EP1294412A4 - Verfahren zur verwendung von lectinen zur geburtenkontrolle und zur vorbeugung gegen durch sexuellen kontakt übertragbare krankheiten und lectine enthaltendes kondom - Google Patents

Verfahren zur verwendung von lectinen zur geburtenkontrolle und zur vorbeugung gegen durch sexuellen kontakt übertragbare krankheiten und lectine enthaltendes kondom

Info

Publication number
EP1294412A4
EP1294412A4 EP00941340A EP00941340A EP1294412A4 EP 1294412 A4 EP1294412 A4 EP 1294412A4 EP 00941340 A EP00941340 A EP 00941340A EP 00941340 A EP00941340 A EP 00941340A EP 1294412 A4 EP1294412 A4 EP 1294412A4
Authority
EP
European Patent Office
Prior art keywords
lectins
lectin
condom
binding
pathogenic microorganism
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00941340A
Other languages
English (en)
French (fr)
Other versions
EP1294412A1 (de
Inventor
Michael J Oldham
Bruce F Rose
Howard C Krivan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Legere Pharmaceuticals Ltd
Original Assignee
Legere Pharmaceuticals 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 Legere Pharmaceuticals Ltd filed Critical Legere Pharmaceuticals Ltd
Publication of EP1294412A1 publication Critical patent/EP1294412A1/de
Publication of EP1294412A4 publication Critical patent/EP1294412A4/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/168—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • 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
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/408—Virucides, spermicides

Definitions

  • TITLE METHOD OF USING LECTINS FOR CONTRACEPTION AND
  • This invention relates generally to methods of contraception and prophylaxis against diseases transmittable by sexual contact and more particularly to a method using intravaginally administered lectins for contraception and to protect against the transmission of diseases that are transmissible by sexual contact and to treat such diseases.
  • the invention also relates to a condom containing lectins.
  • STDs sexually transmitted diseases
  • other diseases that have not traditionally been considered to be STDs have also been found to be transmitted by sexual contact, e.g., hepatitis B.
  • barrier methods which prevent the transfer of body fluids between individuals are the most effective means of preventing transmission of such diseases. Such barrier methods are also effective contraceptive procedures. However, such methods are somewhat inconvenient and require some cooperation between individuals .
  • An example of a commonly used and generally effective barrier method is the use of condom by the male partner or of a similar barrier used by the female partner to provide complete isolation against transfer of bodily fluids from one partner to the other.. Such devices are effective for prevention of transmission of STDs and for contraception, provided that the physical barrier remains intact. In some cases however, the condom or the like may develop microscopic leaks or may contain small and perhaps unnoticeable perforations which can permit the transfer of microorganisms or of sperm across the barrier.
  • the condom may rupture and permit substantial transfer of bodily fluids with the consequence of possible infection or conception.
  • gross rupture of a condom is relatively rare, it has been found that leaks sufficient to permit the escape of microorganisms in infectious amounts are by no means uncommon. Accordingly, the recent emergence of more serious and even fatal STDs such as AIDS has caused concern that even relatively reliable total barrier methods may not be satisfactory.
  • An alternative method for preventing the transmission of sexually transmitted diseases is to kill or inhibit the pathogenic microorganisms in semen and vaginal secretions so that they are incapable of infecting the tissues and causing the disease.
  • intravaginally placed spermatocides have been used for contraception, alone or in combination with barrier methods, antimicrobial materials have not been so used to prevent STDs, probably because many of such materials are irritating to adjacent tissues or are non-specific.
  • Administration of biologically active materials to the vagina for whatever purpose is usually accomplished by the use of some device that provides for convenient application of the medication by the user herself.
  • a variety of devices exist for delivery of bioactive substances such as spermatocides and various medications.
  • vaginal suppositories and ovules may not provide medication to the entire vagina because of their shape and placement by the user in the vagina.
  • Such suppositories are generally comprised of a material that melts at body temperature to allow the medication to spread and contact the tissues.
  • the dosage form melts the medication may drain out of the vagina rather quickly, thus minimizing its potential effectiveness and significantly reducing the extended exposure of the tissues and pathogens to the medication which is often necessary for effective treatment.
  • the effective duration of contraceptives applied in this way tends to be relatively brief.
  • such delivery vehicles even when freshly applied, do not provide any physical barrier to deposition of male ejaculate on the cervix.
  • Such ready access of sperm to the cervix may allow them to escape the action of spermatocides that are diffused throughout the vagina.
