Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/74—Synthetic polymeric materials
  • A61K31/785—Polymers containing nitrogen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/18—Feminine contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
  • A61P31/22—Antivirals for DNA viruses for herpes viruses
• • 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
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S977/00—Nanotechnology
  • Y10S977/70—Nanostructure
  • Y10S977/754—Dendrimer, i.e. serially branching or "tree-like" structure

Definitions

• the present invention relates to a pharmaceutical composition and method of preventing pregnancy and, in particular, to the use of dendrimer compounds including naphthyl disulphonic acid surface groups.
• N9 Nonoxynol-9
• HSV Human Immunodeficiency Virus
• HSV Herpes simplex virus
• N9 which is a detergent based spermicide, may actually have adverse effects in the prevention of STIs. Whilst such detergents act to disrupt HIV and HSV membranes, they may also compromise the natural vaginal barrier and significantly increase susceptibility to infection.
• polylysine, polyamidoamine (PAMAM), poly(etherhydroxylamine) (PEHAM) and polypropyleneimine dendrimers including the compounds represented by Formulae I to III below and bearing naphthyl disulphonic acid surface groups have been shown to exhibit antimicrobial activity, particularly antiviral activity.
• R represents a group of the Formula IV:
• a contraceptive composition including an effective amount of a dendrimer compound including one or more naphthyl disulphonic acid surface groups, or a pharmaceutically acceptable salt or solvate of the dendrimer compound; and a pharmaceutically acceptable carrier, excipient and/or diluent therefor.
• the contraceptive composition may be provided in a topical form, such as a foam, gel, cream, film, or the like.
• the composition may be administered at any time during sexual intercourse, but preferably before and during sexual intercourse.
• the contraceptive composition may further include a secondary pharmaceutically active component.
• the contraceptive composition may also exhibit antimicrobial activity.
• the antimicrobial activity is towards sexually transmitted infections (STIs).
• STIs sexually transmitted infections
• the antimicrobial activity is antiviral activity toward viral sexually transmitted infections (STIs) including HIV, HSV, Hepatitis B and C (HBV and HCV), Human Papilloma Virus (HPV) and Cytomegalovirus (CMV).
• a method of selectively reducing or preventing conception in a female animal includes administering to the animal an effective amount of a contraceptive composition, which composition includes an effective amount of a dendrimer compound including one or more naphthyl disulphonic acid surface groups, or a pharmaceutically acceptable salt or solvate of the dendrimer compound; and a pharmaceutically acceptable carrier, excipient and/or diluent therefor.
• a contraceptive composition which composition includes an effective amount of a dendrimer compound including one or more naphthyl disulphonic acid surface groups, or a pharmaceutically acceptable salt or solvate of the dendrimer compound; and a pharmaceutically acceptable carrier, excipient and/or diluent therefor.
• composition included in the method may further include a secondary pharmaceutically active component.
• the contraceptive composition may be carried on a surface of a prophylactic device with which it is compatible.
• compositions containing certain dendrimer compounds with napthyl disulphonic acid surface groups have unexpectedly exhibited contraceptive activity.
• contraceptive activity as used herein in this specification and claims we mean activity that prevents or reduces the likelihood of a female animal becoming pregnant or giving birth.
• the contraceptive activity of a composition in general may be conferred by a number of mechanisms.
• Non- spermicidal contraceptive compositions may function to change the environment in the vagina.
• a hypertonic composition may result in hardening of the cervical mucus, thereby preventing or hindering entry of sperm into the cervix.
• Other compositions may form a matrix when they come in contact with ejaculate in the vagina, which traps the sperm and again limits their ability to reach the cervix. Maintaining the acidic environment with the vagina can also assist in inactivating sperm, particularly after ejaculation when the vagina pH increases from about 4 to a more "sperm friendly" neutral to slightly basic environment.
• a contraceptive composition may induce acrosomal loss.
• Acrosomes contain enzymes that allow penetration of the sperm into the ova.
• the enzyme hyaluronidase is required to disperse follicular cells surrounding the ova, thereby permitting sperm penetration.
