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WO2006038980A2 - Articles non absorbants et absorbants inhibant la production d'exoproteines - Google Patents

Articles non absorbants et absorbants inhibant la production d'exoproteines Download PDF

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Publication number
WO2006038980A2
WO2006038980A2 PCT/US2005/028366 US2005028366W WO2006038980A2 WO 2006038980 A2 WO2006038980 A2 WO 2006038980A2 US 2005028366 W US2005028366 W US 2005028366W WO 2006038980 A2 WO2006038980 A2 WO 2006038980A2
Authority
WO
WIPO (PCT)
Prior art keywords
absorbent
group
tampon
set forth
benzyl
Prior art date
Application number
PCT/US2005/028366
Other languages
English (en)
Other versions
WO2006038980A3 (fr
Inventor
Rae Ellen Syverson
Kristin A. Goerg-Wood
Daniel J. Devine
Original Assignee
Kimberly-Clark Worldwide, Inc.
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 US10/955,821 external-priority patent/US20060067990A1/en
Priority claimed from US10/955,858 external-priority patent/US20060067991A1/en
Application filed by Kimberly-Clark Worldwide, Inc. filed Critical Kimberly-Clark Worldwide, Inc.
Priority to JP2007534582A priority Critical patent/JP2008514698A/ja
Priority to AU2005292655A priority patent/AU2005292655A1/en
Priority to EP05785615A priority patent/EP1793871A2/fr
Priority to BRPI0515949-0A priority patent/BRPI0515949A/pt
Publication of WO2006038980A2 publication Critical patent/WO2006038980A2/fr
Publication of WO2006038980A3 publication Critical patent/WO2006038980A3/fr
Priority to IL181198A priority patent/IL181198A0/en

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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
    • 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
    • A61L15/20—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing organic materials
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61L2300/21—Acids
    • A61L2300/214—Amino acids
    • 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
    • A61L2300/432—Inhibitors, antagonists
    • 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
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation

Definitions

  • the present invention relates to the inhibition of exoprotein production in and around a woman's vagina in association with a non-absorbent or an absorbent article. More particularly, the present invention relates to the incorporation of a precursor compound into or onto a non- absorbent or an absorbent article such that upon use, the precursor compound can be hydrolyzed by enzymatic activity in and around the vagina to produce an active species that reduces the production of exoproteins from bacteria.
  • Disposable absorbent articles such as vaginal tampons, for the absorption of vaginal exudates are widely used. These disposable articles 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 vaginal tampon, the device is intended to be inserted into the vagina for absorption of the body fluids generally discharged during a woman's menstrual period.
  • yeast Candida albicans
  • protozoa Trichomonas vaginalis
  • mycoplasma Mycoplasma hominis
  • chlamydia Chlamydia trachomatis
  • viruses Herpes simplex
  • Physiological, social, and idiosyncratic factors aff:ect the quantity and species of bacteria present in the vagina.
  • Physiological factors include age, day of the menstrual cycle, and pregnancy.
  • microorganisms present in the vagina throughout the menstrual cycle can include lactobacilli, corynebacterium, ureaplasma, and mycoplasma. The number of microorganisms and the types of microorganisms are unique to an individual.
  • Social and id ⁇ osyncratic factors include method of birth control, sexual practices, systemic disease (e.g., diabetes), and mecLications.
  • Bacterial proteins and metabolic products produced in the vagina can affect other microorganisms and the human host.
  • the vagina between menstrual peuriods 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. 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 lcxw pH is a consequence of the growth of lactobacilli and tlxeir production of acidic products.
  • Microorganisms in the va-gina can also produce antimicrobial compounds such as hydrogen peroxide and bactericides directed at other W
  • lactocins bacteriocin-l ⁇ ke products of lactobacilli directed against other species of lactobacilli.
  • TSST-I Toxic Shock Syndrome Toxin-1
  • enzymes such as esterase and amidase
  • S. aureus is found in the vagina of approximately 16% of healthy women of menstrual age. Not all strains of S. aureus can produce TSST-I. Approximately 25% of these women will harbor TSST-I producing S. aureus. TSST- 1 and some of the Staphylococcal enterotoxins have been identified as causing TSS in humans.
  • Symptoms of TSS generally include fever, diarrhea, vomiting and a rash followed by a rapid drop in blood pressur-e. Multiple organ failure occurs in approximately" 6% of those who develop the disease.
  • S. aureus does not initiate TSS as a result of the invasion of the microorganism into the vaginal cavity. As S. aureus grows and multiplies, it can produce TSST-I. Only after entering the bloodstream does TSST-I act systemically and produce the symptoms attributed to TSS.
  • 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 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 ecosystem.
  • antibiotics that kill S. aureus axe 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 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).
  • inhibitory compounds that will effectively inhibit the production oJE exoproteins, such as TSST-I, from Gram positive bacteria without being substantially harmful to the natural flora 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 throughout manufacturing, storage, and transportation in order to deliver an effective inhibitor to the consumer.
  • the present invention is directed to non- absorbent products and absorbent articles that inhibit the production of exoprotein from Gram positive bacteria. More specifically, the present invention is directed to a vaginal tampon or a non-absorbent substrate, such as a tampon applicator, incorporating one or more precursor compounds that are formed by linking one or more aromatic compounds to one or more secondary compounds via 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 an active species that can inhibit the production of exoproteins from Gram positive bacteria without substantially affecting the flora prresent in the vagina.
  • the precursor compound itself may also inhibit the production of exoproteins from Gram positive bacteria.
  • the present invention is directed to an exoprotein inhibitor for inhibiting the production of exoproteins from Gram positive bacteria.
  • the e ⁇ :oprotein inhibitor comprises a non-absorbent substrate suitable for insertion into the vagina and having deposited thereon an effective amount of a precursor compound having the general formula:
  • R 1 is selected from the group consisting of O
  • R 7 is _ 0CH2 _.
  • x is 0 or 1 /
  • R 5 is a substituted or unsubstituted aromatic ring or a monovalent saturated or unsaturated, substituted or unsubstituted, branched or straight chain hydrocarbyl moiety tl ⁇ at may or may not be substituted with heteroatoms;
  • R 6 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;
  • R 2 , R 3 , and R 4 are independently selected from the group consistirx ⁇ g of H, OH, COOH, wherein upon hydrolysis the precursor compound is capable of producing an active species effective in inhibiting the production of exoprotein from Gr ⁇ am positive bacteria.
  • the present invention is further directed to a tampon applicator for inhibiting the production, of exoprotein from Gram positive bacteria.
  • the tampon 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:
  • R 1 is selected from the group consisting of O
  • R 7 is _ 0C H 2 _.
  • x is o or 1
  • R 5 is 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 heteroatoms,- R ⁇ is selected from ttie group consisting of an amino acid, a methyl ester of an amino acid, and an ethyl ester of an amino acid
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of H, OH, COOH, wherein upon hydrolysis the precursor compound is capable of producing an active species effective in inhibiting the production of exoprotein from Gram positive; bacteria.
  • the present invention is further directed to a. douche formulation for inhibiting the production of exoprotein from Gram positive bacteria located in and around a woman's vagina.