  • cells at the cervix are uniquely sensitive to several pathogens such as Chlamydia trachomatis, the absence of a barrier deprives these cells of a significant means of protection.
  • vaginal rings In order to provide for a longer retention of medication in the vagina and assure a more continuous delivery of active ingredients to the tissue, several types of vaginal rings have been proposed. Such devices are disclosed, for example, in Duncan, U.S. Patent 3,545,439; Rose an, U.S. Patent 3,920,805; Schopflin, U.S. Patents 4,012,496 and 4,012,497; Wong et al . , U.S. Patents 4,237,885 and 4,286,587; and Nash et al . , U.S. Patent 4,-292,965.
  • vaginal rings are generally impregnated with a spermatocide and are designed to be retained in the vaginal vault and to release the spermatocide slowly over a period of time to maintain an effective contraceptive concentration of the active material in the vagina.
  • spermatocide do not prevent the direct contact of ejaculate with the tissues of the cervix, and therefore do not protect those tissues from contact with pathogenic organisms which might be contained in the ejaculate. They are also of questionable efficacy in supplying the spermatocide where it is most needed.
  • Another approach is to use a cervical cap or a diaphragm to serve as a mechanical barrier to the sperm and to dispense medication.
  • These devices are designed for a relatively tight fit either to the cervix or the walls of the vagina to serve as a mechanical barrier to the passage of sperm.
  • Such devices can be effective, especially as contraceptives and when combined with spermatocides.
  • they are frequently relatively complex devices incorporating metallic springs within a rubber or synthetic resin structure to provide the required sealing force.
  • Another approach to providing an effective concentration of spermatocide in the vagina is to provide a sponge impregnated with a spermatocide.
  • Such applicators are not intended to be precisely located and may permit the contact of ejaculate with the tissues of the cervix, with the undesirable consequences outlined above.
  • a need has continued to exist for a method of contraception and prophylaxis against STDs by vaginal administration of a material that inactivates microorganisms or sperm and for a device that assures contact of such a material with microorganisms or sperm present in the male or female urogenital tract or male ejaculate.
  • lectins capable of binding sperm and/or the pathogenic microorganisms responsible for STDs are administered to the vagina or site of infection prior to sexual intercourse.
  • the lectins immobilize sperm to render them incapable of fertilization and also bind to the microorganisms to render them non-pathogenic or to the epithelial cells of the urogenital tract and vagina to prevent infection by the microorganisms.
  • the invention also encompasses a condom having a membrane body and -a hollow interior that carries one or more lectins in its interior or impregnated into the membrane body, or coated on or linked to the membrane body.
  • a further object is to provide a method of contraception.
  • a further object is to provide a method for binding and immobilizing pathogenic microorganisms in the vagina.
  • a further object is to provide a device for delivering lectins to the vagina.
  • a further object is to provide a composition for delivering lectins to the vagina.
  • a further object is to provide a condom coated with lectins .
  • a further object is to provide a condom having lectins covalently bound to the inner and/or outer surfaces thereof.
  • a further object is to provide a condom having a lumen containing lectins .
  • a further object is to provide a condom impregnated with lectins .
  • a further object is to provide a condom containing lectins within its hollow body.
  • a further object is to provide a condom having a reservoir of lectins on its outer surface.
  • Figure 1 is a side elevational view of a condom according to the invention.
  • Figure 2 is a front elevational view of a condom according to the invention.
  • Figure 3 is a longitudinal sectional view of the condom of the invention taken along the line 3-3 in Figure 2.
  • Lectins are carbohydrate-binding proteins of nonimmune origin that agglutinate cells or precipitate polysaccharides or glycoconjugates, i.e., proteins or lipids conjugated to oligo- or polysaccharides. They are widely distributed, and have been isolated from both plant and animal sources. Their reactions with living cells are based on their ability to bind with antibody-like specificity to particular arrangements of the sugar residues that make up oligo- or polysaccharides.
  • the surface of eucaryotic cells contain very numerous molecules of glycoproteins and glycolipids.
  • the cell walls and outer membranes of bacteria and the envelopes of viruses contain structural polysaccharides and/or glycoproteins.
  • the carbohydrate moieties of these molecules which are displayed on the cell surfaces exhibit great variety in composition and structure that serves to distinguish the types of cells and to serve as a signal to other cells or materials which come into contact with the cell.
  • variation in the carbohydrate moieties of glycoproteins and glycolipids in the membrane of red blood cells serves as the basis for the conventional blood typing classification.