• compositions that can inhibit this enzyme may have contraceptive activity.
• antimicrobial activity as used herein in this specification and claims we mean a composition, or components thereof, that kills or inhibits the growth of microbes such as bacteria, viruses, fungi and parasites.
• dendrimer compound as used herein in this specification and claims we mean any suitable highly branched macromolecules.
• the dendrimer compound may be of any suitable type.
• the dendrimer compound includes a polylysine, polyamidoamine (PAMAM), poly(etherhydroxylamine) (PEHAM) or polypropyleneimine dendrimer scaffold. More preferably, the dendrimer compound is selected from a compound of Formula I, Il or
• R represents a group of Formula IV:
• a dendrimer compound including one or more naphthyl disulphonic acid surface groups, or a pharmaceutically acceptable salt or solvate of the dendrimer compound; and a pharmaceutically acceptable carrier, excipient and/or diluent therefor.
• the dendrimer compound of Formula I is particularly preferred.
• the dendrimer compound may be present in the contraceptive composition in any suitable amount.
• the dendrimer compound is present in the composition in an amount of from approximately 0.5% to 70% by weight, based on the total weight of the composition. More preferably, the dendrimer compound is present in an amount of from 1% to 50% by weight, most preferably 1% to 30% by weight, based on the total weight of the composition.
• Suitable pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts such as the aluminium, calcium, lithium, magnesium, potassium, sodium and zinc salts, as well as organic salts made from organic amines such as N 1 N - dibenzylethlenediamine, chloroprocaine, diethanolamine, ethylenediamine, dicyclohexylamine, meglumine (N-methylglucamine) and procaine, quaternary amines such as choline and sulphonium and phosphonium salts.
• metallic salts such as the aluminium, calcium, lithium, magnesium, potassium, sodium and zinc salts
• organic salts made from organic amines such as N 1 N - dibenzylethlenediamine, chloroprocaine, diethanolamine, ethylenediamine, dicyclohexylamine, meglumine (N-methylglucamine) and procaine
• quaternary amines such as choline and sulphonium and phosphonium salts.
• the contraceptive composition may be a topical composition, preferably provided in the form of a foam, gel, cream, film or the like.
• Suitable pharmaceutically acceptable carriers, excipients and diluents may include one or more of any and all conventional solvents, dispersion media, fillers, solid carriers, aqueous solutions, coatings, vehicles suitable for topical administration, other antimicrobial agents, isotonic and absorption enhancing or delaying agents, activity enhancing or delaying agents for pharmaceutically active substances, and are well known in the art. They are described, by way of example, in Remington's Pharmaceutical Sciences, 18 th Edition, Mack Publishing Company, Pennsylvania, USA. Except insofar as any conventional carrier, excipient or diluent incompatible with the active agent, use thereof in the contraceptive composition of the present invention is contemplated.
• Vehicles suitable for topical administration include oil-in-water and water-in-oil emulsions, white petrolatum, hydrophilic petrolatum, lanolin emulsions, polyethylene glycols, cocoa butter, mucoadhesives, gelling agents, buffering agents , emollient oils (e.g.
• water-soluble oils including, for example, polyethylene glycol), a lubricating gel (including, for example, water, propylene glycol, hydroxyethyl cellulose, benzoic acid and sodium hydroxide), a water-soluble oil (including, for example, glycerine, propylene glycol, polyquaternium #5, methyl paraben and propyl paraben), a cream (including, for example, benzyl alcohol, cetearyl alcohol, cetyl esters, wax, octyldodecanol, polysorbate 60, purified water, and sorbitan monostearate), and the like.
• a lubricating gel including, for example, water, propylene glycol, hydroxyethyl cellulose, benzoic acid and sodium hydroxide
• a water-soluble oil including, for example, glycerine, propylene glycol, polyquaternium #5, methyl paraben and propyl paraben
• a cream including, for example
• the carriers, excipients and/or diluents include one or more of the group consisting of sodium hydroxide, water soluble oils, mucoadhesives, gelling agents, buffering agents, lubricating gels, propylene glycol, glycerine and water.