  • the douche formulation comprises a vagi_nal cleansing formulation comprising a pharmaceutically acceptable carrier and an effective amount of a precursor compound having the general formula:
  • R 1 is selected from the group consisting of O
  • R 7 is _ocH 2 - ;
  • X is 0 or 1 ;
  • R 5 is 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 heteroatoms;
  • R 6 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;
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of H, OH, COOH, wherein upon hydrolysis the precursor compound is capable of producing an active species effective in inhibiting the production of exoprotein from Gram positive bacteria, and wherein 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:
  • R 1 is selected from the group consisting of O O
  • R 7 is _ 0C H 2 _.
  • x is 0 or 1 ;
  • R 5 is 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;
  • R 6 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;
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of H, OH, COOH, wherein upon hydrolysis the precursor compound is capable of producing an active species effective in inhibiting the production of exoprotein from Gram positive bacteria.
  • the present invention is further directed to a vaginal tampon for inhibiting the production of exoprotein from Gram positive bacteria.
  • the vaginal tampon comprises an absorbent tampon material and an effective amount of a precursor compound having the general formula:
  • R 1 is selected from the group consisting of O O
  • R 7 is _ 0CH2 _.
  • x is 0 or 1 ;
  • R 5 is 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;
  • R s 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;
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of H, OH, COOH, wherein upon hydrolysis the precursor compound is capable of producing an active species effective in inhibiting the production of exoprotein from Gram positive bacteria.
  • the present invention is generally directed to non-absorbent or absorbent articles comprising a precursor compound that upon hydrolysis produces an active species capable of inhibiting the production of exoproteins from Gram positive bacteria.
  • 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 bond that can be readily hydrolyzed by enzymatic action once inside of the vagina to produce an active species and a second compound.
  • the active species have been found to substantially inhibit the production of exoproteins, such as TSST-I, from Gram positive bacteria.
  • the precursor compound itself may also inhibit the production of exoproteins from Gram positive bacteria.
  • the precursor compounds can be used in combination with surface- active agents such as, for example, myreth-3 myristate, glycerol monolaurate, and/or laureth-4, to substantially inhibit the production of exoproteins from Gram positive bacteria.
  • 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 constructing the non-absorbent articles of the present invention include, for example, rubber, plastic, and cardboard.
  • a tampon applicator typically includes an outer tube, which is preferably in the form of a hollow tube.
  • the tube is formed from paper, paperboard, cardboard, plastic, thermoplastic film, aqueous coating or a combination thereof. If paper, paperboard or cardboard is used, it can be coated with a wax or water-insoluble polymer to render it water- resistant. Suitable plastic materials include polyolefins, such as low density polyethylene and low density polypropylene.
  • the outer tube should have sufficient strength and rigidity to prevent collapse under normal vaginal pressures.
  • the outer tube can also be formed into a cylindrical shape having a longitudinal seam or be spirally or convolutely wound.
  • the outer tube has a relatively small diameter of about 10 mm to about 20 mm.
  • the outer tube has first and second spaced apart ends.
  • the outer tube is formed from at least two distinct layers, which may be constructed of equal or different board weight.
  • the layers can be made from different materials, for example, paperboard and film, or be made from similar material having different properties, for example, different board weight.
  • the exterior layer can be formed from a thin coated paperboard of about 0.06 mm or from a film material having a thickness of about 0.01 mm while one or more inner layers can be formed from a non-coated material having a higher board weight .
  • the exterior layer can consist of a high gloss, coated paper, which is water-degradable or water-dispersible. Alternatively, the exterior layer could 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 exterior layer can also be lubricated or contain an additive. Suitable lubricants and additives include any of the pharmaceutically accepted lubricants or additives conventionally used in tampon applicators. Such lubricants and additives include organic compounds, long chain aliphatic groups, such as derivatives of fatty acids, for example, stearamides and oleamides.
  • Paper used in the construction of the tampon applicator should have a board weight per layer of from between about 20 pounds to about 200 pounds per ream, suitably, between about 25 pounds to about 100 pounds per ream, and more suitably, from about 30 pounds to about 50 pounds per ream.
  • a "ream” is defined as material having dimensions of 24 inches (609.6 mm) by 36 inches (914.4 mm) by 500 sheets.
  • Each paperboard layer should have a thickness of less than about 0.4 mm, suitably, from about 0.04 mm to about 0.2 mm, and more suitably, from about 0.05 mm to about 0.16 mm.
  • the exterior layer will be thinner than the interior paperboard layer(s) .
  • one of the layers is made from a thermoplastic film, it can be polyethylene.
  • a suitable polyethylene film has high slip characteristics and a low dens ⁇ ty.
  • the thermoplastic film should be thin, less than about 0.1 mm, suitably about 0.010 mm to about 0.050 mm, and more suitably about 0.012 mm to about 0.040 mm. Other kinds of f ⁇ lms 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 films of methyl cellulose; flexible, highly plasticized cellulose acetate, formate and similar other alkyIL esters; vinyl vinylidene chloride or rubber hydrochloride, as for example, Pliofilm.TM. , or vinylite resin.
  • thermoplastic film can be clear or opaque.
  • the film may run the entire length of the outer tube or only extend along a portion thereof.
  • the film can be on the extezrior surface of the outer tube or be one of the inner 1aye-trs.
  • the layers of the outer tube can be held together by an adhesive, such as glue, or by heat, pressure, ultrasonics, etc.
  • the adhesive can be either water-soluble or water-insoluble. A water-soluble adhesive is preferred for environmental reasons in that the outer tube will quickly break apart when it is immersed in water. Such immersion will occur should the outer tube be disposed of by flushing it down a toilet.
  • the outer tube is sized and configured to house an absorbent catamenial tampon.
  • the inside diameter of the outer tube is sized to accommodate typical size tampons. Usually, the inside diameter of the outer tube is less than about 0.75 inches (about 19 mm) and more suitably, less than about 0.625 inch.es (about 16 mm) . Although the exterior diameter of tampons does vary, most tampons utilized by women have an external diameter of less than about 0.75 inches (about 19 mm) .
  • the outer tube should have a substantially smooth exterior surface, which will facilitate insertion of the tampon applicator into a woman's vagina.
  • the outer tube can be coated to give it a high slip characteristic. Wax, polyethylene, a combination of wax and polyethylene, cellophane and clay are representative coatings that can be appLied to the exterior layer to facilitate comfortable insertion.
  • the outer tube can be a straight, elongated cylindrical tube formed on a central longitudinal axis. It is also possible to form the outer tube into an arcuate shape.
  • the arcuate or curved shape can assist in providing comfozrt when inserting the outer tube into a woman's vagina.
  • a curved tampon applicator it is possible to empLoy a curved tampon which again may be more comfortable for some women to use since the shape of the tampon may better fit the curvature of a woman's vagina.
  • an insertion tip Integrally formed on the first end of the outer tube and extend ⁇ ng outwardly therefrom is an insertion tip.
  • the insertion tip is designed to facilitate insertion of the outer tube into a woman's vagina in a comfortable manner.
