ether or my
  • a further object of the present invention is to provide a non-absorbent substrate that has incorporated therewith one or more compounds that will inhibit the production of exoproteins from Gram positive bacterium without significantly imbalancing the natural flora present in the vaginal tract.
  • aromatic compounds as described herein can be used in combination with an absorbent article, such as a catamenial tampon, or a non-absorbent substrate, to substantially inhibit the production of exoproteins, such as TSST-1 , from Gram positive bacteria.
  • aromatic compounds can also be used in combination with other surface-active agents such as, for example, compounds with an ether, ester, amide, glycosidic, or amine bond linking a C ⁇ -C-is fatty acid to an aliphatic alcohol, polyalkoxylated sulfate salt, or polyalkoxylated sulfosuccinic salt, to substantially inhibit the production of exoproteins such as TSST-1 from Gram positive bacteria.
  • surface-active agents such as, for example, compounds with an ether, ester, amide, glycosidic, or amine bond linking a C ⁇ -C-is fatty acid to an aliphatic alcohol, polyalkoxylated sulfate salt, or polyalkoxylated sulfosuccinic salt, to substantially inhibit the production of exoproteins such as TSST-1 from Gram positive bacteria.
  • absorbent article generally refers to devices which absorb and contain body fluids, and more specifically, refers to devices which are placed against or near the skin to absorb and contain the various fluids discharged from the body.
  • disposable absorbent articles that are not intended to be laundered or otherwise restored or reused as an absorbent article after a single use.
  • 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 use; personal care absorbent products such as feminine hygiene products (e.g., sanitary napkins, panty liners, and catamenial tampons), diapers, training pants, incontinent products and the like, wherein the inhibition of the production of exoproteins from Gram positive bacteria would be beneficial.
  • health care related products including bandages and tampons such as those intended for medical, dental, surgical and/or nasal use
  • personal care absorbent products such as feminine hygiene products (e.g., sanitary napkins, panty liners, and catamenial tampons), diapers, training pants, incontinent products and the like, wherein the inhibition of the production of exoproteins from Gram positive bacteria would be beneficial.
  • non-absorbent substrates or products such as non-absorbent incontinence devices, barrier birth control devices, contraceptive sponges, tampon applicators, and douches, but will be understood by persons skilled in the art to be applicable to other non-absorbent articles, devices and/or products as well wherein the inhibition of exoproteins from Gram positive bacteria would be beneficial.
  • non-absorbent article generally refers to substrates or devices which include an outer layer formed from a substantially hydrophobic material which repels fluids such as menses, blood products and the like. Suitable materials for construction the non-absorbent articles of the present invention include, for example, rubber, plastic, and cardboard.
  • Catamenial tampons suitable for use with the present invention are typically made of absorbent fibers, including natural and synthetic fibers, compressed into a unitary body of a size which may easily be inserted into the vaginal cavity.
  • Suitable fibers include, for example, cellulosic fibers such as cotton and rayon. Fibers may be 100% cotton, 100% rayon, a blend of cotton and rayon, or other materials known to be suitable for tampon use.
  • Catamenial tampons are typically made in an elongated cylindrical form in order that they may have a sufficiently large body of material to provide the required absorbing capacity, but may be made in a variety of shapes.
  • the tampon may or may not be compressed, although compressed types are now generally preferred.
  • the tampon may be made of various fiber blends including both absorbent and nonabsorbent fibers, which may or may not have a suitable cover or wrapper. Suitable methods and materials for the production of tampons are well known to those skilled in the art.
  • aromatic compounds can substantially inhibit the production of exoprotein by Gram positive bacterium and, specifically, the production of TSST-1 and Enterotoxin B from S. aureus bacterium.
  • the aromatic compounds useful in the present invention have the general chemical structure:
  • R 1 is selected from the group consisting of H, — COR 5
  • R 5 is a monovalent saturated or unsaturated aliphatic hydrocarbyl moiety
  • R 6 is a divalent saturated or unsaturated aliphatic hydrocarbyl moiety
  • R 7 is a trivalent saturated or unsaturated aliphatic hydrocarbyl moiety
  • R 8 is hydrogen or a monovalent substituted or unsubstituted saturated or unsaturated aliphatic hydrocarbyl moiety which may or may not be interrupted with hetero atoms
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of H, OH, COOH, and -C(0)R 9
  • R 9 is a monovalent saturated or unsaturated aliphatic hydrocarbyl moiety.
  • the hydrocarbyl moieties described herein include both straight chain and branched chain hydrocarbyl moieties and may or may not be substituted and/or interrupted with hetero atoms.
  • the aromatic compounds for use in the present invention contain at least one OH and/or COOH group.
  • the OH and/or COOH group can be bonded to the aromatic structure, or can be bonded to an atom which may or may not be directly bonded to the aromatic structure.
  • R 5 is desirably a monovalent saturated aliphatic hydrocarbyl moiety having from 1 to about 15 carbon atoms, preferably from 1 to about 14 carbon atoms.
  • R 6 is desirably a divalent saturated or unsaturated aliphatic hydrocarbyl moiety having from 1 to about 15 carbon atoms, preferably from 1 to about 14 carbon atoms.
  • R 7 is desirably a trivalent saturated or unsaturated aliphatic hydrocarbyl moiety having from 1 to about 15 carbon atoms, preferably from 1 to about 10 carbon atoms, and more preferably from 1 to about 4 carbon atoms.
  • Hetero atoms which can interrupt the hydrocarbyl moiety include, for example, oxygen and sulfur.
  • Preferred aromatic compounds of the present invention include 2- phenylethanol, benzyl alcohol, trans-cinnamic acid, 4-hydroxybenzoic acid, methyl ester, 2-hydroxybenzoic acid, 2-hydoxybenzamide, acetyl tyrosine, 3, 4, 5- trihydroxybenzoic acid, lauryl 3, 4, 5-trihydroxybenzoate, phenoxyethanol, 4- hydroxy-3-methoxybenzoic acid, p-aminobenzoic acid, and 4-acetamidophenol.
  • the absorbent article or non- absorbent substrate including the aromatic compound contains an effective amount of the inhibiting aromatic compound to substantially inhibit the formation of TSST-1 when the absorbent article or non-absorbent substrate is exposed to S. aureus bacteria.
  • the inhibiting aromatic compounds reduce the formation of TSST-1 when the absorbent article is exposed to S.
  • aureus by at least about 40%, more preferably by at least about 50%, still more preferably by at least about 60%, still more preferably by at least about 70%, still more preferably by at least about 80%, still more preferably by at least about 90%, and still more preferably by at least about 95%.