  • lectins When lectins recognize and bind to certain carbohydrate moieties they may serve to cross-link and agglutinate the cells bearing the binding groups, a property that earns for them the alternate name of agglutinins. Furthermore, because the same sort of carbohydrate moieties often serve as attachment points for pathogens to bind to target cells and infect or invade them, lectins may block infection of target cells by blocking the sites used by pathogens as recognition markers. The same type of specific binding occurs between sperm and egg in conception, and can be blocked by lectins.
  • the binding ability of lectins may be very specific for certain mono- or oligosaccharides, allowing lectins to be used as a powerful tool for investigating the oligosaccharide epitopes on the surface of organisms or cells. While glycoproteins, glycolipids, and bacterial cell walls are believed to be the main lectin-binding locations on the surface of cells, it is not excluded that carbohydrate moieties derived from other molecules or cellular structures may be displayed on the cell surface or that other lectin-binding structures may be present on cell surfaces. All such lectin-binding structures may be targets for 'the lectins used in the method of this invention.
  • microorganism includes any microscopic organism within the categories of algae, bacteria, fungi, parasites (helminths, protozoa) , viruses, and subviral agents.
  • Lectins may be used to target such microorganisms in vitro and are also capable of binding to them in vivo, thereby preventing them from infecting living cells.
  • Human disease- causing organisms that can be bound by lectins include Neisseria gonorrhoeae (gonorrhea) ; Chlamydia trachomatis (chlamydia, ly phogranuloma venereum) ; Treponema pallidum (syphilis) ; Haemophilus ducreyi (chancroid) ; Calymmatobacterium granulomatis (donovanosis) ; Mycoplasma pneumoniae, M. hominis, M.
  • Ureaplasma urealyticum mycoplasmas
  • Shigella flexneri shigella
  • Salmonella typhi Salmonella typhi
  • S. choleraesuis S. enteritidis (salmonella)
  • Campylobacter fetus C.
  • STDs sexually transmitted diseases
  • STDs sexually transmitted diseases
  • STDs sexually transmitted diseases
  • lectins are also ' capable of agglutinating human sperm and other components of the male ejaculate, and thereby rendering the sperm immobile
  • intravaginal administration of lectins can also serve as a method of contraception.
  • a dose of lectins adapted to bind and agglutinate pathogenic microorganisms and/or block the recognition sites on target cells is administered to the vagina prior to sexual intercourse.
  • the active ingredients may also include lectins capable of binding and/or inactivating sperm or the male ejaculate to serve as a contraceptive.
  • lectins Because of the specificity of lectins for certain microorganisms, it is preferred to administer a mixture of lectins chosen for their properties of agglutinating specific pathogens. -It is also according to the invention to administer a mixture of sperm-agglutinating lectins and lectins capable of binding to pathogenic organisms to provide simultaneous contraception and protection against infection.
  • Lectin Source AAnA Anguilla anguilla (eel serum) AAur Aleuria aurantia (orange peel fungus) ABA Agaricus bisporus (mushroom) ABrA Amphicarpanea bracteata (hog-peanut) AEP Aedopodium podagraria (ground elder) AL Hippaestrum hybrid (amaryllis bulbs) APA Abrus precatorius (jequirity bean) AS Avena sativa (oat) BDA Bryonia dioica (white bryony) BPA Bauhinia purpurea alba (camel's foot tree) CA Cymbidium species
  • CAA Caragana arborescens (Siberian pea tree)
  • GSA-I /GSA-I I Griffonia simplicifolia HAA Helix aspersa (garden snail) HHA Hippeastrum hybrid HPA Helix pomatia (Roman or edible snail)
  • LCA LCA (LcH) Lens culinaris (lentil)
  • NPL Narcissus pseudonarcissus (daffodil)
  • PHA Phaseolis vulgaris (red kidney bean)
  • PNA Arachis hypogaea (peanut)
  • TMT Tomentine (seaweed Codium tomentosum)
  • VAA Viscum album European mistletoe
  • VFA Vicia faba fava bean
  • N. gonorroeae Triticum vulgaris (wheat germ) suc-WGA(sWGA) Succinyl WGA
  • N. gonorroeae is agglutinated by lectins that bind to N-acetyl-D-glucosamine residues on their surfaces .
  • Such lectins include WGA and STA, which are known to agglutinate all 193 clinical isolates of N. gonorrhoeae.
  • WGA is effective for such agglutination at a concentration of 3.1 micrograms per milliliter.
  • Other lectins showing some agglutination activity with respect to N.
  • gonorrhoeae include RCA-I, RCA-II, GSA-I, and SBA.