  • the insertion tip sriould be made of a thin, flexible material or membrane, which resists rapid absorption of vaginal fluid during the period of insertion of the tampon applicator into the woman's vagina.
  • the insertion tip can be constructed of paper, paperboard or film material.
  • the insertion tip should be formed out of the layer having the lower board weight .
  • the lower board weight layer is normally the thinner layer.
  • a film material is preferred because it is thin, soft and flexible.
  • Suitable materials for the insertion tip include a thin bonded nonwoven fabric layer coated, with low density polyethylene, plasticized polyvinyl chloride or polyurethane.
  • the insertion tip can also contain a coating or impregnation, which inhibits any substantial absorption of vaginal fluids.
  • the coating may be an oil, a wa ⁇ c, or an acceptable organic compound.
  • 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 polyeth/yleneoxide (PEO) .
  • PTFE polytetrafluoroethylene
  • FEP fluorinated ethylene- propylene
  • PEO polyeth/yleneoxide
  • the insertion tip should have an outside diameter, which is approximately equal to or less than the outside diameter of the outer tube. It should be noticed that when the diameter is less than that of the outer tube, the difference should be small so that the end of the exterior layer cannot be felt by the woman during insertion. Generally, the insertion tip has a diameter that is less than the diameter of the outer tube.
  • the insertion tip can be configured to be rounded, semi-spherical or frusto-conical . Other nose or dome-like shapes can also be utilized. The rounded configuration of tlxe insertion tip functions to prevent the forward end of the tampon from exerting an abrasive action upon the wall of the vagina as would be the case if it was uncovered.
  • the insertion tip is formed from at least one of the layers, which form the outer tube and can be formed from more than one layer if desired, provided it has less thickness.
  • the insertion tip can be formed from at least one less layer than the number of layers from which the outer tube is constructed.
  • the insertion tip has a thickness that is less than the thickness of the outer tube so as to assure 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 haxre a plurality of soft and flexible petals, which are arranged to form a dome-shaped nose.
  • the petals are separated by nar-row slots.
  • the petals are capable of radially flexing or bending outward to provide an enlarged opening through which the tampon can exit when it is pushed forward by the inner tube.
  • Either an even or an odd number of petals can be used but preferably, there are an odd number of petals, such as 3, 5, 7, etc. because an odd number of petals will prevent the outer tube from collapsing or flattening after the tampon has been expelled.
  • the insertion tip will contain five petals, each having an elongated, approximately truncated shape with a rounded end and each being about 7/16 of an inch (about I-L.1 mm) in length.
  • the tampon applicator includes an inner tube.
  • the inner tube like the outer tube, can be a spirally wound, convolutely wound or longitudinally seamed, hollow tube constructed from paper, paperboard, cardboard, plastic, film, aqueous coating or a combination thiereof.
  • the inner tube can also be formed into a hollow tube by overlapping the material upon itself.
  • the inner tube can be constructed of the same material as the outer tube or it can be made out of a different material.
  • the inner tube could be constructed as a laminate having two or more plies which are then spirally wound, convolutely wound or longitudinally seamed into a cylindrical tube.
  • Either a wound tube or a longitudinally seamed tube is preferred because the finished tube will have a wall with a constant th ⁇ ckness.
  • some manufacturers may prefer to construct the inner tube as a solid stick or use some other unique shape.
  • the inner tube also has a distal or free end onto which the user's forefinger can rest for facilitating movement of the inner tube into the outer tube. The distal end thereby functions as a seat for the forefinger. It is also possible to form an enlarged ring or flange on the distal end of the inner tube to provide for a larger contact surface.
  • the inner tube functions by telescoplcally moving into the outer tube. As the inner tube is pushed into the outer tube, the tampon is forced forward against the insertion tip. The contact by the tampon causes the petals to radially open to a diameter, which is sufficient to allow the tampon to be expelled from the outer tube. With tlie tampon properly positioned in the woman's vagina, the tampon applicator is withdrawn and discarded.
  • the weight of a tampon applicator wiLl depend on the size and absorbency of the tampon. For example, a longer, more absorbent tampon will be heavier than a shorter, less absorbent tampon. Typically, an applicator suitable for use in the present invention with a regular absorlbency tampon will weigh about 3.62 grams; an applicator suitable for use with a super absorbency or super plus absorbency tampon will weigh about 4.12 grams.
  • non-absorbent incontinent devices include, for example, non-absorbent incontinent devices, non-absorbent contraceptive devices, such as barrier birth control devices, and douches.
  • non-absorbent incontinent device refers to a device designed to be inserted into a woman's vagina and expanded so as to relieve or eliminate the involuntary passage of urine through the uretha from the bladder. The expansion of the non-absorbent urinary incontinent device provides a stable backdrop to the musculature and body tissue located near the urethro-vaginal myofascial area and causes the urethra to be compressed upon itself during episodes of increased intra ⁇ abdominal pressure.
  • Suitable non-absorbent contraceptive devices such as barrier birth control devices, for the present invention are known in the art.
  • U.S. Patent No. 4,711,235 issued to Willis discloses a device comprising a ring having a central sheet of resilient impermeable material sandwiched between two layers of foam rubber.
  • the foam rubber traps sperm and bacteria in a vaginal recess for a time sufficient to be destroyed by the normal acid pH of the vaginal secretions.
  • the ring defines the sheet material into a cup-shape with four sides, one pazLr of opposing sides including a wire core inwardly bent and another pair of sides with one outwardly rounded and the other having a fork configuration.
  • the resilient impermeabl_e material is typically a neoprene non-absorbent rubber material.
  • This invention also relates to absorbent articles, and will also be described herein in detail in connection with a vaginal tampon, but will be understood by persons 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 tampons such as those intended for medical, dental, surgical, and/or nasal use wherein the inhibition of exoproteins from Gram positive bacteria would be beneficial.
  • the phrase "absorbent tampon” generally refers to vaginal tampons, medical tampons, dental tampons, surgical tampons, and nasal tampons.
  • the phrase “absorbent article” generally refers to devices, which absorb and contain body fluids, and more specifically, refers to devices that are placed against or near the skin, or inside of a 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 laundered or otherwise restored or reused as an absorbent article after a single use.
  • 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 use; personal care absorbent products such as feminine hygiene products (e.g., sanitary napkins, panty liners, and vaginal tampons) , diapers, training pants, incontinence products and the like, wherein the inhibition of the production of exoproteins from Gram positive bacteria would be beneficial.
  • Vaginal tampons 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 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.
  • Vaginal 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 generally preferred.
  • the tampon may be made of various fiber blends including both absorbent and nonabsorbent fibers, which may or may not be enclosed in a cover or wrapper.
  • the cover or wrapper can be formed from a nonwoven material such as a polyolefin, particularly polypropylene or polyethylene.
  • a suitable material is a spunbond material.
  • the cover or wrapper is beneficial in assuring that the fibers of the tampon do not directly contact the inner walls of a woman's vagina. This assures that no fibers will be left behind in the vagina after the tampon has been removed.
  • the cover can be tucked into distally spaced ends of the tampon so as to completely surround and enclose the fibers.
