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WO2008147049A1 - A lubricating composition comprising agents which induce the mocosal immunity and a preparation method thereof - Google Patents

A lubricating composition comprising agents which induce the mocosal immunity and a preparation method thereof Download PDF

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Publication number
WO2008147049A1
WO2008147049A1 PCT/KR2008/002396 KR2008002396W WO2008147049A1 WO 2008147049 A1 WO2008147049 A1 WO 2008147049A1 KR 2008002396 W KR2008002396 W KR 2008002396W WO 2008147049 A1 WO2008147049 A1 WO 2008147049A1
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WO
WIPO (PCT)
Prior art keywords
agents
mucosal immunity
immunity
induce
lubricating composition
Prior art date
Application number
PCT/KR2008/002396
Other languages
French (fr)
Inventor
Seung-Hoon Yang
Se-Joong Kim
Sung-Min Park
Hwan-Joon Jung
Woong Kim
Original Assignee
Didimbiotech Co, . Ltd.
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
Application filed by Didimbiotech Co, . Ltd. filed Critical Didimbiotech Co, . Ltd.
Publication of WO2008147049A1 publication Critical patent/WO2008147049A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F6/00—Contraceptive devices; Pessaries; Applicators therefor
    • A61F6/02—Contraceptive devices; Pessaries; Applicators therefor for use by males
    • A61F6/04—Condoms, sheaths or the like, e.g. combined with devices protecting against contagion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a lubricating composition comprising agents which induce the mucosal immunity and a preparation method thereof. Further, the present invention provides a contraceptive device or a medical device containing the lubricating composition for mucosa comprising agents which induce the mucosal immunity.
  • a lubricant is used for the purpose of reducing the friction and wear between two moving surfaces.
  • a biolubricant has been widely used for medical/surgical or personal uses.
  • a medical/surgical lubricant has been used to lessen a patient's discomfort during examination of internal organs such as vagina, anus, digestive organs, urethra, respiratory organs, and external genital organs, or upon inserting a device for the purpose of treating or preventing any disease.
  • a medical/surgical lubricant is widely used, for example, for the measurement of body temperature via the anus, and for insertion of a measuring instrument, surgical instrument, body fluid drainage device, biopsy instrument, or fingers into a narrow body cavity or sphincter during medical treatment or diagnosis, nasal examination, endoscopic examination, rectal examination, and so forth.
  • the lubricant can be used to easily introduce an intra-vaginal device into women after delivery or elderly women with stress-related urinary incontinence in order to prevent unconscious leakage.
  • the lubricant can be used to facilitate delivery of the fetus of animals or humans (see US Pat No. 3971848).
  • a personal lubricant is used to help with vaginal dryness in elderly women or women after gynecological surgery, or to be applied to condom and genital system, or the like.
  • the lubricants are mainly applied to mucosal areas of the body.
  • the mucosal areas cover respiratory organs such as nose, trachea, and tonsils, digestive organs such as small intestine and rectum, and external genital organs.
  • respiratory organs such as nose, trachea, and tonsils
  • digestive organs such as small intestine and rectum
  • external genital organs such as small intestine and rectum
  • pathogen infection can be caused through mucosal areas of genital organs or anus, for example, during sexual contact of humans.
  • chronic inflammation of cervical mucosa may be induced, in the case of placing a contraceptive device inside the uterus for a long period of time (Wagenlehner et al., Clin. Microbiol.
  • mucosal immunoadjuvants examples include ⁇ -glucan, CT B-subunit (cholera toxin B-subunit), LT (E. coli heat-labile toxin), LPS (lipopolysaccharide) including pertusis toxin, MPL (monophosphoryl lipid A), CgP ODN (oligodeoxynucleotides containing unmethylated dinucleotides), an aluminum salt, a mistletoe extract, and alum.
  • ⁇ -glucan CT B-subunit
  • LT E. coli heat-labile toxin
  • LPS lipopolysaccharide
  • MPL monophosphoryl lipid A
  • CgP ODN oligodeoxynucleotides containing unmethylated dinucleotides
  • an aluminum salt a mistletoe extract
  • alum alum
  • a lubricant comprising chlorine dioxide is disclosed in US Pat No. 6114398, in which the lubricant kills fungus Candida and prevents itching.
  • a lubricant comprising an antiviral agent for the prevention of human immunodeficiency virus (HIV) infection is disclosed in US Pat No. 6,545,007.
  • HAV human immunodeficiency virus
  • the present invention provides a lubricating composition comprising agents which induce the mucosal immunity and a preparation method thereof. Further, the present invention provides a contraceptive device and a diagnostic medical device inserted into the body, containing the lubricating composition for mucosa comprising agents which induce the mucosal immunity.
  • the present invention relates to a lubricating composition comprising one or more agents which induce the mucosal immunity and a preparation method thereof. Further, the present invention provides a contraceptive device and a diagnostic medical device inserted into the body, containing the lubricating composition for mucosa comprising agents which induce the mucosal immunity.
  • the present invention relates to the development of a functional lubricant that induces initial immunity against venereal diseases, infections and various diseases, as well as providing its intrinsic functions, so as to substantially prevent the diseases, in which the lubricant is prepared by mixing with a suitable amount of agent which induces the mucosal immunity and is applied to genital system or to contraceptive devices such as condom and pessary, diagnostic or medical devices inserted into a body.
  • the present invention is based on the experimental results of the present inventors, in which in the case of applying the lubricant that is prepared by adding the substance known to have an effect of enhancing the stimulation of mucosal immunity to the vaginas of mice, the values of T-cell differentiation potential and the values of B-cell differentiation potential/T-cell differentiation potential increase in splenocytes, and epithelial cells in respiratory organs such as bronchia and lung, digestive organs such as small intestine and rectum, and genitourinary organs such as genitals are activated to produce a large amount of immunoglobulins, thereby enhancing immunity, as compared to a control lubricant without the substance to enhance the stimulation of mucosal immunity.
  • the present inventors mixed the known lubricant with the substance to enhance the stimulation of mucosal immunity at various concentrations, and applied each of them to the vaginas of female BALB/C mice.
  • B -/T-cell differentiation potential of splenocytes from the mice was examined using a FACScan
  • T-cell differentiation potential of splenocytes was examined using a FACScan, thereby determining the activity of epithelial cells in respiratory organs such as nose, trachea, bronchia and lung, digestive organs such as small intestine, and genitourinary organs such as genitals.