  • the aromatic compound is formulated as a composition which includes a pharmaceutically acceptable carrier
  • the composition typically contains at least about 0.01 % (volume/volume) and desirably at least about 0.04% (volume/volume) aromatic compound (based on the total volume of the composition).
  • the composition will contain no more than about 1.0%(volume/volume) of aromatic compound.
  • concentration of aromatic compound will vary depending upon the compound selected and the other components of the formulation.
  • Particularly suitable formulations for use in vaginal cleansing applications can contain at least about 0.20 millimoles/liter, and desirably no more than about 50 millimoles/liter.
  • vaginal cleansing formulations contain from about 0.3 millimoles/liter to about 30 millimoles/liter of aromatic compound or from about 1 millimoles/liter to about 15 millimoles/liter of aromatic compound.
  • the aromatic compositions of the present invention may contain other additives as appropriate for a desired result so long as the additives do not have a substantially antagonistic effect on the activity of the aromatic compounds.
  • additives include conventional surfactants such as ethoxylated hydrocarbons or surfactants, or co-wetting aids such as low molecular weight alcohols.
  • aromatic compositions of the present invention including nonwovens such as spunbond, meltblown, carded webs and others as well as woven webs and even films and the like.
  • aromatic compounds may be used as an internal additive or added to the polymer melt directly or in a concentrate form. After fiber formation, such additives can migrate to the fiber surface and impart the desired effect.
  • Such internal addition of additives is discuss in U.S. Patent No. 5,540,979 which is incorporated by reference.
  • Effective amounts of aromatic compound that significantly reduce the production of TSST-1 have been found to be at least about 0.1 micromoles of the aromatic compound per gram of the absorbent product or non-absorbent substrate.
  • the aromatic compound ranges from about 0.5 micromoles per gram of absorbent or non-absorbent substrate to about 100 micromoles per gram of absorbent or non-absorbent substrate and more desirably from about 1.0 micromoles per gram of absorbent or non-absorbent substrate to about 50 micromoles per gram of absorbent or non-absorbent substrate.
  • aromatic compound is used in the singular, one skilled in the art would understand that it includes the plural, and that various aromatic compounds within the scope of this invention may be used in combination.
  • the aromatic compounds of the present invention can be prepared and applied in any suitable form, but are preferably prepared in forms including, without limitation, aqueous solutions, lotions, balms, gels, salves, ointments, boluses, suppositories, and the like. One skilled in the art would recognize that other forms may perform equally well.
  • the aromatic compounds may be applied to the absorbent article or non- absorbent substrate using conventional methods for applying an inhibitory agent to the desired absorbent article or non-absorbent substrate.
  • unitary tampons without separate wrappers may be dipped directly into a liquid bath having the inhibitory compound and then can be air dried, if necessary, to remove any volatile solvents.
  • impregnating any of its elements is best done before compressing.
  • the aromatic compounds when incorporated on and/or into the tampon materials may be fugitive, loosely adhered, bound, or any combination thereof.
  • the term "fugitive" means that the composition is capable of migrating through the tampon materials.
  • non-absorbent articles may be dipped directly into a liquid bath having the inhibitory compound and then can be air dried, if necessary, to remove any volatile solvents.
  • the non-absorbent articles of the present invention can be sprayed or otherwise coated with the inhibitory aromatic compounds of the present invention. It is not necessary to impregnate the entire absorbent body of the tampon with the inhibitory agent. Optimum results both economically and functionally can be obtained by concentrating the material on or near the outer surface where it may be most effective during use.
  • an aromatic containing composition may be applied directly onto an individual layer of material before it is incorporated into an article to be manufactured, such as an absorbent product.
  • an aqueous solution containing the aromatic compound can be sprayed onto the surface of a porous cover sheet or absorbent layer designed to be incorporated into an absorbent product. This can be done either during the production of the individual layer or during a fabrication process which incorporates the layer into the article being manufactured.
  • Nonwoven webs coated with the aromatic-containing compositions of the present invention can be prepared by conventional processes.
  • the aromatic composition can be applied to one or both sides of a traveling web.
  • a web such as a spunbond or meltblown nonwoven, can be directed over support rolls to a treating station including rotary spray heads for application to one side of the web.
  • An optional treating station may include rotary spray heads to apply aromatic composition to the opposite side of the web.
  • Each treatment station typically receives a supply of treating liquid from a reservoir.
  • the treated web may then be dried if needed by passing over dryer cans or other drying means and then wound as a roll or converted to the use of which it is intended.
  • Alternative drying means such as ovens, through air dryers, infra red dryers, air blowers, and the like may also be utilized.
  • the substantially inhibitory aromatic compounds may additionally employ one or more conventional pharmaceutically-acceptable and compatible carrier materials useful for the desired application.
  • the carrier can be capable of co- dissolving or suspending the materials used in the absorbent article.
  • Carrier materials suitable for use in the instant invention include those well-known for use in the cosmetic and medical arts as a basis for ointments, lotions, creams, salves, aerosols, suppositories, gels, and the like.
  • the aromatic compounds of the present invention may additionally employ adjunct components conventionally found in pharmaceutical compositions in their art-established fashion and at their art-established levels.
  • the compositions may contain additional compatible pharmaceutically active materials for combination therapy, such as supplementary antimicrobial, antioxidants, anti- parasitic agents, antipruritics, astringents, local anaesthetics, or anti-inflammatory agents.
  • the inhibitory aromatic compounds described above can be used in combination with one or more surface active agents to reduce the production of TSST-1 without significantly eliminating the beneficial bacterial flora.
  • the surface active agents can include, for example, compounds with an ether, ester, amide, glycosidic, or amine bond linking a C 8 -C- ⁇ 8 fatty acid to an aliphatic alcohol, polyalkoxylated sulfate salt, or polyalkoxylated sulfosuccinic salt.
  • inhibitory aromatic compounds described herein can be used in combination with ether compounds having the general formula:
  • R 10 is a straight or branched alkyl or alkenyl group having a chain of from about 8 to about 18 carbon atoms and R 11 is selected from an alcohol, a polyalkoxylated sulfate salt or a polyalkoxylated sulfosuccinate salt.
  • the alkyl, or the R 10 moiety of the ether compounds useful for use in combination with the inhibitory aromatic compounds described herein, can be obtained from saturated and unsaturated fatty acid compounds.