  • the cover or wrapper can also be constructed from a heat-sealable material to assist in bonding it to the fibers, such as by heat and/or pressure. Suitable methods and materials for the production of tampons are well known to those skilled in the art.
  • a suitable tampon for use in the present invention has a cover or wrapper.
  • the weight of the tampon having a cover or wrapper will depend upon the level of absorbency of the tampon. For example, a more absorbent tampon will be heavier than a less absorbent tampon.
  • a regular absorbency tampon with a cover or wrapper will weigh from about 1.77 grams to about 2.67 grams, suitably about 2.22 grams; a super absorbency tampon with a cover or wrapper will weigh from about 2.67 grams to about 3.57 grams, suitably about 3.12 grams; a super plus absorbency tampon with a cover or wrapper will weigh from about 3.67 grams to about 4.97 grams, suitably about 4.32 grams.
  • Tampons come in a variety of sizes.
  • a tampon for use in the present invention does not have a cover or wrapper.
  • a regular absorbency tampon without a cover or wrapper 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 tampon without a cover or wrapper will weigh from about 2.49 grams to about 3.39 grams, suitably about 2.94 grams;
  • a super plus absorbency tampon without a cover or wrapper will weigh from about 3.49 grams to about 4.79 grams, suitably about 4.14 grams.
  • the non-absorbent and absorbent articles of the present invention comprise an effective amount of a precursor compound that, upon hydrolysis, produces an active species that can substantially inhibit the production of exoprotein by Gram positive bacterium and, specifically, the production of TSST-I from S. aureus bacterium.
  • the term "precursor compound” means a compound that is introduced into and/or onto a non- absorbent or an absorbent article that is capable of undergoing hydrolysis inside and/or adjacent to the vagina to produce an active species capable of inhibiting the production of exoproteins from 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 exoprotein production from Gram positive bacteria.
  • enzymes such as lipase, esterase, and/or amidase
  • the hydrolysis reaction produces a second compound that is not critical to the function of the active species.
  • the second compound will be identical or similar to compounds naturally occurring in the human body.
  • the precursor compound should be designed such that upon hydrolysis the formed second compound is not substantially harmful to the vagina or the bacteria located therein.
  • 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 exoproteins from Gram positive bacteria. This property is advantageous as it allows for long-lasting continuous inhibition of exoprotein production by Gram positive bacteria.
  • the precursor compounds of the present invention can inhibit the production of exoproteins prior to hydrolysis; and then, as the precursor compounds are hydrolyzed, the active species are produced, which can further inhibit exoprotein production.
  • the precursor compounds described herein and suitable for introduction into and/or onto a non-absorbent or an absorbent article are both substantially stable in and/or on the non-absorbent or the absorbent article both throughout the manufacturing processes and during shelf storage. Stated another way, the precursor compounds are not easily- volatilized off of or out of the non-absorbent or the absorbent article during high temperature manufacturing processes or during shipment and storage. This property of the precursor compounds is highly desirable as it is important for the precursor compound to remain in or on the non-absorbent or the absorbent article product in an effective amount for ultimate use by the consumer. As noted above, volatility of active compounds from non-absorbent or absorbent articles have been problematic in the past and can result in a non-absorbent product or an absorbent article devoid of active compound.
  • the precursor compounds of the present invention may remain in or on the non-absorbent or the absorbent articles in an increased amount as compared to prior ingredients due to their increased molecular weight.
  • the precursor compounds of the present invention have a generally higher molecular weight as compared to some active ingredients utilized 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 the production of exoprotein by Gram positive bacteria.
  • the precursor compounds described herein, along with the hydrolyzed active species and second compounds produced in the body do not kill a substantial amount of naturally occurring bacteria found in the vagina. This property is significant as the complete, or substantially complete, non-specific killing of bacteria located in and around the vagina can be very harmful for the host as natural flora are ⁇ required to maintain a healthy vagina.
  • the precursor compounds and hydrolyzed compounds produced in and around the vaginal cavity do not have a substantial killing effect on bacteria at the concentration incorporated into the product; fcmt the active species produced by hydrolysis can substantially inhibit the production of exotoxins from Gram positive bacteria.
  • the precursor compounds have the general chemical structure:
  • R 1 is -[R] x CH 2 OCR .
  • R 5 is 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 rxot be substituted with heteroatoms,- and
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of H, OH, COOH.
  • hydrocarbyl moieties described herein include both straight chain and branched chain hydrocarbyl moieties that 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 atoms. Hetero atoms that can interrupt tlie hydrocarbyl moiety include, for example, oxygen, nitirogen, and sulfur.
  • R 5 is a monovalent saturated, substituted or unsubstituted, branched or straight chain hydrocarbyl moiety having from 1 to 15 carbon atoms, more suitably from 1 to 12 carbon atoms.
  • enzymes such as esterase produced by bacteria such as S. aureus found in the vaginal flora along with enzymes naturally occurring in the menstrual fluid, can hydrolyze the precursor compounds described herein to produce an active species and a second compound.
  • the enzyme esterase can react with the ester linkage of the precursor compounds described above to form the active species benzyl alcohol a.nd a hydrocarbon.
  • Benzyl alcohol has been found to substantially inhibit exoproteins from Gram positive bacteria without substantially eliminating the bacteria .
  • the precursor compounds have the general chemical structure :
  • R is ' ⁇ ;
  • 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;
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of H, OH, COOH.
  • Amino acids are organic compounds containing an amino group and a carboxylic acid group.
  • Suitable amino acids that can be used for R 6 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, le-ucine, cysteine, and combinations thereof.
  • enzymes such as amidase produced by bacteria such as S. aureus found, in the vaginal flora along with enzymes naturally occurring in the menstrual fluid can hydrolyze the precursor compounds containing the amino acid.
  • the enzyme amidase can react with the precursor compound and break the amide bonds of the compounds in this embodiment to release benzoic acid and an amino acid.
  • benzoic acid has been found to substantially inhibit exoproteins from Gram positive bacteria without substantially eliminating the naturally occurring flora.
  • the non-absorbent or the absorbent article comprises an effective amount of the precursor compound such that upon hydrolysis of the precursor compound, there is a sufficient amount of active agent produced to substantially inhibit the formation of exoproteins such as TSST-I when the non-absorbent or the absorbent article is exposed to S. aureus bacteria.
  • active agent produced to substantially inhibit the formation of exoproteins such as TSST-I when the non-absorbent or the absorbent article is exposed to S. aureus bacteria.
  • Several methods are known in the art for testing the effectiveness of potential inhibitory agents, such as benzyl alcohol-oar benzoic acid on the inhibition of the production of TSST-I in the presence of S. aureus.
  • One such preferred method is set forth in Example 1.
  • the active species produced from the hydrolysis of the precursor compouncd reduces the formation of TSST-I by 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 precursor compound may also inhibit the production of exoproteins from 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.
  • the precursor compound may reduce the formation of TSST-I by at least about 50%, preferably at least about 80%.
  • the non-absorbent or the absorbent products comprise a suitable amount of precursor compound such that, upon use, the precursor compound and/or the active species produced therefrom in or around the vagina as discussed herein can substantially inhibit the production of exoprotein from Gram positive bacteria.