  • IgA and IgG titration was analyzed in serum, oral wash samples, nasal wash samples, tracheal wash samples, urinary wash samples, and vaginal wash samples.
  • gonorrhea, syphilis, and vaginitis-causing microbes were inoculated into the vaginas of the mice treated with the substance to enhance the stimulation of mucosal immunity or a cocktail thereof, and then the survival rate of the mice was observed.
  • ⁇ - glucan, CT B-subunit (cholera toxin B-subunit), LT E.
  • LPS lipopolysaccharide
  • pertusis toxin monophosphoryl lipid A (MPL)
  • MPL monophosphoryl lipid A
  • CgP ODN oli- godeoxynucleotides containing unmethylated dinucleotides
  • Al salt an Acanthopanax Senticosus extract, European mistletoe lectin, European mistletoe lectin B -chain, a Korean mistletoe extract, Korean mistletoe lectin, Korean mistletoe lectin B-chain, and cocktails thereof were used in the experiments.
  • the substances for enhancing the mucosal immunity or cocktails thereof were added to a commercially available lubricant (for example, Unidus gel®, Astroglide®).
  • test groups treated with the lubricants comprising the effective substances to enhance the stimulation of mucosal immunity or cocktails thereof exhibited twice higher B-cell and T-cell activity than the control group treated with the lubricant comprising a phosphate buffer solution instead of the substances.
  • the test groups treated with the lubricant comprising mistletoe lectin or with lubricants comprising the cocktail of mistletoe lectin and other substances for enhancing the mucosal immunity showed high activity.
  • the test groups treated with the lubricants comprising the effective substances to enhance the stimulation of mucosal immunity or cocktails thereof showed at least 1 :64,000 or more of IgG titration in serum, at least 1 : 16,000 or more of IgG titration in mucosal wash samples, and at least 1:8,000 of IgA titration in mucosal wash samples, as compared to the control group treated with the lubricant added with a phosphate buffer solution instead of the substances.
  • a phosphate buffer solution instead of the substances.
  • mice in the challenge tests with gonorrhea, syphilis, and vaginitis-causing microbes which were inoculated into the vaginas of the mice all the mice in the control group died after 10 days, but the mice in the test groups treated with the lubricants comprising the effective substances to enhance the stimulation of mucosal immunity or cocktails thereof exhibited higher survival rates, in particular, the mice in the test groups treated with the cocktail comprising mistletoe lectin and other substances for enhancing the mucosal immunity had showed highest survival rates.
  • the present invention provides a lubricating composition comprising agents which induce the mucosal immunity, based on the above experimental results.
  • the lubricant prepared by the present invention stimulates mucous membranes of organs including female and male genitals to induce the mucosal immunity, thereby forming nonspecific immunity to spread the mucosal immunity to all the mucous membranes of other organs in the body. Therefore, the lubricant increases the immunity against initial pathogen infection, so as to have a function of increasing the initial immunity against infectious diseases conveyed via respiratory organs, food, anus and rectum, genital, and urinary organs.
  • a lubricant to induce nonspecific, systematic immunity is developed by adding the aforesaid effective substance to enhance the stimulation of mucosal immunity to conventional genital lubricants, so that a functional product which can prevent infectious diseases worldwide such as AIDS, SARS, and avian influenza, or maintains healthy genital may be provided.
  • the present invention provides a composition for inducing mucosal immunity in serum, oral mucous membranes, ocular mucous membranes, nasal mucous membranes, gastrointestinal mucous membranes, respiratory mucous membranes, urinary mucous membranes, and genital mucous membranes by adding a variety of effective substance to enhance the stimulation of mucosal immunity or cocktails thereof to commercially available lubricating compositions.
  • the composition activates nonspecific immunity to initially block infectious diseases caused by microorganisms and a few viruses, so as to be used as valuable drugs or non-drug products.
  • any agent known in the related art may be used, without departing from the scope of the present invention.
  • examples thereof include ⁇ -glucan, CT B-subunit (cholera toxin B-subunit), LT (E.
  • coli heat-labile toxin LPS (lipopolysaccharide) including pertusis toxin, monophosphoryl lipid A (MPL), oli- godeoxynucleotides containing unmethylated dinucleotides (CgP ODN), an aluminum salt, an Acanthopanax Senticosus extract, European mistletoe lectin, European mistletoe lectin B -chain, a Korean mistletoe extract, Korean mistletoe lectin, Korean mistletoe lectin B -chain, and cocktails thereof.
  • Mistletoe extract, mistletoe lectin, or cocktails comprising mistletoe extract or mistletoe lectin with other substances for enhancing the mucosal immunity are preferable.
  • the lubricating composition provided in the present invention may be a medical/ surgical lubricating composition, or a personal lubricating composition.
  • the lubricating composition can be applied to devices introduced into the areas covered with mucous membranes, including rectal thermometers, intrauterine devices, urinary incontinence control devices, endoscopes, contraceptive devices (pessary, tampon, condom, loop, ring, intra-vaginal sponge, diaphragm, cervical cap, etc.), intra-vaginal devices, and diagnostic medical devices inserted into the body.
  • the lubricating composition can be used for the preparation of personal lubricants, and used to facilitate delivery of the fetus of a mammal, and to prevent the vagina from being damaged.
  • the lubricant provided in the present invention can be prepared by further adding the agents which induce the mucosal immunity to any lubricant known in the related art or commercially available, as long as not departing from the scope of the present invention.
  • the lubricating composition according to the present invention comprises more than
  • lubricant of the present invention 0 % up to 30 %, preferably 2 to 10 % of the agent which induces the mucosal immunity, based on the total composition.
  • the administration dosage and method of the lubricant of the present invention are the same as those of conventional lubricants.
  • the lubricant comprising the agents which induce the mucosal immunity may be formulated into any of the conventional forms that can be applied to mucous membranes, for example, aqueous solutions, aqueous alcoholic solutions, or oily solutions, dispersions such as lotion or serum type, anhydrous or hydrophobic gels, liquid or semi-solid dispersions obtained by suspending fatty phase in aqueous phase or suspending aqueous phase in fatty phase, cream or gel-type dispersions or suspensions, microemulsions, microcapsules, foam type, ionic and/or nonionic vesicular suspensions or powder type.