  • Certain species of Chlamydia trachomatis, psittaci, and pneumoniae are known to be bound by the lectins ConA, DBA, UEA-1, SBA, and PNA.
  • WGA also binds to the receptors on certain cells, thereby blocking infection by C. trachomatis and C. psittaci.
  • PHA binds to several isolates of H. ducreyi, suggesting that N-acetyl-D-glucosamine is present in the outer membrane polysaccharide.
  • WGA has been found to agglutinate a variety of bacterial cells, including Escherichia coli, Micrococcus luteus, and some types of Staphylococcus aureus .
  • WGA specific for N-acetyl-D- glucosamine and SBA, specific for N-acetyl-D-galactosamine, are capable of agglutinating the many bacterial species which contain these sugar residues in their cell wall polysaccharides .
  • lectins are capable of binding to certain glycoproteins present in the envelope of HIV virus.
  • ConA has been found to block infection of certain cell lines against infection by HIV in vitro
  • conglutinin a lectin derived from bovine serum
  • GNA has been found to prevent infection of T-cells by HIV in vitro. Consequently, ConA, and GNA have been found to be effective at preventing infection of target cells by HIV-1 and HIV-2 in vitro.
  • NPL and conglutinin have shown some activity as well.
  • HPA ConA, BPA, and EHL have demonstrated efficacy in the prevention of infection of target cells by HSV-1 and HSV-2.
  • Lectins are also useful in aggregation of sperm.
  • PHA, WGA, STA, ConA, PSA, APA, ECA, and ECorA have demonstrated varying degrees of efficacy in agglutination of sperm.
  • lectins discussed above and the microorganisms against which they are effective are representative of useful lectins according to the invention, it is to be understood that other lectins may be discovered which are active in the binding and agglutination of the pathogens of sexually transmitted diseases, and that the use of such lectins is intended to be included within the scope of the invention.
  • the amount of lectin to be administered for effective binding and/or agglutination of the pathogenic microorganisms of STDs the amount of lectin that might be bound to vaginal tissues and thereby made unavailable for agglutination of pathogens must be considered.
  • lectins to be administered will depend on the diseases sought to be prevented. It is preferred to administer a mixture of lectins, each selected for best agglutinative efficacy against a particular pathogen.
  • the lectins may be administered in any fluid or ointment vehicle ' suitable for topical administration of pharmaceutical compounds.
  • creams, ointments, foams, suppositories, liposomes, ovules and the like may be formulated in which the selected lectins are dispersed in a non-toxic vehicle suitable for topical and in particular for vaginal administration.
  • vehicles include oil-in-water and water-in-oil emulsions, white petrolatum, hydrophilic petrolatum, lanolin emulsions. polyethylene glycols, cocoa butter and the like.
  • Useful vehicles include emollient oils such as water-soluble oils, e.g., liquid polyethylene glycols, which promote complete and uniform distribution of the medicament within the vagina.
  • emollient oils such as water-soluble oils, e.g., liquid polyethylene glycols, which promote complete and uniform distribution of the medicament within the vagina.
  • suitable vehicles include a lubricating jelly comprised of water, propylene glycol, hydroxyethyl cellulose, benzoic acid and ' sodium hydroxide, a water-soluble oil
  • lectins comprised of water, glycerin, propylene glycol, polyquaternium #5, methyl paraben and propyl paraben; a cream comprised of benzyl alcohol, cetearyl alcohol, cetyl esters wax, octyldodecanol, polysorbate 60, purified water, and sorbitan monostearate; and a suppository comprised of polyethylene glycol (PEG) 13, PEG-32, PEG-20 stearate, benzethonium chloride, methyl paraben and lactic acid.
  • the lectins can also be incorporated into any conventional controlled release system for releasing them gradually or in a controlled timed release profile to the site of intended activity.
  • Such systems include particles having coatings that dissolve or erode at different controlled rates in a body fluid, matrices, e.g., polymers from which the lectins can diffuse, erodible matrices that release lectins to the site of intended activity, or the like.
  • the invention encompasses a composition having one or more lectins dispersed in a pharmaceutically acceptable non- toxic vehicle.
  • a composition may be in the form of a cream, lotion, ointment, salve, foam, meltable solid or the like.
  • the dispersion, suspension, emulsion, or solution of lectins in the vehicle may be applied to the site of a lesion on the external genitalia, such as the lesions produced by herpes simplex virus type 1 or type 2, chancroid, genital warts, chancre of syphilis, and the like, to prevent the transfer of pathogens.