  • 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) precursor compound
  • absorbent articles will comprise from about 0.15% (by weight of the absorbent structure) to about 2.0% (by weight of the absorbent structure) precursor compound.
  • 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) precursor compound, and the absorbent products will comprise from about 0.17% (by weight of the absorbent structure) to about 1.7% (by weight of the absorbent structure) precursor compound.
  • a tampon applicator as described herein comprises a suitable amount of precursor compound such that, upon use, the precursor compound and/or the active species produced therefrom in or around the vagina as discussed herein can substantially inhibit the production of exoprotein from Gram positive bacteria.
  • the tampon 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) precursor compound.
  • the tampon 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) precursor compound.
  • a vaginal tampon as described herein without a cover or wrapper material comprises a suitable amount of precursor compound such that, upon use, the precursor compound and/or the active species produced therefrom in or around the vagina as discussed herein can substantially inhibit the production of exoprotein from Gram positive bacteria.
  • the vaginal tampon without a cover or wrapper will comprise from about 0.15% (by weight of the absorbent tampon material) to about 2.0% (by weight of the absorbent tampon material) precursor compound.
  • the vaginal tampon will comprise from about 0.17% (by weight of the absorbent tampon material) to about 1.7% (by weight of the absorbent tampon material) precursor compound.
  • a vaginal tampon as described herein having a cover or wrapper material that comprises a suitable amount of precursor compound such that, upon use, the precursor compound and/or the active species produced therefrom in or around the vagina as discussed herein can substantially inhibit the production of exoprotein from Gram positive bacteria.
  • the precursor compound is introduced directly into or onto the cover or wrapper material as opposed to being introduced into or onto the absorbent substrate of the vaginal tampon.
  • the cover or wrapper material of the vaginal tampon will comprise from about 2.6% (by weight of the cover or wrapper material) to about 35.0% (by weight of the cover or wrapper material) precursor compound. More desirably, the cover or wrapper material of the vaginal tampon will comprise from about 2.95% (by weight of the cover or wrapper material) to about 29.5% (by weight of the cover or wrapper material) precursor compound.
  • 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 surface- active agents to further reduce the production of exoproteins such as TSST-I without significantly eliminating the beneficial bacterial flora.
  • the surface-active agents used in combination with the precursor compounds may also act as lubricants and/or emollients to further improve product performance. When used in combination with a vaginal tampon, the surface-active agents can further aid in the removal of a "dry tampon" .
  • a suitable surface-active agent is myreth-3-myristate, which is commercially sold as CETIOL 1414 by Kraft Chemical Corp. (Melrose Park, Illinois) .
  • Other suitable surface-active agents for the present invention include, for example, glycerol monolaurate and laureth-4.
  • the non-absorbent or the absorbent products can comprise a suitable amount of surface-active agents such that, upon use, the surface-active agents can further inhibit the production of exoprotein from Gram positive bacteria.
  • 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) surface-active agent.
  • the non-absorbent product is a tampon applicator comprising about 0.75% (by weight of the non-absorbent substrate) surface-active agent.
  • 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) surface-active agent.
  • the absorbent product is a vaginal tampon having a cover and will comprise about 0.75% (by weight of the total tampon including a cover) surface-active agent.
  • the surface-active ingredient can be introduced directly into or onto the cover or wrapper material as opposed to being introduced into or onto the absorbent substrate of the vaginal tampon.
  • the cover or wrapper material of the vaginal tampon will comprise about 13% (by weight of the cover material) surface-active agent.
  • the precursor compounds described herein can be introduced into and/or onto the non- absorbent or the absorbent product in combination with one or more secondary agents to further reduce the production of exoproteins such as TSST-I without significantly eliminating the beneficial bacterial flora.
  • secondary agents useful in the present invention include agents selected from the group consisting of: compounds with an ether, ester, amide, glycosidic, or amine bond linking a C 8 -Ci 8 fatty acid to an aliphatic alcohol.
  • the precursor compound described herein can be used in combination with ester compounds having the general formula:
  • R 27 is a straight or branched alkyl or straight or branched alkenyl having from 8 to about 18 carbon atoms and R 28 is selected from the group consisting of an alcohol, a polyhydric alcohol, and an ethoxylated alcohol.
  • polyhydric refers to the presence in a chemical compound of at least two hydroxyl (OH) groups. Suitable compounds include glyceryl monolaurate, glyceryl dilaurate, myreth-3-myristate, and mixtures thereof.
  • the precursor compound described herein can be used in combination with ether compounds having the general formula:
  • R 10 is a straight or branched alkyl or straight or branched alkenyl having from 8 to about 18 carbon atoms and R 11 is selected from the group consisting of an alcohol, an ethoxylated alcohol, a polyalkoxylated sulfate salt and a polyalkoxylated sulfosuccinate salt.
  • Suitable compounds 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) sorbital ether.
  • 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:
  • Z is a saccharide 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.
  • Glucopon 220, 225, 425, 600, and 625 are suitable alkyl polyglycosides for use in combination with the precursor compounds of the present invention.
  • the precursor compounds described herein can be used in combination with an amide containing compound having the general formula: O R 17 CN R18
  • R 17 inclusive of the carbonyl carbon, is an alkyl group having 8 to 18 carbon atoms
  • 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 .
  • Preferred amide compounds for use in combination with the precursor compounds described herein include sodium lauryl sarcosinate, lauramide monoethanolamide, lauramide diethanolamide, lauramidopropyl ditnethylamine, disodium lauramido monoethanolamide sulfosuccinate, and disodium lauroamphodiacetate.
  • precursor 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.
  • Preferred amine compounds for use with the precursor compounds described herein include triethanolamide laureth sulfate, lauramine, lauramino propionic acid, sodium lauriminodipropionic acid, lauryl hydroxyethyl imidazoline, and tnixttires thereof.
  • 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 8 to about 18 carbon atoms and 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 2 ⁇ can be saturated or unsaturated.
  • a preferred compound illustrative of an amine salt is TEA laureth sulfate.
  • Amounts of secondary compounds described herein to be added to the non-absorbent products to further reduce tt ⁇ e production of TSST-I 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) 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) secondary compound.
  • Amounts of secondary compounds described herein to be added to the absorbent articles to further reduce th.e production of TSST-I 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) secondary compound. More sixitably, the absorbent products comprise from about 0.17% (by weight of the absorbent structure) to about 1.7% (by weight of the absorbent structure) secondary compound.
  • the precursor compounds may be applied to the non-absorbent substrate using conventional methods for applying a chemical agent to the desired non-absorbent substrate.
  • non-absorbent articles may be dipped directly into a liquid bath containing the precursor 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 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 ais to facilitate absorption into the absorbent product .
  • the carrier can be capable of co- dissolving or suspending the precursor compound used in the non-absorbent or ttie absorbent article.
  • Carrier materials suitable for use in the instant invention include those well- known for use in trie cosmetic and medical arts as a basis for ointments, lotions, creams, salves, aerosols, suppositories, gels, and the like.
  • one suitable carrier is Cetiol. AdditionaXly, as discussed above, Cetiol can also act as both a lubr ⁇ cant and an emollient.