  • the lubricant is prepared by standard methods employed in the related art.
  • the ingredients contained in the composition of the present invention are also used in the amounts which are normally used in pharmaceutical fields.
  • the amount of the fatty phase may be 5 to 80 % by weight, based on the total weight of the composition.
  • the oil and dispersing agent used in the dispersion type composition those conventionally used in the related art can be used.
  • the dispersing agent of the composition of the present invention may be used in an amount of 0.3 to 30 % by weight, based on the total weight of the composition.
  • the amount of the fatty phase may be 90 % by weight or more, based on the total weight of the composition.
  • the lubricating powder of the present invention may be in a form of capsule filled with lubricating fluid.
  • composition of the lubricant of the present invention is not specifically limited, and may include water, thickening agents (for example, cellulose, cellulose derivatives, acacia, agar, alginate, carrageenan, xanthan gum, collagen, carboxypolymethylene, glyceryl monostearate, polyvinylpyrrolidone and polyacrylamide) and lubricating ingredients (for example, glycerin, propylene glycol, polyethylene glycol, polypropylene glycol, polyisobutene, poly oxye thy lene, behenic acid, behenyl alcohol, sorbitol and polydimethylsiloxane).
  • thickening agents for example, cellulose, cellulose derivatives, acacia, agar, alginate, carrageenan, xanthan gum, collagen, carboxypolymethylene, glyceryl monostearate, polyvinylpyrrolidone and polyacrylamide
  • lubricating ingredients for example
  • the composition of the present invention may include auxiliaries that are conven- tionally used in the related art, for example, a hydrophilic or hydrophobic gelling agent, a preservative, an antioxidant, a solvent, a perfume, a filler, a coloring agent, a buffering agent to control pH, a surfactant, a polysaccharide, an oligosaccharide, a lipid, a protein, a vitamin, a steroid, a hormone, a lower alcohol, a polyalcohol, a vasodilator, a spermicide, an antibacterial agent or an antiviral agent.
  • auxiliaries are also used in the amounts which are normally used in pharmaceutical or dermatological fields.
  • the lubricant of the present invention is prepared using the known lubricating composition and preparation method thereof, and the substances to enhance the stimulation of mucosal immunity are added thereto by a method being suitable for the type of formulations.
  • the lubricant comprising agents which induce the mucosal immunity can be applied to a condom during the manufacture process thereof.
  • the preferred lubricant comprises one or more lubricating ingredients such as glycerin and propylene glycol, and agents which induce the mucosal immunity.
  • thickening agents such as cellulose derivatives, natural rubber compounds, and hydrophilic polymers, or suspensions may be further added to prepare into a gel type product.
  • the lubricant can be prepared into the types of cream, dispersions, and ointment.
  • condom of the present invention examples include condoms for women to be inserted into the vagina, as well as typical condoms for men. Further, the present invention provides contraceptive devices and medical devices comprising the lubricating composition of the present invention. Examples thereof may include sanitary tampons, urinary incontinence control devices, drugs, bandages, sanitary products for contraception, and other similar members.
  • the present invention provides a functional lubricant composition for enhancing immunity, as well as providing its intrinsic functions, for the purpose of preventing pathogen infections and inflammations, in which the composition is prepared by adding substances for enhancing the mucosal immunity to a conventional lubricating composition. If each of the lubricating compositions prepared by the method in the present invention is applied to condoms, gels, medical/surgical instruments including instruments for urinary examination, or human body, the mucosal tissues of the body are stimulated to enhance basic immunity.
  • the enhanced basic immunity can initially prevent a variety of infections and can provide effects of preventing infectious diseases worldwide, such as AIDS, SARS, and avian influenza.
  • the enhanced basic immunity also help to maintain healthy genital.
  • the mucosal immunity induced in one organ enhances the mucosal immunity of other organs in the body, thereby enhancing the immunity against infectious diseases from respiratory and gastrointestinal organs, as well as from genital or urinary organs.
  • Fig. 1 is a drawing illustrating a ratio of B-/T-cells in splenocytes from mice, of which vaginas are stimulated with lubricating compositions of the present invention
  • FIG. 2 is a drawing illustrating differentiation potential of T-cells in splenocytes from mice, of which vaginas are stimulated with lubricating compositions of the present invention
  • FIG. 3 is a drawing illustrating IgG and IgA titration in sera from mice, of which vaginas are stimulated with lubricating compositions of the present invention
  • FIG. 4 is a drawing illustrating IgG and IgA titration in oral wash samples from mice, of which vaginas are stimulated with lubricating compositions of the present invention
  • FIG. 5 is a drawing illustrating IgG and IgA titration in nasal wash samples from mice, of which vaginas are stimulated with lubricating compositions of the present invention
  • Fig. 6 is a drawing illustrating IgG and IgA titration in tracheal wash samples from mice, of which vaginas are stimulated with lubricating compositions of the present invention
  • Fig. 7 is a drawing illustrating IgG and IgA titration in urinary and vaginal wash samples from mice, of which vaginas are stimulated with lubricating compositions of the present invention
  • FIG. 8 is a drawing illustrating a survival rate, in which 2 X 10 4 cells of a gonorrhea- causing microbe Neisseria gonorrheae are inoculated into the vaginas of mice, which are stimulated with lubricating compositions of the present invention;
  • FIG. 9 is a drawing illustrating a survival rate, in which 2 X 10 4 cells of a syphilis- causing microbe Treponema pallidum die, inoculated into the vaginas of mice, which are stimulated with lubricating compositions of the present invention.
  • Fig. 10 is a drawing illustrating a survival rate, in which 2 X 10 4 cells of a vaginitis- causing microbe Candida albicans are inoculated into the vaginas of mice, which are stimulated with lubricating compositions of the present invention.
  • Mode for Invention 2 X 10 4 cells of a vaginitis- causing microbe Candida albicans are inoculated into the vaginas of mice, which are stimulated with lubricating compositions of the present invention.
  • lubricant products are basically composed of the lubricant glycerin or the like as a lubricating ingredient and propylene glycol or the like as water-soluble alcohol, and a moisturizing agent.
  • the effective substances to enhance the stimulation of mucosal immunity were added to the lubricants in various ratios, and used for experiments.