  • Suitable compounds include, C ⁇ -Ci ⁇ fatty acids, and preferably, fatty acids include, without limitation, caprylic, capric, lauric, myristic, palmitic and stearic acid whose carbon chain lengths are 8, 10, 12, 14, 16, and 18, respectively.
  • Highly preferred materials include capric, lauric, and myristic acids.
  • Preferred unsaturated fatty acids are those having one or two cis-type double bonds and mixtures of these materials. Suitable materials include myrystoleic, palmitoleic, linolenic and mixtures thereof.
  • the R 11 moiety is an aliphatic alcohol which can be ethoxylated or propoxylated for use in the ether compositions in combination with the inhibitory aromatic compounds described herein.
  • Suitable aliphatic alcohols include glycerol, sucrose, glucose, sorbitol and sorbitan.
  • Preferred ethoxylated and propoxylated alcohols include glycols such as ethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol.
  • the aliphatic alcohols can be ethoxylated or propoxylated by conventional ethoxylating or propoxylating compounds and techniques.
  • the compounds are preferably selected from the group consisting of ethylene oxide, propylene oxide, and mixtures thereof, and similar ringed compounds which provide a material which is effective.
  • the R 11 moiety can further include polyalkoxylated sulfate and polyalkoxylated sulfosuccinate salts.
  • the salts can have one or more cations. Preferably, the cations are sodium, potassium or both.
  • Preferred ether compounds for use in combination with the inhibitory aromatic compounds described herein include laureth-3, laureth-4, laureth-5, PPG- 5 lauryl ether, 1-0-dodecyl-rac-glycerol, sodium laureth sulfate, potassium laureth sulfate, disodium laureth (3) sulfosuccinate, dipotassium laureth (3) sulfosuccinate, and polyethylene oxide (2) sorbitol ether.
  • the absorbent article or non- absorbent substrate contains an effective amount of the combination of the inhibitory aromatic and ether compounds.
  • the amount of ether compound included in the absorbent article is at least about 0.1 micromoles of ether compound per gram of absorbent article, and desirably at least about 0.005 millimoles of ether compound per gram of absorbent article.
  • the absorbent article contains from about 5.0 micromoles of ether compound per gram of absorbent article to about 2 millimoles of ether compound per gram of absorbent article.
  • the amount of ether compound introduced onto the non-absorbent article is at least about 0.0001 millimoles of ether compound per gram of non-absorbent article, and desirably at least about 0.005 millimoles of ether compound per gram of non-absorbent article.
  • the non-absorbent article contains from about 0.005 millimoles of ether compound per gram of non-absorbent article to about 2 millimoles of ether compound per gram of non-absorbent article.
  • the absorbent articles of the present invention containing a combination of two active ingredients can be a variety of absorbent articles including, for example, catamenial tampons, sanitary napkins, panty liners, incontinent undergarments, diapers, wound dressings, dental tampons, medical tampons, surgical tampons, nasal tampons and the like.
  • the non-absorbent articles of the present invention containing a combination of two active ingredients can be a variety of non-absorbent articles including, for example, incontinence devices, barrier birth control devices, contraceptive sponges, douches, tampon applicators, and the like.
  • the composition contains an effective amount of the combination of the inhibitory aromatic and ether compounds.
  • the amount of ether compound included in the composition is at least about 0.01% (weight/volume) and desirably at least about 0.04% (weight/volume) (based on the total volume of the composition).
  • the composition contains no more than about 0.3% (weight/volume) ether compound.
  • Particularly suitable formulations for use in vaginal cleansing applications will contain at least about 0.25 millimoles/liter, desirably no more than about 10 millimoles/liter, and most desirably from about 0.5 millimoles/liter to about 5 millimoles/liter of ether compound.
  • the absorbent articles and non-absorbent substrates of the present invention containing a first inhibitory aromatic compound and a second inhibitory ether compound contain a sufficient amount of both inhibitory compounds to substantially inhibit the formation of TSST-1 when the absorbent article or non- absorbent substrate is exposed to S. aureus bacteria.
  • the combination of inhibitory compounds reduces the formation of TSST-1 when the absorbent article or non-absorbent substrate is exposed to S. aureus by at least about 40%, more preferably at least about 50%, still more preferably at least about 60%, still more preferably by at least about 70%, still more preferably by at least about 80%, still more preferably by at least about 90%, and still more preferably by at least about 95%.
  • the absorbent articles and non-absorbent substrates of the present invention containing the combination of aromatic inhibitory compounds and ether inhibitory compounds may additionally employ adjunct components conventionally found in pharmaceutical compositions in their art-established fashion and at their art-established levels.
  • the compositions may contain additional compatible pharmaceutically active materials for combination therapy, such as supplementary antimicrobial, antioxidants, anti-parasitic agents, antipruritics, astringents, local anaesthetics, or anti-inflammatory agents.
  • the absorbent article will contain a molar ratio of inhibitory aromatic compound to ether compound of from about 1 :6 to about 1 :0.05.
  • inhibitory aromatic compounds described herein can be used in combination with an alkyl polyglycoside compound.
  • Suitable alkyl polyglycosides for use in combination with the inhibitory aromatic compounds include alkyl polyglycosides having the general formula:
  • Z is a saccharide residue having 5 or 6 carbon atoms
  • n is a whole number from 1 to 6
  • R 14 is a linear or branched alkyl group having from about 8 to about 18 carbon atoms.
  • suitable alkyl polyglycosides having differing carbon chain lengths include Glucopon 220, 225, 425, 600, and 625, all available from Henkel Corporation (Ambler, Pennsylvania). These products are all mixtures of alkyl mono- and oligoglucopyranosides with differing alkyl group chain lengths based on fatty alcohols derived from coconut and/or palm kernel oil.
  • Glucopon 220, 225, and 425 are examples of particularly suitable alkyl polyglycosides for use in combination with the inhibitory aromatic compounds of the present invention.
  • Another example of a suitable commercially available alkyl polyglycoside is TL 2141 , a Glucopon 220 analog available from ICI Surfactants (Wilmington, Delaware).
  • an alkylpolyglycoside may consist of a single type of alkyl polyglycoside molecule or, as is typically the case, may include a mixture of different alkyl polyglycoside molecules.
  • the different alkyl polyglycoside molecules may be isomeric and/or may be alkyl polyglycoside molecules with differing alkyl group and/or saccharide portions.
  • alkyl poyglycoside isomers reference is made to alkyl polyglycosides which, although including the same alky ether residues, may vary with respect to the location of the alkyl ether residue in the alkyl polyglycoside as well as isomers which differ with respect to the orientation of the functional groups about one or more chiral centers in the molecules.