  • Other suitable carrier materials include water, various alcohols, and other organic solvents.
  • the precursor compounds of this invention can be formulated into a variety of formulations such a.s those in current commercial douche formulations, or in higher viscosity douches.
  • the precursor compounds of the present invention can be incorporated in formulations used to irrigate and cleanse the vagina and prevent vaginal infections.
  • 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 greater viscosity, such as propylene glycol, may be added to the formulations of this indention. Generally, higher viscosity formulations are preferred in order to create formulations that will tend to remain in the vagina for a relatively long time period after administration.
  • the formulation typically contains at least about 0.01% (wt/vol) and desirably at least about 0.4%(wt/vol) precursor compound (based on the total weight of the formulation) .
  • the formulations contain no more than about 0.3%(wt/vol) precursor compound.
  • Particularly suitable formulations 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 millimole/liter to about 15 millimoles/liter of the precursor compound.
  • the precursor compounds of the present invention can be prepar/ed and applied to the absorbent article 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.
  • the precursor compounds may be applied to the absorbent article using conventional methods for applying a chemical agent to the desired absorbent article. For example, unitary tampons without separate wrappers may be sprayed with a solution containing the desired concentration of the precursor compound and them, can be air dried, if necessary, to remove any volatile solvents.
  • the tampon For compressed tampons, it is generally preferable to impregnate the tampon with any chemical compounds before compressing.
  • the precursor 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.
  • the precursor compounds of the present invention may, in some embodiments, be used in combinations with adjunct components conventionally found in pharmaceutical compositions in their art-established fashion and at concentrations that would not alter the normal vaginal flora.
  • the compositi-ons may contain additional compatible pharmaceutically active materials for combination therapy, such as supplementary selective antibacterials, antioxidants, anti-parasitic agents, antipruritics, astringents, local anaesthetics, or anti-inflammatory agents.
  • the precursor compounds can be microencapsulated in a shell-type material that will dissolve, disintegrate, rupture, or otherwise breakdown upon contact with menses or other vaginal secretions to release the component.
  • the encapsulation material retards volatilization of the precursor compound until wetted with a bodily secretion, which results in a release of the precursor compound.
  • Such encapsulation can significantly increase the amount of precursor compound present in the product after manufacturing and storage.
  • Suitable microencapsulated shell materials are known in the art and include cellulose-based polymeric materials (e.g., ethyl cellulose), carbohydrate-based materials (e.g., cationic starches and sugars) and materials derived therefrom (e.g., dextrins and cyclodextrins) as well as other materials compatible with human tissues.
  • cellulose-based polymeric materials e.g., ethyl cellulose
  • carbohydrate-based materials e.g., cationic starches and sugars
  • materials derived therefrom e.g., dextrins and cyclodextrins
  • the microencapsulation shell thickness may vary and is generally manufactured to allow the encapsulated precursor compound to be covered by a thin layer of encapsulation material, which may be a monolayer or thicker laminate layer, or may be a composite layenr.
  • the microencapsulation layer should be thick enough to resist cracking or breaking of the shell during handling or shipping of the product .
  • the microencapsulation layer should be constructed such that humidity from atmospheric conditions during storage, shipment, or wear will not cause a breakdown of the microencapsulation layer and result in a release of the precursor compound.
  • Microencapsulated formulations or components applied directly to the non-absorbent or trie absorbent articles should be of a size such that the user cannot feel the encapsulated shell on the skin or mucosa during use.
  • the capsules typically have a diameter of no more than about 25 micrometers, and desirably no more than about 10 micrometers. At these sizes, there is no "gritty” or "scratchy” feeling when the formulation contacts the skin.
  • 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 wt% (w/v) ) was placed in 10 mL 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 rnL distilled water and sterilizing the broth according to the manufacturer's instructions.
  • BHI brain heart infusion broth
  • the BHI was supplemented with 100 mL fetal bovine serum (FBS) (Sigma Chemica.1 Company, St. Louis, Missouri) .
  • FBS fetal bovine serum
  • Ten mL of a 0.021 M sterile solution of hexahydrate of magnesium chloride was added to the BHI-FBS mixture.
  • Ten mL of a 0.027 M sterile solution of L-glutamine was also added to the BHI-FBS mixture.
  • N-benzoyl-DL- leucine Sigma B-1504
  • N-benzoyl-DL-valine Sigma B- 6500
  • Test compounds were received as solids. The solids were dissolved in BHI prepared as described afoove. The test compounds were added to the growth medium in the amount necessary to obtain the desired final concentration. Cetiol 1414E (myreth-3-myristate) (Kraft Chemical Courp. , Melrose Park, Illinois) was included in the growth medium in some assays at a 10 mM 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 in this example 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 10 mL of growth medium. The tube of inoculated growth medium was incubated at 35 0 C in atmospheric air. After 24 hours of incubation, the culture was removed from the incubator and mixed well on a S/P brand vortex mixer.
  • a second tube containing 10 mL of the growth medium was inoculated with 0.5 mL of the above-described 24 hour old culture and. incubated at 35 0 C in atmospheric air. After 24 hours of incubation 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 s CFU/mL in 10 rnL of growth medium was determined using a previously prepared standard curve.
  • This Example included tubes of girowth. medium with varying concentrations of test compounds, varying concentrations of test compounds and Cetiol 1414E, and tubes of growth medium without test compounds (control ) .
  • Each tube was inoculated with the amount of inoculum deteirmined as described above.
  • the tubes were capped with foa. ⁇ n plugs (IDENTI-PLUG plastic foam plugs, Jaece Industries, purchased from VWR Scientific Products, South Plainfield, New Jersey) .
  • the tubes were incubated at 35 0 C in atmospheric air containing 5% by volume CO 2 . After 24 hours of incixbation the tubes were removed from the incubator, the cultore fluid was assayed for the number of colony forming units of S. aureus, and the culture fluid was prepared for the analysis of TSST-I as described below.
  • the number of colony forming units per mL after incubation was determined using standard plate count procedures.
  • the culture fluid broth was centrifuged at 2500 rpm at 2-10 0 C for 15 minutes and the supernatant was subsequently filter sterilized through a FISHERBRAND 0.45 ⁇ m MCE filter, 0.2 ⁇ M pore size.
  • the resulting fluid was frozen at -70 0 C in a FISHERBRAND 12 x 75 mm polystyrene culture tube (Fisher Scientific, Pittsburgh, Pennsylvania) .
  • TSST-I The amount of TSST-I per mL was determined by a non-competitive, sandwich enzyme-linked immunoabsorbent assay (ELISA) .
  • ELISA sandwich enzyme-linked immunoabsorbent assay
  • the method employed was as follows: four reagents, TSST-I (#TT-606) , rabbit polyclonal anti-TSST-1 IgG
  • LTC-101 rabbit polyclonal anti-TSST-1 IgG conjugated to horseradish peroxidase (#LTC-101) , and normal rabbit serum
  • NBS phosphate buffered saline
  • PBS phosphate buffered saline
  • the PBS was prepared from 0.016 M NaH 2 PO 4 , 0.004 M NaH 2 PO 4 -H 2 O, 0.003 M KCl and 0.137 M NaCl, all available from Sigma Chemical Company (St. Louis, Missouri) .