  • the effective substances to enhance the stimulation of mucosal immunity were added singly or in cocktails thereof.
  • the detailed compositions and ratio thereof are shown in Table 1.
  • the compositions listed in Table 1 were directly mixed with commercially available lubricant products (Unidus gel®, Astroglide®) to prepare the lubricants used in the experiments.
  • the effective substances to enhance the stimulation of mucosal immunity were dissolved in propylene glycol, which is water-soluble alcohol dissolving the lubricating ingredients, and then mixed with glycerin to prepare the lubricants used in the experiments.
  • mice were stimulated with the lubricants comprising a substance or cocktail composition in Table 2 using a sterilized cotton swab.
  • the added amount of the substance or the cocktail composition was 0.1 ⁇ g/head.
  • a phosphate buffer solution (PBS) was added, instead of the substances to enhance the stimulation of mucosal immunity.
  • Experiment was performed for 15 days (one application per day), and a nonspecific immunity test was performed. On day 16, the mice were sacrificed, and splenocytes were isolated from the spleens. Then, the B- /T-cell distribution was observed using antibodies by a FACScan.
  • the test groups treated with the lubricants comprising the effective substances to enhance the stimulation of mucosal immunity showed twice higher B-cell and T-cell activity than the control group (Fig. 1).
  • mice After treated mice according to the method described in Example 2, T-cell differentiation potential was examined in mouse splenocytes treated with the lubricants comprising the phosphate buffer solution (control group) and the compositions listed in Table 2 (test groups). It can be seen that more CD3 was observed since the response was a nonspecific immune response, as shown in Fig. 2. If antigens had been administered together, more CD4 or CD8 would have been observed than CD3. To conclude, although the specific immune response did not occur, the T-cell distribution was obviously observed in the groups treated with the lubricants comprising various compositions, as compared to the control group. Accordingly, it is thought that immunity against a variety of antigens or pathogens was activated.
  • 500 ⁇ L of PBS was added to the mucous membranes of other organs except serum, and washed 20 times.
  • the wash samples of the mucous membranes were placed in sterile E-tubes. Such performances were repeated 10 times to obtain 5 mL of wash samples, which were centrifuged at 6,000 rpm. Only the supernatants were taken and stored at 4 ° C for 24 hours.
  • a protein G column chromatography was performed with the wash samples to isolate IgG, and fractionated IgA was separately taken.
  • TR-FIA time-resolved fluorescence immunoassay
  • the plates were repeatedly washed 5 to 6 times using an automatic washer, and goat IgG anti-mouse IgG-Eu particle conjugates were added thereto at a diluted concentration of 1:5000, and reacted at 37 ° C for 2 hours. Subsequently, the plates were repeatedly washed 5 to 6 times using an automatic washer. 200 ⁇ L of enhancement solution was added thereto, and further reacted for 5 minutes. Measurement was made using DELFIA (Wallac, Model 1420).
  • mice of which vaginas were stimulated with the lubricants comprising the effective substances to enhance the stimulation of mucosal immunity or cocktails thereof, showed at least 1:64,000 or more of IgG titration in sera, and at least 1 : 16,000 or more of IgG titration in mucosal wash samples, as compared to the control group. Further, it was found that IgA was not observed in the sera, and IgA titration in the mucosal wash samples excluding the sera was at least 1:8,000.

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Abstract

The present invention relates to a lubricating composition comprising agents which induce the mucosal immunity and a preparation method thereof. Further, the present invention provides a contraceptive device or medical device containing the lubricating composition for mucosa comprising agents which induce the mucosal immunity. The lubricating composition of the present invention increases immunity against infections and diseases in the mucosal areas of mammals that are more likely to be exposed to a variety of infections, thereby further providing an effect of preventing infections and diseases, as well as providing the intrinsic functions thereof such as lubrication.

Description

Description
A LUBRICATING COMPOSITION COMPRISING AGENTS WHICH INDUCE THE MOCOSAL IMMUNITY AND A PREPARATION METHOD THEREOF
Technical Field
[1] The present invention relates to a lubricating composition comprising agents which induce the mucosal immunity and a preparation method thereof. Further, the present invention provides a contraceptive device or a medical device containing the lubricating composition for mucosa comprising agents which induce the mucosal immunity. Background Art
[2] A lubricant is used for the purpose of reducing the friction and wear between two moving surfaces. A biolubricant has been widely used for medical/surgical or personal uses. A medical/surgical lubricant has been used to lessen a patient's discomfort during examination of internal organs such as vagina, anus, digestive organs, urethra, respiratory organs, and external genital organs, or upon inserting a device for the purpose of treating or preventing any disease. A medical/surgical lubricant is widely used, for example, for the measurement of body temperature via the anus, and for insertion of a measuring instrument, surgical instrument, body fluid drainage device, biopsy instrument, or fingers into a narrow body cavity or sphincter during medical treatment or diagnosis, nasal examination, endoscopic examination, rectal examination, and so forth. Further, the lubricant can be used to easily introduce an intra-vaginal device into women after delivery or elderly women with stress-related urinary incontinence in order to prevent unconscious leakage. In addition, the lubricant can be used to facilitate delivery of the fetus of animals or humans (see US Pat No. 3971848). A personal lubricant is used to help with vaginal dryness in elderly women or women after gynecological surgery, or to be applied to condom and genital system, or the like.
[3] The lubricants are mainly applied to mucosal areas of the body. The mucosal areas cover respiratory organs such as nose, trachea, and tonsils, digestive organs such as small intestine and rectum, and external genital organs. Thus, when an external substance included in food or air enters the body, it first comes into contact with the mucosal areas. Hence, pathogen infection can be caused through mucosal areas of genital organs or anus, for example, during sexual contact of humans. Further, it has been reported that chronic inflammation of cervical mucosa may be induced, in the case of placing a contraceptive device inside the uterus for a long period of time (Wagenlehner et al., Clin. Microbiol. Infect. 9(8), 881-5, 2003). In addition, in the case of introducing a medical device into the body, or vaginal delivery in mammals, the corresponding mucous membranes of the body can be often damaged, and the damaged regions can be at high risk of infection, which may induce inflammation. When the body's immune system is weakened, pathogen infection and inflammation are more likely to occur.