  • an alkyl polyglycoside can include a mixture of molecules with saccharide portions which are mono, di-, or oligosaccharides derived from more than one 6 carbon saccharide residue and where the mono-, di- or oligosaccharide has been etherified by reaction with a mixture of fatty alcohols of varying carbon chain length.
  • the present alkyl polyglycosides desirably include alkyl groups where the average number of carbon atoms in the alkyl chain is about 8 to about 14 or from about 8 to about 12.
  • a suitable alkyl polyglycoside is a mixture of alkyl polyglycoside molecules with alkyl chains having from about 8 to about 10 carbon atoms.
  • the alkyl polyglycosides employed in the absorbent articles in combination with the inhibiting aromatic compounds can be characterized in terms of their hydrophilic lipophilic balance (HLB). This can be calculated based on their chemical structure using techniques well known to those skilled in the art.
  • the HLB of the alkyl polyglycosides used in the present invention typically falls within the range of about 10 to about 15.
  • the present alkyl polyglycosides have an HLB of at least about 12 and, more desirably, about 12 to about 14.
  • the absorbent article or non- absorbent substrate contains an effective amount of the combination of the inhibitory aromatic and alkyl polyglycoside compounds.
  • the amount of alkyl polyglycoside compound included in the absorbent article or non-absorbent substrate is at least about 0.0001 millimoles of alkyl polyglycoside per gram of absorbent article or non-absorbent substrate, and preferably at least about 0.005 millimoles of alkyl polyglycoside per gram of absorbent article or non-absorbent substrate.
  • the absorbent article or non-absorbent substrate contains from about 0.005 millimoles per gram of absorbent article or non-absorbent substrate to about 2 millimoles per gram of absorbent article or non-absorbent substrate.
  • the absorbent articles of the present invention containing a combination of inhibitory or active ingredients such as aromatic inhibitory compounds and alkyl polyglycoside inhibitory compounds can be a variety of absorbent articles including, for example, catamenial tampons, sanitary napkins, panty liners, incontinent undergarments, diapers, wound dressings, dental tampons, medical tampons, surgical tampons, nasal tampons and the like.
  • the non-absorbent articles of the present invention containing a combination of inhibitory or active ingredients such as aromatic inhibitory compounds and alkyl polyglycoside inhibitory compounds can be a variety of non- absorbent articles including, for example, incontinence devices, barrier birth control devices, contraceptive sponges, douches, tampon applicators, and the like.
  • the composition contains an effective amount of the combination of the inhibitory aromatic and alkyl polyglycoside compounds.
  • the amount of alkyl polyglycoside compound included in the composition is at least about 0.01% (weight/volume) and desirably at least about 0.04% (weight/volume) (based on the total volume of the composition).
  • the composition contains no more than about 0.3% (weight/volume) alkyl polyglycoside compound.
  • Particularly suitable formulations for use in vaginal cleansing applications will contain at least about 0.25 millimoles/liter, desirably no more than about 5 millimoles/liter, and most desirably from about 0.5 to about 3 millimoles/liter of alkyl polyglycoside compound.
  • the absorbent articles or non-absorbent substrates of the present invention containing a first inhibitory aromatic compound and a second inhibitory alkyl polyglycoside compound contain a sufficient amount of both inhibitory compounds to substantially inhibit the formation of TSST-1 when the absorbent article or non- absorbent substrate is exposed to S. aureus bacteria.
  • the combination of inhibitory compounds reduces the formation of TSST-1 when the absorbent article or non-absorbent substrate is exposed to S. aureus by at least about 40%, more preferably at least about 50%, still more preferably at least about 60%, still more preferably by at least about 70%, still more preferably by at least about 80%, still more preferably by at least about 90%, and still more preferably by at least about 95%.
  • the absorbent articles or non-absorbent substrates of the present invention containing the combination of aromatic inhibitory compounds and alkyl polyglycoside inhibitory compounds may additionally employ adjunct components conventionally found in pharmaceutical compositions in their art-established fashion and at their art-established levels.
  • the compositions may contain additional compatible pharmaceutically active materials for combination therapy, such as supplementary antimicrobial, antioxidants, anti-parasitic agents, antipruritics, astringents, local anaesthetics, or anti-inflammatory agents.
  • the absorbent article will contain a molar ratio of inhibitory aromatic compound to alkyl glycoside compound of from about 1 :1 to about 1 :0.005.
  • the non-absorbent substrate will contain a molar ratio of inhibitory aromatic compound to alkyl glycoside of from about 1:1 to about 1:0.05.
  • the inhibitory aromatic compounds described herein can be used in combination with an amide containing compound having the general formula:
  • R 17 inclusive of the carbonyl carbon, is an alkyl group having 8 to 18 carbon atoms, and R 18 and R 19 are independently selected from hydrogen or an alkyl group having from 1 to about 12 carbon atoms which may or may not be substituted with groups selected from ester groups, ether groups, amine groups, hydroxyl groups, carboxyl groups, carboxyl salts, sulfonate groups, sulfonate salts, and mixtures thereof.
  • R 17 can be derived from saturated and unsaturated fatty acid compounds.
  • Suitable compounds include, C ⁇ -C-ia fatty acids, and preferably, the fatty acids include, without limitation, caprylic, capric, lauric, myristic, palmitic and stearic acid whose carbon chain lengths are 8, 10, 12, 14, 16, and 18, respectively. Highly preferred materials include capric, lauric, and myristic. Preferred unsaturated fatty acids are those having one or two cis-type double bonds and mixtures of these materials. Suitable materials include myrystoleic, palmitoleic, linolenic and mixtures thereof.
  • the R 18 and R 19 moieties can be the same or different and each being selected from hydrogen and an alkyl group having a carbon chain having from 1 to about 12 carbon atoms.
  • the R 18 and R 19 alkyl groups can be straight or branched and can be saturated or unsaturated.
  • the alkyl group can include one or more substituent groups selected from ester, ether, amine, hydroxyl, carboxyl, carboxyl salts, sulfonate and sulfonate salts.
  • the salts can have one or more cations selected from sodium, potassium or both.
  • Preferred amide compounds for use in combination with the inhibitory aromatic compounds described herein include sodium lauryl sarcosinate, lauramide monoethanolamide, lauramide diethanolamide, lauramidopropyl dimethylamine, disodium lauramido monoethanolamide sulfosuccinate and disodium lauroamphodiacetate.