  • One hundrecl microliters of the polyclonal rabbit anti-TSST-1 IgG solution was pipetted into the inner wells of polystyrene microplates,
  • TSST-I was diluted to 10 ng/mL with phosphate buffered saline (PBS) (pH 7.4) containing 0.05% (vol/vol) Tween-20 (PBS-Tween) (Sigma Chemical Company, St. Louis, Missouri) and 1% (vol/vol) NRS and incubated at 4 0 C overnight. Test samples were combined with 1% NRS (vol/vol) and incubated at 4°C overnight. Samples of the culture fluid and the TSST-I reference standard were assayed in triplicate.
  • PBS phosphate buffered saline
  • the TSST-I reference standard and test samples were then serially diluted 5 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. Samples of the test samples and the TSST-I reference standard were assayed in triplicate. 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 rabbit polyclonal anti-TSST-I IgG conjugated to horseradish peroxidase was diluted according to manufacturer's instructions and 50 microliters was added to each microtiter well, except well A-I, the conjugate control well. The plates were covered and incubated at 35°C for one hour.
  • TSST-I concentrations in 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-I is shown in Table 3 below.
  • the data in Table 3 shows that S. aureus MN8, when compared to the control, produced less TSST-I in the presence of the amino acid containing test compounds. At the concentrations tested, these compounds reduced the amount of toxin produced by 79% to 93%. Also the data shows that S. aureus MN8, when compared to the control, produced less TSST-I in the presence of the 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, although the amount of toxin produced was significantly reduced, there was minimal, if any, effect on the growth of S. aureus.
  • benzyl (s)-(-)- lactate reduced the amount of toxin produced by 97%. Also, the data shows that S. aureus MN8, when compared to the control, produced less TSST-I in the presence of benzyl (s) - (-) -lactate when combined with Cetiol 1414E (myreth-3- myristate) . At the concentration tested, benzyl (s)-(-)- lactate, when combined with Cetiol 1414E, reduced the amount of toxin produced by 99%.
  • tube #1 contained 0.O mM Cetiol 1414E and 0.0% benzyl (s) -(-) -lactate (w/v) in 10 mL of growth medium (as prepared in Example 1) .
  • Each of the tubes #l-#20 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 S. aureus MN8 and on the production of TSST-I is shown in Table 6 below.
  • benzyl laurate reduced the amount of toxin produced by 62% to 91%.
  • benzyl laurate when combined with Cetiol 1414E (myreth-3-myristate) , reduced the amount of toxin produced by 86% to 90%.
  • the pledgets were inoculated with 5 mL of five concentrations (0.0, 0.3%, 0.15%, 0.075%, and 0.03%) of benzyl alcohol dissolved in Brain Heart Infusion Broth (BHI) .
  • BHI Brain Heart Infusion Broth
  • Each pledget was then inoculated with 5.5 mL of an inoculating broth containing 5 X 10 6 + 1 X 10 6 CFU/mL of S. aureus MN8 to achieve a final volume of 10.5 mL.
  • the tubes were capped with foam plugs (IDENTI-PLUG plastic foam plugs, Jaece Industries, purchased from VWR Scientific Products, South Plainfield, New Jersey) and incubated at 37°C for 24 hours.
  • the pledgets were removed from the incubator and individually placed into sterile STOMACHER bags (Seward Ltd. , Norfolk, United Kingdom) , which contained 50 mL sterile BHI .
  • the pledgets and fluid were then stomached or blended in the bags. Aliquots of fluid were removed from the STOMACHER bags and placed into sterile tubes for testing.
  • Plate count samples were prepared by vortexing the sample, withdrawing 5 mL of the sample and placing the 5 mL in a new sterile 50 mL centrifuge tube. The sample was then sonicated using a Virsonic 600 Ultrasonic Cell Disruptor
  • CFU colony forming units
  • the culture fluid broth was centrifuged at 9000 rpm at 4°C for 5 minutes and the supernatant was subsequently filter sterilized through 0.45 ⁇ m MCE filter, 0.2 ⁇ M pore size.
  • the resulting fluid was frozen at -70 0 C in two 1 mL aliquots in 1.5 mL polypropylene screw cap freezer vials.
  • TSST-I The amount of TSST-I per mL was determined by a non-competitive, sandwich enzyme-linked immunoabsorbent assay (ELISA) .
  • ELISA sandwich enzyme-linked immunoabsorbent assay
  • the method employed was as follows: four reagents, TSST-I (#606) , rabbit polyclonal anti-TSST-1 IgG
  • LTC-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, Inc. (Sarasota, Florida) . Sixty-two microliters of #LTI-101 was diluted so that a 1:100 dilution gave an absorbance of 0.4 at 205 nm and subsequently added to 6.5 mL of Na 2 CO 3 buffer, pH 7.2, 0.5 M carbonate buffer, pH 9.6, and 100 ⁇ L of the solution was pipetted into each of the inner wells of the polystyrene microplates (available from Nunc-Denmark, Catalogue Number #439454) . The plates were covered and incubated at 37 0 C overnight.
  • the unbound anti-toxin was removed by four washes in an automatic plate washer with phosphate buffered saline (0.016 M Na 2 HPO 4 , available from Sigma Chemical Co., St. Louis, Missouri) , pH 7.2, and 0.9% (w/v) NaCl (VWR Scientific Products, South Plainfield, New Jersey) containing 0.5% (v/v) Tween 20 (Sigma Chemical Co. St. Louis, Missouri) .
  • the plates were treated with 100 ⁇ L of a 1% (w/v) solution of bovine serum albumin (BSA) fraction V (Sigma Chemical Co., St. Louis, Missouri), in the Na 2 CO 3 plus NaHCO 3 buffer described above. The plates were again covered and incubated at 37 0 C for one hour. Unbound BSA was removed by six washes of 250 ⁇ L PBS-Tween.
  • BSA bovine serum albumin
  • test samples were then treated with normal rabbit serum (10% (v/v) concentration) for 15 minutes at room temperature.
  • the TSST-I reference standard serum (serially diluted from 2-20 ng/mL in PBS-Tween) and the NRS treated test samples (serially diluted in PBS-Tween so that the resultant TSST-I concentration is between 2-20 ng) , were pipetted in 100 ⁇ L volumes to their respective wells.
  • the samples were then incubated for two hours at 37 0 C and unbound toxins were then removed with four washes of 250 ⁇ L PBS-Tween.
  • the rabbit polyclonal anti-TSST-I IgG conjugated to horseradish peroxidase was diluted according to the manufacturer's instructions. The final use dilution of the conjugate was determined by running standard curves of TSST-I reference standard with the conjugate at undiluted, 1:2, and 1:4 dilutions. The dilution that gave results most comparable to previous lots of conjugate was selected. One hundred ⁇ L volumes of this dilution were added to each microtiter well. The plates were covered and incubated at 37 0 C for one hour.
  • TSST-I concentrations in the test samples were derived from the reference toxin regression equations for each assay procedure.