[4] Accordingly, in order to prevent the pathogen infection caused by sexual contact or a medical device inserted into a body, it is necessary to enhance immunity against cancer cells or pathogens and microorganisms from external environment by activating an immunomodulatory system of the body. The immunomodulatory system is generally activated by systemic or mucosal immunity.
[5] Examples of mucosal immunoadjuvants include β-glucan, CT B-subunit (cholera toxin B-subunit), LT (E. coli heat-labile toxin), LPS (lipopolysaccharide) including pertusis toxin, MPL (monophosphoryl lipid A), CgP ODN (oligodeoxynucleotides containing unmethylated dinucleotides), an aluminum salt, a mistletoe extract, and alum. If mucous membranes are continuously stimulated by such adjuvants, immunity may be improved, which contributes to immune defense against infection such as AIDS (Mario C. et al., Immunology Letters 66 (1999) 21-25; Hirosh K, et al., Advanced Drug Delivery Reviews 18 (1995) 23-51).
[6] A lubricant comprising chlorine dioxide is disclosed in US Pat No. 6114398, in which the lubricant kills fungus Candida and prevents itching. A lubricant comprising an antiviral agent for the prevention of human immunodeficiency virus (HIV) infection is disclosed in US Pat No. 6,545,007. However, there has been no prior document that describes a method for inhibiting pathogen infection with a lubricant comprising a substance capable of activating immunomodulatory system.
[7] It is apparent that the information described herein is provided for a better understanding of this field, and does not act as prior arts. Disclosure of Invention Technical Problem
[8] It is at once the problem to be solved by the present invention and the object of the invention to provide a functional lubricant having an effect of enhancing initial immunity against venereal diseases, infections and various diseases, as well as providing its intrinsic functions such as lubrication, etc. Technical Solution
[9] In order to achieve the aforesaid object of the present invention, the present invention provides a lubricating composition comprising agents which induce the mucosal immunity and a preparation method thereof. Further, the present invention provides a contraceptive device and a diagnostic medical device inserted into the body, containing the lubricating composition for mucosa comprising agents which induce the mucosal immunity.
[10] Hereinafter, the present invention will be described in detail.
[11] The present invention relates to a lubricating composition comprising one or more agents which induce the mucosal immunity and a preparation method thereof. Further, the present invention provides a contraceptive device and a diagnostic medical device inserted into the body, containing the lubricating composition for mucosa comprising agents which induce the mucosal immunity.
[12] More specifically, the present invention relates to the development of a functional lubricant that induces initial immunity against venereal diseases, infections and various diseases, as well as providing its intrinsic functions, so as to substantially prevent the diseases, in which the lubricant is prepared by mixing with a suitable amount of agent which induces the mucosal immunity and is applied to genital system or to contraceptive devices such as condom and pessary, diagnostic or medical devices inserted into a body.
[13] The present invention is based on the experimental results of the present inventors, in which in the case of applying the lubricant that is prepared by adding the substance known to have an effect of enhancing the stimulation of mucosal immunity to the vaginas of mice, the values of T-cell differentiation potential and the values of B-cell differentiation potential/T-cell differentiation potential increase in splenocytes, and epithelial cells in respiratory organs such as bronchia and lung, digestive organs such as small intestine and rectum, and genitourinary organs such as genitals are activated to produce a large amount of immunoglobulins, thereby enhancing immunity, as compared to a control lubricant without the substance to enhance the stimulation of mucosal immunity.
[14] The present inventors mixed the known lubricant with the substance to enhance the stimulation of mucosal immunity at various concentrations, and applied each of them to the vaginas of female BALB/C mice. B -/T-cell differentiation potential of splenocytes from the mice was examined using a FACScan, and T-cell differentiation potential of splenocytes was examined using a FACScan, thereby determining the activity of epithelial cells in respiratory organs such as nose, trachea, bronchia and lung, digestive organs such as small intestine, and genitourinary organs such as genitals. Further, IgA and IgG titration was analyzed in serum, oral wash samples, nasal wash samples, tracheal wash samples, urinary wash samples, and vaginal wash samples. In addition, gonorrhea, syphilis, and vaginitis-causing microbes were inoculated into the vaginas of the mice treated with the substance to enhance the stimulation of mucosal immunity or a cocktail thereof, and then the survival rate of the mice was observed. [15] As the tested substance to enhance the mucosal immunity in the present invention, β- glucan, CT B-subunit (cholera toxin B-subunit), LT (E. coli heat-labile toxin), LPS (lipopolysaccharide) such as pertusis toxin, monophosphoryl lipid A (MPL), oli- godeoxynucleotides containing unmethylated dinucleotides (CgP ODN), an aluminum salt, an Acanthopanax Senticosus extract, European mistletoe lectin, European mistletoe lectin B -chain, a Korean mistletoe extract, Korean mistletoe lectin, Korean mistletoe lectin B-chain, and cocktails thereof were used in the experiments. The substances for enhancing the mucosal immunity or cocktails thereof were added to a commercially available lubricant (for example, Unidus gel®, Astroglide®).
[16] The test groups treated with the lubricants comprising the effective substances to enhance the stimulation of mucosal immunity or cocktails thereof exhibited twice higher B-cell and T-cell activity than the control group treated with the lubricant comprising a phosphate buffer solution instead of the substances. In particular, the test groups treated with the lubricant comprising mistletoe lectin or with lubricants comprising the cocktail of mistletoe lectin and other substances for enhancing the mucosal immunity showed high activity.
[17] The test groups treated with the lubricants comprising the effective substances to enhance the stimulation of mucosal immunity or cocktails thereof showed at least 1 :64,000 or more of IgG titration in serum, at least 1 : 16,000 or more of IgG titration in mucosal wash samples, and at least 1:8,000 of IgA titration in mucosal wash samples, as compared to the control group treated with the lubricant added with a phosphate buffer solution instead of the substances. As a result, it can be seen that immunity of the body was increased on the whole.
[18] Further, in the challenge tests with gonorrhea, syphilis, and vaginitis-causing microbes which were inoculated into the vaginas of the mice, all the mice in the control group died after 10 days, but the mice in the test groups treated with the lubricants comprising the effective substances to enhance the stimulation of mucosal immunity or cocktails thereof exhibited higher survival rates, in particular, the mice in the test groups treated with the cocktail comprising mistletoe lectin and other substances for enhancing the mucosal immunity had showed highest survival rates.