  • the absorbent article or non- absorbent substrate contains an effective amount of the combination of the inhibitory aromatic and amide-containing compounds.
  • the amount of amide- containing compound included in the absorbent article or non-absorbent substrate is at least about 0.0001 millimoles of nitrogen containing compound per gram of absorbent article or non-absorbent substrate, and preferably at least about 0.005 millimoles of nitrogen containing compound per gram of absorbent article or non- absorbent substrate.
  • the absorbent article or non- absorbent substrate contains from about 0.005 millimoles per gram of absorbent article or non-absorbent substrate to about 2 millimoles per gram of absorbent article or non-absorbent substrate.
  • the composition contains an effective amount of the combination of the inhibitory aromatic and amide compounds.
  • the amount of amide compound included in the composition is at least about 0.01 % (weight/volume) and desirably at least about 0.04% (weight/volume) (based on the total weight of the composition).
  • the composition contains no more than about 0.3% (weight/volume) amide compound.
  • Particularly suitable formulations for use in vaginal cleansing applications will contain at least about 0.25 millimoles/liter, desirably no more than about 5 millimoles/liter, and most desirably from about 0.5 to about 3 millimoles/liter of amide compound.
  • the absorbent articles of the present invention containing a combination of inhibitory or active ingredients such as aromatic inhibitory compounds and amide- containing inhibitory compounds can be a variety of absorbent articles including, for example, catamenial tampons, sanitary napkins, panty liners, incontinent undergarments, diapers, wound dressings, dental tampons, medical tampons, surgical tampons, nasal tampons and the like.
  • non-absorbent articles of the present invention containing a combination of inhibitory or active ingredients such as aromatic inhibitory compounds and amide-containing inhibitory compounds can be a variety of non- absorbent articles including, for example, incontinence devices, barrier birth control devices, contraceptive sponges, douches, tampon applicators, and the like.
  • the absorbent articles or non-absorbent substrates of the present invention containing a first inhibitory aromatic compound and a second inhibitory amide- containing compound contain a sufficient amount of both inhibitory compounds to substantially inhibit the formation of TSST-1 when the absorbent article or non- absorbent substrate is exposed to S. aureus bacteria.
  • the combination of inhibitory compounds reduces the formation of TSST-1 when the absorbent article or non-absorbent substrate is exposed to S. aureus by at least about 40%, more preferably at least about 50%, still more preferably at least about 60%, still more preferably by at least about 70%, still more preferably by at least about 80%, still more preferably by at least about 90%, and still more preferably by at least about 95%.
  • the absorbent articles or non-absorbent substrates of the present invention containing the combination of aromatic inhibitory compounds and amide-containing inhibitory compounds may additionally employ adjunct components conventionally found in pharmaceutical compositions in their art-established fashion and at their art-established levels.
  • the compositions may contain additional compatible pharmaceutically active materials for combination therapy, such as supplementary antimicrobial, antioxidants, anti-parasitic agents, antipruritics, astringents, local anaesthetics, or anti-inflammatory agents.
  • the absorbent article or non-absorbent substrate will contain a molar ratio of inhibitory aromatic compound to amide-containing compound of from about 1 :2 to about 1 :0.05.
  • the inhibitory compounds described herein can be used in combination with amine compounds having the general formula:
  • R 20 is an alkyl group having from about 8 to about 18 carbon atoms and R 21 and R 22 are independently selected from the group consisting of hydrogen and alkyl groups having from 1 to about 18 carbon atoms and which can have one or more substitutional moieties selected from the group consisting of hydroxyl, carboxyl, carboxyl salts and imidazoline
  • the combination of aromatic compounds and amine compounds are effective in substantially inhibiting the production of exoprotein from Gram positive bacteria.
  • R 20 is derived from fatty acid compounds which include, without limitation, caprylic, capric, lauric, myristic, palmitic and stearic acid whose carbon chain lengths are 8, 10, 12, 14, 16, and 18, respectively. Highly preferred materials include capric, lauric, and myristic.
  • Preferred unsaturated fatty acids are those having one or two cis-type double bonds and mixtures of these materials. Suitable materials include myrystoleic, palmitoleic, linolenic, and mixtures thereof.
  • the R 21 and R 22 alkyl groups can further include one or more substitutional moieties selected from hydroxyl, carboxyl, carboxyl salts, and R 1 and R 2 can form an unsaturated heterocyclic ring that contains a nitrogen that connects via a double bond to the alpha carbon of the R 1 moiety to form a substituted imidazoline.
  • the carboxyl salts can have one or more cations selected from sodium potassium or both.
  • the R 20 , R 21 , and R 22 alkyl groups can be straight or branched and can be saturated or unsaturated.
  • Preferred amine compounds for use with the aromatic compounds described herein include triethanolamide laureth sulfate, lauramine, lauramino propionic acid, sodium lauriminodipropionic acid, lauryl hydroxyethyl imidazonline and mixtures thereof.
  • the composition contains an effective amount of the combination of the inhibitory aromatic and amine compounds.
  • the amount of amine compound in the composition is at least about 0.01 % (weight/volume) and desirably at least about 0.04% (weight/volume) (based on the total weight of the composition).
  • the composition contains no more than about 0.3% (weight/volume) ether compound.
  • Particularly suitable formulations for use in vaginal cleansing applications will contain at least about 0.25 millimoles/liter, desirably no more than about 5 millimoles/liter, and most desirably from about 0.5 to about 3 millimoles/liter of amine compound.
  • the amine compound can be an amine salt having the general formula:
  • R 23 is an anionic moiety associated with the amine and is derived from an alkyl group having from about 8 to about 18 carbon atoms
  • R 24 , R 25 , and R 26 are independently selected from the group consisting of hydrogen and alkyl group having from 1 to about 18 carbon atoms and which can have one or more substitutional moieties selected from the group consisting of hydroxyl, carboxyl, carboxyl salts, and imidazoline.
  • R 24 , R 25 , and R 26 can be saturated or unsaturated.
  • R 23 is a polyalkyloxylated alkyl sulfate.
  • a preferred compound illustrative of an amine salt is TEA laureth sulfate.
  • the absorbent article or non- absorbent substrate contains an effective amount of the combination of the inhibitory aromatic and amine and/or amine salt compounds.
  • the amount of amine and/or amine salt compound included in the absorbent article or non- absorbent substrate is at least about 0.0001 millimoles of ether per gram of absorbent article or non-absorbent substrate, and preferably at least about 0.005 millimoles of ether per gram of absorbent article or non-absorbent substrate.