  • the lectins may also be introduced into the vagina in order to prevent conception or infection by pathogens introduced during sexual intercourse.
  • the amount of lectins to be applied will be an amount that is effective to prevent conception or infection or substantially reduce the risk thereof.
  • the amounts needed to achieve these goals will depend on the effectiveness of the individual lectins, their affinity for the target cell and the like. The effective amounts can be determined by the skilled practitioner by routine experimentation.
  • the lectins can be delivered to the desired site of activity either as a bolus or in the form of a controlled release composition, as is well-known in the art.
  • lectins are also useful in therapy of topical infections of the vagina.
  • administration of lectins alone or in combination with other antimicrobial materials, such as antibodies, can assist in the treatment and cure of the infections
  • a device which will remain in the vagina and dispense the lectins over a prolonged period of time in order to maintain an effective concentration of the lectins in the vagina.
  • a device may also be designed to provide a barrier that will prevent the access of pathogenic organisms into the uterus and may also function as a contraceptive device.
  • the lectins to be introduced into the vagina can be incorporated in any conventional vaginal medication-dispensing device such as suppositories, ovules, pessaries and the like, including controlled-release systems as discussed above.
  • the lectins may also be incorporated into conventional contraceptive devices such as diaphragms, cervical caps, vaginal sponges or the like.
  • the lectins may be incorporated into the body of such devices or coated on the surface thereof either neat, or in a vehicle, e.g., as a dusting powder, or in a binder that provides a coating from which the lectins are released over a period of time.
  • a particularly preferred method of administering lectins to the urogenital tract and vagina according to the invention for contraception and prevention and therapy of STDs is to incorporate the lectins into a condom.
  • the lectins may be coated on the inside or outside surface of the condom either neat, or in a dusting powder vehicle, or in a binder that affixes the lectins to the surface of the condom.
  • the coating may be comprised of polymeric materials, either polymerized in situ on the surface of the condom or coated from conventional solvent or dispersant coating systems.
  • the coating may be dry or may be a fluid having an appropriate viscosity.
  • the lectins may be covalently bound by a linking agent to the surface of the membrane body of the condom.
  • the binder can be of the type that releases the lectins immediately into the vagina or may provide for gradual release over a period of time.
  • sustained release binders are known to those skilled in the art and may be of the same type and composition as used for solid dosage forms incorporating lectins discussed above.
  • Lectins may be covalently bound to the surface of the membrane body of the condom by means of difunctional or polyfunctional reagents capable of reacting with the -lectins and also with reactive groups present on the surface of the latex membrane body of the condom.
  • the -lectins may also be incorporated into a structure in the condom specially adapted to hold and dispense the lectins, e.g., into one or more depressions, pockets or the like formed in the surface of the condom or a portion thereof, e.g., at the tip of the condom.
  • the lectins contained in such a reservoir will then be released from the depressions, pockets, etc., into the vagina during sexual intercourse.
  • a condom according to the invention having a reservoir containing lectins is illustrated in the drawings wherein the reference numerals refer to the same elements throughout.
  • a condom 100 according to the invention has a membrane body 102 surrounding a hollow interior 106.
  • the membrane body has an exterior surface 104 and an interior surface 108.
  • a reservoir 112 At the tip 110 of the condom 100 is formed a reservoir 112 that is suitable for containing a charge of lectins, either neat or in a composition as described above, indicated as 116.
  • the reservoir has an opening 114 through which the lectins can escape into the vagina to exercise their antimicrobial and/or contraceptive activity.
  • the lectins may also be incorporated into the membrane body of the condom or a portion thereof, e.g., a specially formed or thickened portion at the tip thereof.
  • the lectins will be released from such a condom by leaching or migration from the body of the condom into the vagina during sexual intercourse.
  • Another way in which lectins may be used in a condom for prevention of STDs or contraception is by introducing a charge of lectins inside the hollow interior of the condom.
  • the lectins may be present in the condom neat, or in a powder vehicle, or in a fluid vehicle, preferably a thickened fluid vehicle such as a cream, salve or thickened lotion, or the like, or in a dry coating of a natural or synthetic polymer or other suitable material.
  • a fluid vehicle preferably a thickened fluid vehicle such as a cream, salve or thickened lotion, or the like
  • a dry coating of a natural or synthetic polymer or other suitable material When lectins are used in the interior of the condom they serve primarily as a safety factor to prevent infection or contraception in case the condom should leak or become ruptured in use. In this application, the lectins may also serve for therapy of diseases of the male urogenital tract.