[19] The present invention provides a lubricating composition comprising agents which induce the mucosal immunity, based on the above experimental results.
[20] The lubricant prepared by the present invention stimulates mucous membranes of organs including female and male genitals to induce the mucosal immunity, thereby forming nonspecific immunity to spread the mucosal immunity to all the mucous membranes of other organs in the body. Therefore, the lubricant increases the immunity against initial pathogen infection, so as to have a function of increasing the initial immunity against infectious diseases conveyed via respiratory organs, food, anus and rectum, genital, and urinary organs.
[21] In the present invention, a lubricant to induce nonspecific, systematic immunity is developed by adding the aforesaid effective substance to enhance the stimulation of mucosal immunity to conventional genital lubricants, so that a functional product which can prevent infectious diseases worldwide such as AIDS, SARS, and avian influenza, or maintains healthy genital may be provided.
[22] The present invention provides a composition for inducing mucosal immunity in serum, oral mucous membranes, ocular mucous membranes, nasal mucous membranes, gastrointestinal mucous membranes, respiratory mucous membranes, urinary mucous membranes, and genital mucous membranes by adding a variety of effective substance to enhance the stimulation of mucosal immunity or cocktails thereof to commercially available lubricating compositions. According to the present invention, the composition activates nonspecific immunity to initially block infectious diseases caused by microorganisms and a few viruses, so as to be used as valuable drugs or non-drug products.
[23] As the agents capable of inducing the mucosal immunity that are added to the lubricating composition, any agent known in the related art may be used, without departing from the scope of the present invention. Examples thereof include β-glucan, CT B-subunit (cholera toxin B-subunit), LT (E. coli heat-labile toxin), LPS (lipopolysaccharide) including pertusis toxin, monophosphoryl lipid A (MPL), oli- godeoxynucleotides containing unmethylated dinucleotides (CgP ODN), an aluminum salt, an Acanthopanax Senticosus extract, European mistletoe lectin, European mistletoe lectin B -chain, a Korean mistletoe extract, Korean mistletoe lectin, Korean mistletoe lectin B -chain, and cocktails thereof. Mistletoe extract, mistletoe lectin, or cocktails comprising mistletoe extract or mistletoe lectin with other substances for enhancing the mucosal immunity are preferable.
[24] The lubricating composition provided in the present invention may be a medical/ surgical lubricating composition, or a personal lubricating composition. The lubricating composition can be applied to devices introduced into the areas covered with mucous membranes, including rectal thermometers, intrauterine devices, urinary incontinence control devices, endoscopes, contraceptive devices (pessary, tampon, condom, loop, ring, intra-vaginal sponge, diaphragm, cervical cap, etc.), intra-vaginal devices, and diagnostic medical devices inserted into the body. Further, the lubricating composition can be used for the preparation of personal lubricants, and used to facilitate delivery of the fetus of a mammal, and to prevent the vagina from being damaged.
[25] The lubricant provided in the present invention can be prepared by further adding the agents which induce the mucosal immunity to any lubricant known in the related art or commercially available, as long as not departing from the scope of the present invention.
[26] The lubricating composition according to the present invention comprises more than
0 % up to 30 %, preferably 2 to 10 % of the agent which induces the mucosal immunity, based on the total composition. The administration dosage and method of the lubricant of the present invention are the same as those of conventional lubricants.
[27] The lubricant comprising the agents which induce the mucosal immunity according to the present invention may be formulated into any of the conventional forms that can be applied to mucous membranes, for example, aqueous solutions, aqueous alcoholic solutions, or oily solutions, dispersions such as lotion or serum type, anhydrous or hydrophobic gels, liquid or semi-solid dispersions obtained by suspending fatty phase in aqueous phase or suspending aqueous phase in fatty phase, cream or gel-type dispersions or suspensions, microemulsions, microcapsules, foam type, ionic and/or nonionic vesicular suspensions or powder type. The lubricant is prepared by standard methods employed in the related art. The ingredients contained in the composition of the present invention are also used in the amounts which are normally used in pharmaceutical fields.
[28] When the lubricant of the present invention is a dispersion type, the amount of the fatty phase may be 5 to 80 % by weight, based on the total weight of the composition. As the oil and dispersing agent used in the dispersion type composition, those conventionally used in the related art can be used. The dispersing agent of the composition of the present invention may be used in an amount of 0.3 to 30 % by weight, based on the total weight of the composition.
[29] When the composition of the present invention is an oily gel or an oily solution, the amount of the fatty phase may be 90 % by weight or more, based on the total weight of the composition.
[30] The lubricating powder of the present invention may be in a form of capsule filled with lubricating fluid.
[31] The composition of the lubricant of the present invention is not specifically limited, and may include water, thickening agents (for example, cellulose, cellulose derivatives, acacia, agar, alginate, carrageenan, xanthan gum, collagen, carboxypolymethylene, glyceryl monostearate, polyvinylpyrrolidone and polyacrylamide) and lubricating ingredients (for example, glycerin, propylene glycol, polyethylene glycol, polypropylene glycol, polyisobutene, poly oxye thy lene, behenic acid, behenyl alcohol, sorbitol and polydimethylsiloxane). In addition, various thickening agents and lubricating ingredients can be selected to be used, in order to attain the purpose of the present invention.
[32] The composition of the present invention may include auxiliaries that are conven- tionally used in the related art, for example, a hydrophilic or hydrophobic gelling agent, a preservative, an antioxidant, a solvent, a perfume, a filler, a coloring agent, a buffering agent to control pH, a surfactant, a polysaccharide, an oligosaccharide, a lipid, a protein, a vitamin, a steroid, a hormone, a lower alcohol, a polyalcohol, a vasodilator, a spermicide, an antibacterial agent or an antiviral agent. The auxiliaries are also used in the amounts which are normally used in pharmaceutical or dermatological fields.
[33] It is another object of the present invention to provide a preparation method of the lubricant by adding the substances to enhance the stimulation of mucosal immunity. The lubricant of the present invention is prepared using the known lubricating composition and preparation method thereof, and the substances to enhance the stimulation of mucosal immunity are added thereto by a method being suitable for the type of formulations.