  • the absorbent article or non-absorbent substrate contains from about 0.005 millimoles per gram of absorbent article or non-absorbent substrate to about 2 millimoles per gram of absorbent article or non-absorbent substrate.
  • the absorbent articles of the present invention containing a combination of two active ingredients can be a variety of absorbent articles including, for example, catamenial tampons, sanitary napkins, panty liners, incontinent undergarments, diapers, wound dressings, dental tampons, medical tampons, surgical tampons, nasal tampons and the like.
  • the non-absorbent articles of the present invention containing a combination of two active ingredients can be a variety of non-absorbent articles including, for example, incontinence devices, barrier birth control devices, contraceptive sponges, douches, tampon applicators, and the like.
  • the absorbent articles or non-absorbent substrates of the present invention containing a first inhibitory aromatic compound and a second inhibitory amine and/or amine salt compound contain a sufficient amount of both inhibitory compounds to substantially inhibit the formation of TSST-1 when the absorbent article or non-absorbent substrate is exposed to S. aureus bacteria.
  • the combination of inhibitory compounds reduces the formation of TSST-1 when the absorbent article or non-absorbent substrate is exposed to S.
  • aureus by at least about 40%, more preferably at least about 50%, still more preferably at least about 60%, still more preferably by at least about 70%, still more preferably by at least about 80%, still more preferably by at least about 90%, and still more preferably by at least about 95%.
  • the composition contains an effective amount of the combination of the inhibitory aromatic and amine salt.
  • the amount of amine salt included in the composition is at least about 0.01% (weight/volume) and desirably at least about 0.04% (weight/volume) (based on the total weight of the composition).
  • the composition contains no more than about 0.3% (weight/volume) amine salt compound.
  • Particularly suitable formulations for use in vaginal cleansing applications will contain at least about 0.25 millimoles/liter, desirably no more than about 5 millimoles/liter, and most desirably from about 0.5 to about 3 millimoles/liter of amine salt compound.
  • the absorbent articles or non-absorbent substrates of the present invention containing the combination of aromatic inhibitory compounds and amine and/or amine salt inhibitory compounds may additionally employ adjunct components conventionally found in pharmaceutical compositions in their art-established fashion and at their art-established levels.
  • the compositions may contain additional compatible pharmaceutically active materials for combination therapy, such as supplementary antimicrobial, antioxidants, anti-parasitic agents, antipruritics, astringents, local anaesthetics, or anti-inflammatory agents.
  • the absorbent article or non-absorbent substrate will contain a molar ratio of inhibitory aromatic compound to amine and/or amine salt compound of from about 1 :2 to about 1 :0.05.
  • the present invention is illustrated by the following examples which are merely for the purpose of illustration and are not to be regarded as limiting the scope of the invention or manner in which it may be practiced.
  • test compound in the desired concentration (expressed in percent of active compound) was placed in 10mL of a growth medium in a sterile, 50 mL conical polypropylene tube (Sarstedt, Inc. Newton, North Carolina).
  • the growth medium was prepared by dissolving 37 grams of brain heart infusion broth (BHI) (Difco Laboratories, Cockeysville, Maryland) in 880 mL of distilled water and sterilizing the broth according to the manufacturer's instructions.
  • BHI brain heart infusion broth
  • the BHI was supplemented with fetal bovine serum (FBS) (100mL) (Sigma Chemical Company, St. Louis, Missouri).
  • FBS fetal bovine serum
  • Hexahydrate of magnesium chloride 0.021 M, 10mL
  • L-glutamine 0.027 M, 10mL
  • Test compounds included phenylethyl alcohol, benzyl alcohol, and 2-hydroxybenzamide.
  • Test compounds were both liquids and solids. The liquid test compounds were added directly to the growth medium and diluted in growth medium to obtain the desired final concentrations. The solid test concentrations were dissolved in methanol, spectrophotometric grade (Sigma Chemical Company, St. Louis, Missouri) at a concentration that permitted the addition of 200 microliters of the solution to 10 mL of growth medium for the highest concentration tested. Each test compound that was dissolved in methanol was added to the growth medium in the amount necessary to obtain the desired final concentration.
  • an inoculating broth was prepared as follows: S. aureus (MN8) was streaked onto a tryptic soy agar plate (TSA; Difco Laboratories Cockeysville, Maryland) and incubated at 35°C.
  • TSA tryptic soy agar plate
  • the test organism was obtained from Dr. Pat Schlievert, Department of Microbiology, University of Minnesota Medical School, Minneapolis, Minnesota. After 24 hours of incubation three to five individual colonies were picked with a sterile inoculating loop and used to inoculate 10mL of growth medium.
  • the tube of inoculated growth medium was incubated at 35°C in atmospheric air.
  • the culture was removed from the incubator and mixed well on a S/P brand vortex mixer.
  • a second tube containing 10mL of the growth medium was inoculated with 0.5mL of the above-described 24 hour old culture and incubated at 35°C in atmospheric air.
  • the culture was removed from the incubator and mixed well on a S/P brand vortex mixer.
  • the optical density of the culture fluid was determined in a microplate reader (Bio-Tek Instruments, Model EL309, Winooski, Vermont). The amount of inoculum necessary to give 5 x 10 6 CFU/mL in 10 mL of growth medium was determined using a standard curve.
  • This Example included tubes of growth medium with varying concentrations of test compounds, tubes of growth medium without test compounds (control) and tubes of growth medium with 20-400 microliters of methanol (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, Jaece Industries purchased from VWR Scientific Products, South Plainfield, New Jersey). The tubes were incubated at 35°C in atmospheric air containing 5% by volume C0 2 . After 24 hours of incubation the tubes were removed from the incubator and the optical density (600nm) of the culture fluid was determined and the culture fluid was assayed for the number of colony forming units of S. aureus and was prepared for the analysis of TSST-1 as described below.
  • the number of colony forming units per mL after incubation was determined by standard plate count procedures.
  • the culture fluid broth was centrifuged and the supernatant subsequently filter sterilized through an Autovial 5 syringeless filter, 0.2 micrometers pore size (Whatman, Inc., Clifton, New Jersey). The resulting fluid was frozen at -70°C until assayed.
  • TSST-1 The amount of TSST-1 per mL was determined by a non-competitive, sandwich enzyme-linked immunoabsorbent assay (ELISA). Samples of the culture fluid and the TSST-1 reference standard were assayed in triplicate. The method employed was as follows: four reagents, TSST-1 (#TT-606), rabbit polyclonal anti- TSST-1 IgG (LTI-101 ), rabbit polyclonal anti-TSST-1 IgG conjugated to horseradish peroxidase (LTC-101), and normal rabbit serum (NRS) certified anti- TSST-1 free (NRS-10) were purchased from Toxin Technology (Sarasota, Florida).