  • the method of using lectins according to the invention to prevent the transmission of STDs can also be used in a broader application to prevent the spread of STDs accidentally during surgical or diagnostic procedures.
  • Lectins may be incorporated into the membrane body of surgical gloves or placed within the interior " of surgical gloves of the conventional type having a relatively thin rubber or polymer membrane surrounding a hollow interior and shaped to cover the hand.
  • the lectins can protect surgeons and other medical personnel from infection by contact with blood or other bodily fluids of infected patients if the surgical gloves should leak or become punctured or cut, allowing such fluids to contact an open lesion on the hand of the wearer.
  • the gloves will contain one or more lectins that can bind to and inactivate any pathogenic microorganisms that might find their way into the interior of the glove through a small, perhaps undetected, hole.
  • the lectins can be placed within the glove in the form of a neat powder or a formulated powder containing the lectins in a powder vehicle, or in the form of lectins dispersed in a liquid or semisolid vehicle such as a cream, salve, lotion or the like, or in a dry coating of a natural or synthetic- polymer or other suitable material.
  • EXAMPLE 1 This example illustrates the utility of various lectins in binding to certain microorganisms and to seminal plasma, sperm, human serum -and cervical mucus.
  • a cervical isolate of Chlamydia trachomatis serovar G ATCC VR-878 was grown in 175 cm 2 McCoy cell monolayers in the presence of 2 ⁇ g of cycloheximide per ml.
  • the culture medium was 90% Dulbecco's Eagle's minimum essential medium-10% fetal calf serum-20 ⁇ M HEPES (pH 7.3) supplemented with 50 ⁇ g of gentamycin sulfate per ml.
  • Elementary bodies were purified by differential centrifugation followed by density gradient centrifugation in Percoll as described by Newhall et al . (Newhall, W.J., Baheiger, B., and Jones, R.B.
  • Neisseria gonorrhoeae ATCC 19424 were grown on chocolate agar plates for 48-72 hrs at 37°C in a C0 2 incubator (5% C0 2 and 80% humidity) and were harvested by scraping bacteria from the agar surface and resuspending the cells in sterile phosphate buffered saline. The cells were washed three times by centrifugation at 5000 x g and resuspended in bicarbonate buffer, the density of which was adjusted to a McFarland No. 2 standard (optical density as measured by a spectrometer - 0.4 at 650 nm) . The cells were stored on ice prior to immediately testing in the lectin binding assay.
  • Lactobacillus jensenii ATCC 25258 was grown 48 - 72 hrs. at 37°C in a shaking incubator in MRS broth at pH 5.5 containing 2% glucose. After incubation, cells were centrifuged at 5000 x g for 10 min and washed twice in phosphate buffered saline, and 'the density was adjusted to a McFarland No. 2 standard with bicarbonate buffer. Haemophilus ducreyi was grown on chocolate agar plates for 72 hrs in a C0 2 incubator
  • Bacteria were harvested by scraping bacteria from the agar surface and resuspending the cells in sterile phosphate buffered saline. The cells were washed three times by centrifugation at 5000 x g, resuspended in bicarbonate buffer and the cell density adjusted to a
  • McFarland No. 2 standard The cells were stored on ice prior to immediately testing in the lectin binding assay.
  • Biotinylated lectins were reconstituted in phosphate buffered saline (10 mM sodium phosphate-150 M NaCl, pH 7.2) and stored in a freezer at -70°C until used. Microtiter plates washed with 95% ethanol and dried were coated with bacteria (Chlamydia trachomatis or Neisseria gonorrhoeae or Haemophilus ducreyi or Lactobacillus jensenii) ' by adding 200 ⁇ l of a -bacterial suspension (in bicarbonate buffer) to each well and incubating overnight at room temperature.
  • bacteria Cholamydia trachomatis or Neisseria gonorrhoeae or Haemophilus ducreyi or Lactobacillus jensenii
  • Wells coated with bacteria were washed three times in either sodium acetate Buffered saline, pH 4.0, containing 0.1% Tween detergent (ABST) or phosphate buffered saline, pH 7.2, containing 0.1% Tween (PBST) .
  • Lectins defrosted at room temperature were diluted in each buffer, and 100 ⁇ l of various lectins was added to bacteria-coated wells at a final concentration of 50 ⁇ g/ml.