[34] It is still another object of the present invention to provide a product coated with the lubricating composition of the present invention. For example, the lubricant comprising agents which induce the mucosal immunity can be applied to a condom during the manufacture process thereof. The preferred lubricant comprises one or more lubricating ingredients such as glycerin and propylene glycol, and agents which induce the mucosal immunity. In the case of using water, thickening agents such as cellulose derivatives, natural rubber compounds, and hydrophilic polymers, or suspensions may be further added to prepare into a gel type product. Alternatively, the lubricant can be prepared into the types of cream, dispersions, and ointment. Examples of the condom of the present invention include condoms for women to be inserted into the vagina, as well as typical condoms for men. Further, the present invention provides contraceptive devices and medical devices comprising the lubricating composition of the present invention. Examples thereof may include sanitary tampons, urinary incontinence control devices, drugs, bandages, sanitary products for contraception, and other similar members. Advantageous Effects
[35] The present invention provides a functional lubricant composition for enhancing immunity, as well as providing its intrinsic functions, for the purpose of preventing pathogen infections and inflammations, in which the composition is prepared by adding substances for enhancing the mucosal immunity to a conventional lubricating composition. If each of the lubricating compositions prepared by the method in the present invention is applied to condoms, gels, medical/surgical instruments including instruments for urinary examination, or human body, the mucosal tissues of the body are stimulated to enhance basic immunity. The enhanced basic immunity can initially prevent a variety of infections and can provide effects of preventing infectious diseases worldwide, such as AIDS, SARS, and avian influenza. The enhanced basic immunity also help to maintain healthy genital. Further, the mucosal immunity induced in one organ (for example, genital or urinary organ) enhances the mucosal immunity of other organs in the body, thereby enhancing the immunity against infectious diseases from respiratory and gastrointestinal organs, as well as from genital or urinary organs.
[36] There has been no case that agents to induce the mucosal immunity are introduced to the body by utilizing a lubricant. Therefore, the present invention provides a safe, convenient and new method capable of enhancing basic immunity, as well as providing the intrinsic functions of the lubricant. Description of Drawings
[37] Fig. 1 is a drawing illustrating a ratio of B-/T-cells in splenocytes from mice, of which vaginas are stimulated with lubricating compositions of the present invention;
[38] Fig. 2 is a drawing illustrating differentiation potential of T-cells in splenocytes from mice, of which vaginas are stimulated with lubricating compositions of the present invention;
[39] Fig. 3 is a drawing illustrating IgG and IgA titration in sera from mice, of which vaginas are stimulated with lubricating compositions of the present invention;
[40] Fig. 4 is a drawing illustrating IgG and IgA titration in oral wash samples from mice, of which vaginas are stimulated with lubricating compositions of the present invention;
[41] Fig. 5 is a drawing illustrating IgG and IgA titration in nasal wash samples from mice, of which vaginas are stimulated with lubricating compositions of the present invention;
[42] Fig. 6 is a drawing illustrating IgG and IgA titration in tracheal wash samples from mice, of which vaginas are stimulated with lubricating compositions of the present invention;
[43] Fig. 7 is a drawing illustrating IgG and IgA titration in urinary and vaginal wash samples from mice, of which vaginas are stimulated with lubricating compositions of the present invention;
[44] Fig. 8 is a drawing illustrating a survival rate, in which 2 X 104 cells of a gonorrhea- causing microbe Neisseria gonorrheae are inoculated into the vaginas of mice, which are stimulated with lubricating compositions of the present invention;
[45] Fig. 9 is a drawing illustrating a survival rate, in which 2 X 104 cells of a syphilis- causing microbe Treponema pallidum die, inoculated into the vaginas of mice, which are stimulated with lubricating compositions of the present invention; and
[46] Fig. 10 is a drawing illustrating a survival rate, in which 2 X 104 cells of a vaginitis- causing microbe Candida albicans are inoculated into the vaginas of mice, which are stimulated with lubricating compositions of the present invention. Mode for Invention
[47] Hereinafter, the present invention will be described in detail with reference to examples. However, these examples are for the illustrative purpose only, and the invention is not intended to be limited by the examples.
[48] Examples
[49] <Example 1> Preparation of lubricant
[50] Commercially available lubricant products are basically composed of the lubricant glycerin or the like as a lubricating ingredient and propylene glycol or the like as water-soluble alcohol, and a moisturizing agent. The effective substances to enhance the stimulation of mucosal immunity were added to the lubricants in various ratios, and used for experiments. The effective substances to enhance the stimulation of mucosal immunity were added singly or in cocktails thereof. The detailed compositions and ratio thereof are shown in Table 1. The compositions listed in Table 1 were directly mixed with commercially available lubricant products (Unidus gel®, Astroglide®) to prepare the lubricants used in the experiments. Alternatively, the effective substances to enhance the stimulation of mucosal immunity were dissolved in propylene glycol, which is water-soluble alcohol dissolving the lubricating ingredients, and then mixed with glycerin to prepare the lubricants used in the experiments.
[51] The effective substances to enhance the stimulation of mucosal immunity were commercially available ones, or the Korean mistletoe extract was prepared according to the method described in Korean Patent Application Nos. 10-1996-5732, 10-2004-31109 or 10-1999-41288 to be used.
[52] [Table 1]
[53] Effective substances to enhance stimulation of mucosal immunity
[Table 1] [Table ]
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
[54] <Example 2> Examination of B-/T-cell differentiation potential of mouse splenocytes using FACScan [55] Among lubricating compositions comprising agents which induce the mucosal immunity prepared according to the above compositions, compositions exhibiting particularly higher activity were identified. High active substances and cocktail compositions are shown in Table 2.
[56] [Table 2] [57] High active substances and cocktail compositions [Table 2] [Table ]
CT B-subunit
European mistletoe lectin
Korean mistletoe lectin
European mistletoe lectin + CpG ODN (1: 1)
Korean mistletoe lectin + CpG ODN (1:1)
LPS + Korean mistletoe lectin (1:1)
CT B-subunit + Korean mistletoe lectin (1 :1) β-glucan + Korean mistletoe lectin (1:1)
[58] The vaginas of mice were stimulated with the lubricants comprising a substance or cocktail composition in Table 2 using a sterilized cotton swab. The added amount of the substance or the cocktail composition was 0.1 μ g/head. As a control group, a phosphate buffer solution (PBS) was added, instead of the substances to enhance the stimulation of mucosal immunity. Experiment was performed for 15 days (one application per day), and a nonspecific immunity test was performed. On day 16, the mice were sacrificed, and splenocytes were isolated from the spleens. Then, the B- /T-cell distribution was observed using antibodies by a FACScan. As a result, the test groups treated with the lubricants comprising the effective substances to enhance the stimulation of mucosal immunity showed twice higher B-cell and T-cell activity than the control group (Fig. 1).