  • a 10 microgram/millimeter solution of the polyclonal rabbit anti-TSST-1 IgG was prepared in phosphate buffered saline (PBS) (pH 7.4).
  • PBS phosphate buffered saline
  • the PBS was prepared from 0.016 molar NaH 2 P0 4 , 0.004 molar NaH 2 P0 4 -H 2 0, 0.003 molar KCI and 0.137 molar NaCl, (Sigma Chemical Company, St. Louis, Missouri).
  • One hundred microliters of the polyclonal rabbit anti-TSST-1 IgG solution was pipetted into the inner wells of polystyrene microplates (Nunc-Denmark, Catalogue Number 439454). The plates were covered and incubated at room temperature overnight.
  • TSST-1 was diluted to 10 nanograms/milliliter in PBS with phosphate buffered saline (pH7.4) containing 0.05% (vol/vol) Tween-20 (PBS-Tween) (Sigma Chemical Company, St. Louis, Missouri) and 1 % NRS (vol/vol) and incubated at 4°C overnight. Test samples were combined with 1% NRS (vol/vol) and incubated at 4°C overnight. The plates were treated with 100 microliters of a 1 % solution of the sodium salt of casein in PBS (Sigma Chemical Company, St. Louis, Missouri), covered and incubated at 35°C for one hour.
  • Unbound BSA was removed by 3 washes with PBS-Tween.
  • TSST-1 reference standard (10 nanograms/milliliter) treated with NRS, test samples treated with NRS, and reagent controls were pipetted in 200 microliter volumes to their respective wells on the first and seventh columns of the plate.
  • One hundred microliters of PBS-Tween was added to the remaining wells.
  • the TSST-1 reference standard and test samples were then serially diluted 6 times in the PBS-Tween by transferring 100 microliters from well-to-well. The samples were mixed prior to transfer by repeated aspiration and expression. This was followed by incubation for 1.5 hours at 35°C and five washes with PBS-T and three washes with distilled water to remove unbound toxin.
  • the plates were covered and incubated at 35°C for one hour. Following incubation the plates were washed five times in PBS-Tween and three times with distilled water. Following the washes, the wells were treated with 100 microliters of horseradish peroxidase substrate buffer consisting of 5 milligrams of o-phenylenediamine and 5 microliters of 30% hydrogen peroxide in 11 mL of citrate buffer (pH 5.5).
  • the citrate buffer was prepared from 0.012 M anhydrous citric acid and 0.026 molar dibasic sodium phosphate. The plates were incubated for 15 minutes at 35°C. The reaction was stopped by the addition of 50 microliters of a 5% sulfuric acid solution. The intensity of the color reaction in each well was evaluated using the BioTek Model EL309 microplate reader (OD 490 nanometers). TSST-1 concentrations in the test samples were determined from the reference toxin regression equation derived during each assay procedure. The efficacy of the compound in inhibiting the production of TSST-1 is shown in Table I below.
  • the data in Table 1 shows that S. aureus (MN8), when compared to the control, produced significantly less TSST-1 in the presence of the aromatic compounds.
  • the aromatic compounds reduced the amount of exotoxin production ranging from about 91% to about 96%.
  • the amount of toxin produced was significantly reduced, there was minimal, if any, effect on the growth of S. aureus cells.
  • Example 2 the effect of various test compounds on the growth of S. 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 percent of the active compound, in 10mL of a growth medium as described in Example 1. The test compounds were then tested and evaluated as in Example 1.
  • Table 2 shows that S. aureus (MN8), when compared to the control, produced significantly less TSST-1 in the presence of the aromatic compounds.
  • the aromatic compounds reduced the amount of exotoxin production ranging from about 82% to 97%.
  • the amount of toxin produced was significantly reduced, there was minimal, if any, effect on the growth of S. aureus cells.
  • EXAMPLE 3 In this Example, the effect of various test compounds on the growth of S. aureus and the production of TSST-1 was determined. The effect of the test compounds tested in Example 3 was determined by placing the desired concentration, expressed in percent of the active compound, in 10mL of a growth medium as described in Example 1. The test compounds were then tested and evaluated as in Example 1.
  • Table 3 shows that S. aureus (MN8), when compared to the control, produced significantly less TSST-1 in the presence of the aromatic compounds.
  • the aromatic compounds reduced the amount of exotoxin production ranging from about 69% to 98%.
  • the amount of toxin produced was significantly reduced, there was minimal, if any, effect on the growth of S. aureus cells.
  • EXAMPLE 4 In this Example, the effect of various test compounds on the growth of S. aureus and the production of TSST-1 was determined. The effect of the test compounds tested in Example 4 was determined by placing the desired concentration, expressed in percent of the active compound, in 10mL of a growth medium as described in Example 1. The test compounds were then tested and evaluated as in Example 1.
  • Table 4 shows that S. aureus (MN8), when compared to the control, produced significantly less TSST-1 in the presence of the aromatic compounds.
  • the aromatic compounds reduced the amount of exotoxin production ranging from about 79% to 98%.
  • the amount of toxin produced was significantly reduced, there was minimal, if any, effect on the growth of S. aureus cells.
  • EXAMPLE 5 In this Example the growth of S. aureus and the production of TSST-1 in the presence of phenylethyl alcohol was measured using different TSST-1 producing strains of S. aureus.
  • S. aureus FRI-1187 and FRI-1169 were obtained as lyophilized cultures from the stock collection of Dr. Merlin Bergdoll, Food Research Institute (Madison Wisconsin).
  • the effect of the phenylethyl alcohol was determined by placing the desired concentration, expressed in percent of the active compound, in 10 mL of a growth medium as in Example 1. The phenylethyl alcohol was then tested and evaluated as in Example 1.
  • Table 5 shows that S. aureus when compared to the control, produced significantly less TSST-1 in the presence of the phenylethyl alcohol.
  • the phenylethyl alcohol reduced the amount of exotoxin production from the FRI-1169 culture from about 95% to about 100%.
  • the phenylethyl alcohol also significantly reduced the amount of exotoxin production from the FRI-1187 culture.
  • the amount of toxin produced was significantly reduced, there was minimal, if any, effect on the growth of S. aureus cells.