  • Cervical Mucus A sample of cervical mucus was obtained from a healthy donor and the gel phase separated by centrifugation. The pellet was washed three times by centrifugation and the mucin stabilized and alkylated before dialysis against a low ionic strength, pH 8.0 buffer. The cervical mucus was bound to flat-bottomed plates by incubating in bicarbonate coating buffer at 4°C overnight. The plates were washed to remove unbound ligand. Biotinylated lectins were serially diluted across the plates in the wash buffer and the plates incubated at room temperature for 2 hrs.
  • Unbound lectin was removed by washing, .and the bound lectins were tagged by incubating with streptavidin-alkaline phosphatase at room temperature for 1 hr. Unbound streptavidin-alkaline phosphatase was removed by washing and the assay completed by adding freshly prepared p-nitrophenylphosphate (1 mg/ml) in 0.1 M Tris buffer-0.15 M NaCl and monitoring the rate of color production.
  • Serum ' A sample of blood was collected from a healthy donor, the serum separated by centrifugation and stored at -20°C. The binding assay was performed in the same way as for cervical mucus and seminal fluid. Analysis of data: Sigma Plot was used for graphing and curve fitting of binding plots. Velocity of the color-forming reaction versus concentration of lectin added was plotted.
  • the binding "quotient” is defined as a/b.
  • Lactobacillus jensenii are summarized in the following tables wherein WB signifies weak binding, NB signifies no binding and N/A signifies not available.
  • the affinity of the lectin for a particular substrate is inversely proportional to the maximum velocity of the color-forming reaction. Consequently, those lectins having a smaller b value ( [lectin] ⁇ /2 max) bind more firmly to the substrate.
  • a high binding efficacy (low m 0D /min) is preferable for binding to sperm or seminal plasma for contraceptive purposes or to a pathogen, such as Neisseria gonorrhoeae, ' whose infectious activity is to be " inhibited.
  • vaginal flora some microorganisms of the vaginal flora, e.g., Lactobacillus jensenii, are desirable and may even provide some protection against pathogenic organisms. Accordingly, if possible, it is desirable to select a lectin for contraception and/or prophylaxis against sexually transmitted diseases that combines great binding affinity for the constituents of the male ejaculate or for a pathogenic microorganism, but has a lesser, preferably minimal, binding affinity for beneficial vaginal flora. A skilled practitioner may select the most efficacious lectins by consulting the data provided in the tables of this example.
  • EXAMPLE 2 This example illustrates the effectiveness of lectins in inhibiting the infective activity of Chlamydia trachomatis.
  • Chlamydia trachomatis serovar G was cultured as described in Example 1. Lyophilized lectins were reconstituted in phosphate buffered saline (PBS) to a concentration of 1 mg/ l and frozen at -20°C. The lectins were prepared for testing in the Chlamydia trachomatis inactivation assay by diluting them in Minimum Essential Medium (MEM) with 10 mM HEPES and 50 ⁇ g/ml gentamycin sulfate to appropriate concentrations. Chlamydia trachomatis serovar G elementary bodies were added to the diluted lectins and the mixture was incubated for 1.5 hours at MEM
  • Chlamydia-lectin mixture was added to monolayers of McCoy cells in 15 x 45 mm shell vials and centrifuged at 3500xg for 60 minutes at 37°C. Following centrifugation, the medium in the vials was removed and 1 ml of fresh Chlamydia overlay medium (with cycloheximide ) was added to each vial. The vials were incubated for 40-43 hours and the cells were then fixed and stained for Chlamydia trachomatis using Syva MicrotrakTM Chlamydia trachomatis culture confirmation reagent.
  • Table 9 shows the number of mean Chlamydia trachomatis inclusions per 160x microscopic field on a 12 mm circular glass coverslip as a percentage of a positive control sample which was not exposed to any lectins.
  • WGA 118%) and ConA (121%) show enhanced infectivity of Chlamydia trachomatis serovar G in having more inclusions per 160x field than the positive control which had not been exposed to any lectins.
  • exposure to Jacalin shows significantly reduced infectivity of Chlamydia trachomatis serovar G as evidenced by the 65% reduction in the number of inclusions per 160x field (35% of the positive control value) .
  • Table 10 shows the results of additional experiments for determining the anti-Chlamydia activity of selected lectins.
  • the data in the table show that at concentrations of 150 ⁇ g/ml, the lectins designated HAA, ABA, and RPA significantly reduced infection of McCoy cells by C. trachomatis. However, of these three, only the lectin designated RPA was cytotoxic to McCoy cells.
  • the lectins WGA and ConA potentiated chlamydial infectivity compared to control samples devoid of lectins.