[59] <Example 3> Examination of T-cell differentiation potential of mouse splenocytes using FACScan
[60] After treated mice according to the method described in Example 2, T-cell differentiation potential was examined in mouse splenocytes treated with the lubricants comprising the phosphate buffer solution (control group) and the compositions listed in Table 2 (test groups). It can be seen that more CD3 was observed since the response was a nonspecific immune response, as shown in Fig. 2. If antigens had been administered together, more CD4 or CD8 would have been observed than CD3. To conclude, although the specific immune response did not occur, the T-cell distribution was obviously observed in the groups treated with the lubricants comprising various compositions, as compared to the control group. Accordingly, it is thought that immunity against a variety of antigens or pathogens was activated.
[61] <Example 4> Examination of antibody titration in mucosal wash samples of mouse
[62] After treated mice according to the method described in Example 2, serum, oral wash samples, nasal wash samples, tracheal wash samples, urinary and vaginal wash samples were obtained from mice treated with the lubricants comprising the phosphate buffer solution (control group) and the compositions of Table 2 (test groups). For this purpose, 500 μ L of PBS was added to the mucous membranes of other organs except serum, and washed 20 times. Then, the wash samples of the mucous membranes were placed in sterile E-tubes. Such performances were repeated 10 times to obtain 5 mL of wash samples, which were centrifuged at 6,000 rpm. Only the supernatants were taken and stored at 4 ° C for 24 hours. A protein G column chromatography was performed with the wash samples to isolate IgG, and fractionated IgA was separately taken.
[63] Each of two samples obtained by the method was subjected to time-resolved fluorescence immunoassay (TR-FIA), which was performed according to the method by Kensner et al. (Steroids, 59, 1994, 206). The method will be put simply in the following. The isolated IgG antibodies were diluted from 1000 to 128,000 times by 2-fold serial dilution, and each 0.1 ml of eight diluted samples was applied to 96-well plates and left at 37 ° C for 2 hours. Then, the plates were repeatedly washed 5 to 6 times using an automatic washer, and goat IgG anti-mouse IgG-Eu particle conjugates were added thereto at a diluted concentration of 1:5000, and reacted at 37 ° C for 2 hours. Subsequently, the plates were repeatedly washed 5 to 6 times using an automatic washer. 200 μ L of enhancement solution was added thereto, and further reacted for 5 minutes. Measurement was made using DELFIA (Wallac, Model 1420).
[64] Titration of fractionated IgA from IgG was performed in the same manner as mentioned above, and goat IgG anti-mouse IgA-Eu particle conjugates were used differentially. The detailed results are shown in Figs. 3, 4, 5, 6, and 7.
[65] From the results of this example, it was found that the mice, of which vaginas were stimulated with the lubricants comprising the effective substances to enhance the stimulation of mucosal immunity or cocktails thereof, showed at least 1:64,000 or more of IgG titration in sera, and at least 1 : 16,000 or more of IgG titration in mucosal wash samples, as compared to the control group. Further, it was found that IgA was not observed in the sera, and IgA titration in the mucosal wash samples excluding the sera was at least 1:8,000.
[66] <Example 5> Challenge test on mucosal immunity enhanced mouse
[67] Each 2 X 104 cells of the gonorrhea-causing microbe, Neisseria gonorrheae, the syphilis causing microbe, Treponema pallidum, and the vaginitis -causing microbe, Candida albicanswere inoculated into the vaginas of female mice, of immunity which were enhanced in Example 4. The inoculation was performed at the same concentration everyday for first 3 days, and the number of surviving mice was observed for 10 days. The results are shown in Figs. 8, 9, and 10. This test using the arbitrary pathogens confirmed that a high survival rate can be obtained by nonspecifically enhanced immunity.
[68] While the present invention has been described with an emphasis upon preferred embodiments, it will be obvious to those skilled in the art that variations in the preferred embodiments may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the claims that follow.

Claims

Claims
[1] A lubricating composition comprising one or more agents which induce mucosal immunity.
[2] The lubricating composition according to claim 1, wherein one or more agents which induce the mucosal immunity are selected from the group consisting of β- glucan, cholera toxin B-subunit (CT B-subunit), E. coli heat-labile toxin (LT), pertusis toxin, lipopolysaccharide (LPS), monophosphoryl lipid A (MPL), oli- godeoxynucleotides containing unmethylated dinucleotides (CgP ODN), an aluminum salt, an Acanthopanax Senticosus extract, European mistletoe lectin, European mistletoe lectin B -chain, a Korean mistletoe extract, Korean mistletoe lectin, Korean mistletoe lectin B-chain, and cocktails thereof.
[3] The lubricating composition according to claim 1, wherein one or more agents which induce the mucosal immunity are selected from the group consisting of CT B-subunit, European mistletoe lectin, Korean mistletoe lectin, European mistletoe lectin + oligodeoxynucleotides containing unmethylated dinucleotides (CpG ODN), Korean mistletoe lectin + CpG ODN, lipopolysaccharide (LPS) + Korean mistletoe lectin, CT B-subunit + Korean mistletoe lectin, and β-glucan + Korean mistletoe lectin.
[4] A preparation method of a lubricating composition, comprising adding one or more agents which induce mucosal immunity.
[5] A contraceptive device or medical/diagnostic device, comprising a lubricating composition comprising one or more agents which induce mucosal immunity.
[6] A condom coated with a lubricating composition comprising one or more agents which induce mucosal immunity.
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US12043598B2 (en) 2018-03-20 2024-07-23 Lanvira, Llc Condoms lubricated with antiviral lubricious compositions containing lambda-carrageenan
CN109730985A (en) * 2019-03-27 2019-05-10 丹东欣时代生物医药科技有限公司 A kind of production method of conception control gel
WO2021262141A1 (en) * 2020-06-22 2021-12-30 Mario Elmen Tremblay Personal lubricants comprising lambda-carrageenan

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