  • EXAMPLE 6 In this Example, the effect of test compounds in combination with surface active agents was evaluated utilizing a checkerboard experimental design. This allowed the evaluation of the interaction of two test compounds on the growth of S. aureus and the production of TSST-1. Four concentrations of one test compound (including zero) were combined with five concentrations of a second test compound (including zero) in test tubes. In this Example, phenyethyl alcohol (0%, 0.5%, 0.3%, 0.15%, and 0.05%) was combined with Cetiol 1414E (myreth-3 myristate) (10mM, 5mM, 2.5mM and 0). The test solutions were otherwise prepared as described in Example 1 and evaluated in the same manner as Example 1. As Table 6 below indicates, at every concentration of Cetiol 1414E, the phenylethyl alcohol increased the inhibition of production of TSST-1 , and vice versa. The effect appears to be additive.
  • EXAMPLE 7 In this Example, the effect of phenylethyl alcohol and 4-hydroxybenzoic acid, methyl ester on the production of alpha-toxin from S. aureus strain RN 6390 was evaluated utilizing a standard hemolytic assay.
  • the S. aureus alpha-toxin is a hemolytic exoprotein that causes target cell membrane damage and cell death. It is produced under environmental conditions similar to those seen with TSST-1 production.
  • the effect of the test compounds on the growth of S. aureus and the production of alpha-toxin was carried out by placing the desired concentrations, expressed in percent of the active compound, in 100mL of growth medium in 500 mL fleakers capped with aluminum foil.
  • the growth medium and inoculum were prepared as described in Example 1.
  • the fleakers were incubated in a 37°C water bath with a gyratory shaker set at 180 rpm. Growth was followed by periodic optical density measurements at 600 nm.
  • Culture supernatants were serially diluted in Tris-saline buffer from 1 :2 to 1 :256. One hundred microliters of each dilution was added to nine hundred microliters of the rabbit red blood cells. Each dilution was set up in triplicate. The tubes were incubated for 30 minutes at 37°C. The samples were then centrifuged at 800 x g for 6 minutes. Two two-hundred microliter aliquots of each tube were transferred to a microtiter plate and the optical density determined at 410 nm.
  • Control fluids used in place of the culture supematants included tris-saline buffer (zero lysis), 10% sodium dodecyl sulfate (100% lysis), and sterile growth medium containing the test compound. Units of activity are expressed as the reciprocal of the dilution of each test sample giving 50% lysis in samples that were adjusted to the same initial optical density. As Tables 7 and 8 below indicate both phenylethyl alcohol and 4-hydroxybenzoic acid methyl ester significantly reduced production of the alpha toxin. Table 7
  • Tube #1 contained 0 mM of Glucopon and 0.5% phenylethyl alcohol (vol/vol) in 10 mL of growth medium (as prepared in Example 1 ).
  • Each of tubes #1-#20 contained a unique combination of Glucopon and phenylethyl alcohol. These combinations were tested and evaluated as in Example 1. The effect of the test compounds on the growth of S. aureus and on the production of TSST-1 is shown in Table 9 below.
  • EXAMPLE 10 In this Example, the effect of Cetiol in combination with para-aminobenzoic acid was evaluated utilizing a checkerboard experimental design. This allowed the evaluation of the interaction of two test compounds on the growth of S. aureus and the production of TSST-1.
  • Tube #1 contained 0 % of para-aminobenzoic acid and 0 mM Cetiol (vol/vol) in 10 mL of growth medium (as prepared in Example 1 ).
  • Each of tubes #1-#20 contained a unique combination of Cetiol and para-aminobenzoic acid. These combinations were tested and evaluated as in Example 1. The effect of the test compounds on the growth of S. aureus and on the production of TSST-1 is shown in Table 10 below.

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Abstract

L'invention concerne des articles absorbants et non absorbants. Ces articles comprennent une quantité efficace d'un composé aromatique inhibiteur destiné à inhiber sensiblement la production d'exotoxines par des bactéries gram positif. Les composés aromatiques inhibiteurs de la présente invention sont représentés par la formule générale (I), dans laquelle R1 est sélectionné dans le groupe composé de H, (a), -OR5, -R6C(O)H, -R6OH, -R6COOH, -OR6OH, -OR6COOH, -C(O)NH2, et NH2 et les sels de ceux-ci; R5 est un fragment hydrocarbyle aliphatique monovalent saturé ou non saturé; R6 est un fragment hydrocarbyle aliphatique divalent saturé ou non saturé; R7 est un fragment hydrocarbyle aliphatique trivalent saturé ou non saturé; R8 est un fragment hydrocarbyle aliphatique monovalent saturé ou non saturé substitué ou non substitué pouvant ou ne pouvant pas être interrompu par des hétéroatomes; R2, R3 et R4 sont indépendamment sélectionnés dans le groupe composé de H, OH, COOH, et -C(O)R9; et R9 est hydrogène ou un fragment hydrocarbyle aliphatique monovalent saturé ou non saturé.
EP02773321A 2001-10-02 2002-09-09 Inhibition de la production d'exoproteines a l'aide de compositions aromatiques Withdrawn EP1432459A1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US969391 2001-10-02
US09/969,299 US20030135173A1 (en) 2001-10-02 2001-10-02 Inhibition of exoprotein production in absorbent articles using aromatic compositions
US09/969,218 US7026354B2 (en) 2001-10-02 2001-10-02 Aromatic compositions for the inhibition of exoprotein production from gram positive bacteria
US969299 2001-10-02
US969218 2001-10-02
US09/969,391 US7022333B2 (en) 2001-10-02 2001-10-02 Inhibition of exoprotein production in non-absorbent articles uisng aromatic compositions
PCT/US2002/028756 WO2003030953A1 (fr) 2001-10-02 2002-09-09 Inhibition de la production d'exoproteines a l'aide de compositions aromatiques

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BR (1) BR0212679A (fr)
CA (1) CA2461291A1 (fr)
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WO2018064978A1 (fr) * 2016-10-09 2018-04-12 曾忠铭 Utilisation d'une formule renfermant un agent bactériostatique pour la préparation d'un composé à application vaginale et ledit composé

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AU2002336472B2 (en) 2007-08-23
KR20040044950A (ko) 2004-05-31
JP2005523239A (ja) 2005-08-04
WO2003030953A1 (fr) 2003-04-17
AR037505A1 (es) 2004-11-17
CA2461291A1 (fr) 2003-04-17
BR0212679A (pt) 2005-04-12
MXPA04002474A (es) 2004-05-31
KR100918887B1 (ko) 2009-09-23

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