  • GNA 150 82.0 94.2 83.4 86.5 sWGA 100 95.8 75.8 93.6 88.4
  • LAA 150 86.7 92.3 86.5 88.5
  • MAA 150 94.4 101.0 82.5 92.6
  • EXAMPLE 3 This example illustrates the effectiveness of lectins in blocking the infectivity of human immunodeficiency viruses Type 1 and 2 (HIV-l/HIV-2) .
  • a number of lectins were evaluated for possible inhibitory effects against HIV-1 and HIV-2 replication in primary infected human T-lymphocyte CEM cells.
  • the effect of lectins on the infectivity of HIV-1 and HIV-2 toward human lymphocytes was investigated in vitro by a standard technique (Balzarini et al., 1991, Antimicrobial Agents and Chemotherapy, March 1991, pages 410-416) wherein the toxicity of the lectins toward the infected cells was determined (human T-lymphocytes CEM/0) and also the ability of the lectins to block the fusion of infected cells (HUT-78/HIV-1 (III B ) ) with other cells (MOLT/4 clone 8).
  • CC 50 is the cytotoxic concentration without virus and corresponds to lectin concentrations required to reduce by 50% the number of viable cells in the virus-infected cultures.
  • Lectin EC50 ( ⁇ g/ml) a CC 50 b ( ⁇ g/ml)
  • GSA-I >100 >100 >200
  • GSA-II >100 >100 +90
  • ND means not determined
  • the lectins designated GNA, NPA and ConA inhibited virus-induced cytopathogenicity in CEM cells by 50%; however, the lectin designated ConA also was found to by cytotoxic to CEM cells at about 20 ⁇ g/ml.
  • lectins for contraceptive, prophylactic, and/or therapeutic use, it is not always the preferred to use the lectin that binds most strongly to the target microorganism. For example, it is preferable to use lectins that will not stimulate a mitogenic response in the host.

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EP00941340A 2000-06-12 2000-06-12 Verfahren zur verwendung von lectinen zur geburtenkontrolle und zur vorbeugung gegen durch sexuellen kontakt übertragbare krankheiten und lectine enthaltendes kondom Withdrawn EP1294412A4 (de)

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US7320891B2 (en) 2004-09-10 2008-01-22 Promega Corporation Methods and kits for isolating sperm cells
JP2013146352A (ja) * 2012-01-18 2013-08-01 Jex Inc コンドーム、および、コンドームの製造方法
WO2015116375A1 (en) 2014-01-28 2015-08-06 The Population Council, Inc. Combination product for the prevention of sexually transmitted infections
US10195169B2 (en) 2014-12-19 2019-02-05 Good Clean Love, Inc. Systems and methods for bio-matching gels, creams and lotions
US9470676B2 (en) 2014-12-19 2016-10-18 Good Clean Love, Inc. Systems and methods for bio-matching gels, creams and lotions
US10952979B2 (en) 2014-12-19 2021-03-23 Good Clean Love, Inc. Topical fertility promoting product and manufacturing method
GB201617063D0 (en) * 2016-10-07 2016-11-23 Cambridge Design Research Llp Condoms
CN118542697B (zh) * 2024-05-13 2025-07-08 广州万方健医药有限公司 性生活使用后的避孕套在同时采集和/或检测男性和女性生殖道病原体中的应用

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WO1993018650A1 (en) * 1992-03-18 1993-09-30 Trustees Of Columbia University In The City Of New York Antiviral contraceptive devices, particularly condoms
FR2696319A1 (fr) * 1992-10-02 1994-04-08 Berque Jean Utilisation de produits biologiques atoxiques et principalement de la riboflavine dans la fabrication des préservatifs et des gants de protection médico-chirurgicaux.
WO1995009641A1 (en) * 1993-10-01 1995-04-13 Lectin Biopharma, Inc. Using lectins for contraception, prophylaxis and therapy

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US5766632A (en) * 1993-10-01 1998-06-16 Legere Pharmaceuticals, Ltd. Method of using lectins for contraception

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WO1993018650A1 (en) * 1992-03-18 1993-09-30 Trustees Of Columbia University In The City Of New York Antiviral contraceptive devices, particularly condoms
FR2696319A1 (fr) * 1992-10-02 1994-04-08 Berque Jean Utilisation de produits biologiques atoxiques et principalement de la riboflavine dans la fabrication des préservatifs et des gants de protection médico-chirurgicaux.
WO1995009641A1 (en) * 1993-10-01 1995-04-13 Lectin Biopharma, Inc. Using lectins for contraception, prophylaxis and therapy

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