  • this Example uses commercial tampons. As such, this sample contains about 0.75% (by weight of tampon with cover) Cetiol 1414E (myreth-3-myristate) .
  • the data shows that S.aureus MN8 produced less TSST-I in the presence of tampons that contain both benzyl alcohol and Cetiol 1414E (myreth-3-myristate) as compared to the control tampons that contain only Cetiol 1414E.
  • benzyl alcohol reduced the amount of toxin produced by 8% to 50%.
  • Example 2 the effect of the growth of S. aureus MN8 on the integrity of various test compounds was determined by measuring the amount of breakdown of the test compounds caused by the enzymes produced by S. aureus MN8 bacte-tria.
  • the test compounds in the desired concentrations, were placed in 100 mL of a growth medium in a sterile, 500 mL Corning Fleaker (Fisher Scientific, Pittsbury, Pennsylvania) .
  • the growth medium and inoculum were prepared as in Example 1.
  • Each fleaker was inoculated with the amount of inoculum determined as described above.
  • the fleakers were capped with sterile aluminum foil and incubated at 35 0 C in atmospheric air in a Lab-Line orbital water bath (available from VWR Scientific Products, McGaw Park, Illinois) at 180 rpm. 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 at 24 hours was assayed for the number of colony forming units of S. aureus MN8 using standard plate count procedures.
  • the culture fluid was centrifuged at 3000 .rpm at 2-10 0 C for 15 minutes.
  • the supernatant was filteir sterilized through an AUTOVIAL 5 syringeless filter, 0.45 juM pore size (available from Whatman, Inc., Clifton, New Jersey) .
  • the resulting fluid was frozen at -70 0 C in a FISHERBRAND (12 mm X 75 mm) polystyrene culture tube (Fisher Scientific, Pittsburgh, Pennsylvania) until chemical analysis could fc>e performed.
  • [O127] (-) -lactate as the test compound was found to contain benzyl alcohol as the dominant compound. Further, 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. Further, it was found that the concentration of benzyl alcohol increased over time.
  • the GC/MS analysis above show that the precursor compounds were broken, down by the enzymes produced by S. aureus MN8 to produce the active species. It can further be seen that the precursor compounds were slowly broken down over time to allow for a long-lasting continous inhibition of exoprotein production by the active species.
  • the liquid chromatography analysis of the test compounds showed that the compounds were broken down into 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's breakdown to benzoic acid. Additionally, the 6 hour and 24 hour samples containing benzyl (s) - (-) -lactate and benzyl ethyl malonate showed evidence of the compounds' breakdown to benzyl alcohol . As can further be seen, the 24 hour samples containing benzyl (s) -(-) -lactate and benzyl ethyl malonate showed evidence of an elevated level of benzyl alcohol compared to the 6 hour samples.

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Abstract

L'invention concerne des articles non absorbants et absorbants destinés à inhiber la production d'exoprotéines provenant de bactéries Gram positif. Lesdits articles comprennent une quantité efficace d'un composé précurseur représenté par la formule générale (I). Dans la formule, R1 est sélectionné dans le groupe constitué par les formules (II) et (III); R7 représente -OCH2-; X égale 0 ou 1; R5 représente un noyau aromatique substitué ou non substitué ou une fraction hydrocarbyle monovalente, saturée ou insaturée, substituée ou non substituée, ramifiée ou à chaîne droite, pouvant éventuellement être substituée par des hétéroatomes; R6 est sélectionné dans le groupe constitué par un acide aminé, un ester méthylique d'acide aminé et un ester éthylique d'acide aminé; R2, R3 et R4 sont sélectionnés indépendamment dans le groupe constitué par H, OH, COOH.
PCT/US2005/028366 2004-09-30 2005-08-10 Articles non absorbants et absorbants inhibant la production d'exoproteines WO2006038980A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2007534582A JP2008514698A (ja) 2004-09-30 2005-08-10 外来蛋白質の生成を阻害するための非吸収性物品及び吸収性物品
AU2005292655A AU2005292655A1 (en) 2004-09-30 2005-08-10 Non-absorbent and absorbent articles for inhibiting the production of exoproteins
EP05785615A EP1793871A2 (fr) 2004-09-30 2005-08-10 Articles non absorbants et absorbants inhibant la production d'exoproteines
BRPI0515949-0A BRPI0515949A (pt) 2004-09-30 2005-08-10 artigos não-absorventes e absorventes para inibir a produção de exoproteìnas
IL181198A IL181198A0 (en) 2004-09-30 2007-02-07 Non-absorbent and absorbent articles for inhibiting the production of exoproteins

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US10/955,821 2004-09-30
US10/955,821 US20060067990A1 (en) 2004-09-30 2004-09-30 Absorbent articles for inhibiting the production of exoproteins
US10/955,858 US20060067991A1 (en) 2004-09-30 2004-09-30 Non-absorbent articles for inhibiting the production of exoproteins
US10/955,858 2004-09-30

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WO2006038980A2 true WO2006038980A2 (fr) 2006-04-13
WO2006038980A3 WO2006038980A3 (fr) 2006-06-29

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JP (1) JP2008514698A (fr)
KR (1) KR20070057884A (fr)
AU (1) AU2005292655A1 (fr)
BR (1) BRPI0515949A (fr)
IL (1) IL181198A0 (fr)
RU (1) RU2007111692A (fr)
WO (1) WO2006038980A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2189153A3 (fr) * 2008-11-21 2011-04-13 McNeil-PPC, Inc. Article de fabrication utilisé au contact avec des surfaces du corps humain

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE524930A (fr) * 1952-12-09
GB830139A (en) * 1954-12-29 1960-03-09 George Van Norden Morin Fabrics containing bactericidal agents
US3027301A (en) * 1959-03-16 1962-03-27 Us Vitamin Pharm Corp Therapeutic wound healing composition of hydroxypropylamides of hydroxybenzoic acids
US4431427A (en) * 1981-10-05 1984-02-14 University Of Delaware Tampons and their manufacture
US4725590A (en) * 1983-08-24 1988-02-16 Lever Brothers Company Method of relieving pain and inflammatory conditions employing substituted salicylamides
US5663357A (en) * 1995-11-22 1997-09-02 Allergan Substituted heteroarylamides having retinoid-like biological activity
US6676957B1 (en) * 2000-11-28 2004-01-13 Kimberly-Clark Worldwide, Inc. Non-absorbent substrates for the inhibition of exoprotein production from gram positive bacteria
US7691403B2 (en) * 2001-11-21 2010-04-06 Kimberly-Clark Worldwide, Inc. Non-absorbent tampon containing additives inhibiting TSST-1

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2189153A3 (fr) * 2008-11-21 2011-04-13 McNeil-PPC, Inc. Article de fabrication utilisé au contact avec des surfaces du corps humain

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BRPI0515949A (pt) 2008-08-12
JP2008514698A (ja) 2008-05-08
AU2005292655A1 (en) 2006-04-13
WO2006038980A3 (fr) 2006-06-29
EP1793871A2 (fr) 2007-06-13
RU2007111692A (ru) 2008-11-10
IL181198A0 (en) 2007-07-04
KR20070057884A (ko) 2007-06-07

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