• the carriers, excipients and/or diluents include one or more of the group consisting of sodium hydroxide, water soluble oils, Carbopol ® , propylene glycol, glycerine, hydroxyethylcellulose and water. More preferably, they include sodium hydroxide, EDTA disodium dihydrate, methyl paraben, propyl paraben, Carbopol ® 971 P, propylene glycol, glycerine, and purified water in combination.
• the contraceptive composition may also exhibit antimicrobial activity.
• the antimicrobial activity is towards microbes that cause sexually transmitted infections (STIs).
• the contraceptive composition according to the present invention may be administered in an amount sufficient for the prevention of sexually transmitted infections. This amount may depend on the particular sexually transmitted infection sought to be prevented, and individual patient parameters including age, physical condition, size, weight and concurrent factors are well known to those of ordinary skilled in the art and can be addressed with no more than routine experimentation.
• STIs include, but are not limited to papillomaviruses, Chlamydia trachomatis, Candida Albicans, Trichomonas vaginalis, Herpes simplex viruses (HSV), Cytomegalovirus (CMV), Neisseria gonorrhoeae, Human Immunodeficiency virus (HIV), Treponema pallidum, Hepatatis B and C viruses (HBV and HCV), Calymmato bacterium granulomatis, Haemophilus ducreyi, Sarcoptes scabeie, Phthirus pubis, Mycoplasma, Gardnerella vaginalis.
• the antimicrobial activity is antiviral, exhibiting activity against sexually transmitted viruses including HIV, HSV, HCV, HBV, human papillomavirus (HPV) and CMV.
• sexually transmitted viruses including HIV, HSV, HCV, HBV, human papillomavirus (HPV) and CMV.
• the contraceptive composition of the present invention may further include a secondary pharmaceutically active component exemplified by, but not limited to, one or more compounds selected from the group consisting of:
• the secondary pharmaceutically active component is selected from one or more of the group consisting of secondary microbicidal components, spermicides and contraceptive agents.
• the secondary pharmaceutically active component may be selected from one or more of the group consisting of, but not limited to, podophyllin, tetracycline, nystatin, fluconazole, metronidazole, acyclovir, penicillin, cefotaxime, specinomycin, retrovir, erythromycin, ceftriaxone, cotrimoxazole, cotrimoxazole, benzyl benzoate, malathion, menfegol, progestin, estrogen, estradiol, and the like.
• Other suitable secondary pharmaceutically active components suitable for preventing contraception and preferably preventing STIs would be known to the skilled person.
• a contraceptive antimicrobial composition including an effective amount of a dendrimer compound including one or more naphthyl disulphonic acid surface groups, or a pharmaceutically acceptable salt or solvate of the dendrimer compound; and a pharmaceutically acceptable carrier, excipient and/or diluent therefore.
• Such a composition may be used to selectively reduce or prevent conception, and prevent sexually transmitted infections particularly viral sexually transmitted infections.
• a method of selectively reducing or preventing conception in a female animal including a human, which method includes administering to the animal an effective amount of a contraceptive composition which composition includes an effective amount of a dendrimer compound including one or more naphthyl disulphonic acid surface groups, or a pharmaceutically acceptable salt or solvate of the dendrimer compound; and a pharmaceutically acceptable carrier, excipient and/or diluent therefor.
• the contraceptive composition may be administered at any time, ie, before and/or during and/or after sexual intercourse, but preferably before and/or during sexual intercourse.
• the contraceptive composition included in the method of the present invention may further include a secondary pharmaceutically active component as described above.
• the dendrimer compounds described above may also be used for the manufacture of a medicament for selectively reducing or preventing conception in a female animal.
• the dendrimer compounds include a polylysine, polyamidoamine (PAMAM), poly(etherhydroxylamine) (PEHAM) or polypropyleneimine dendrimer scaffold. More preferably, the dendrimer compound is selected from a compound of Formula I, Il or III:
• R represents a group of Formula IV:
• the dendrimer polymer of formula I is particularly preferred.
• a method of selectively reducing or preventing conception in a female animal, including a human, and preventing one or more sexually transmitted infections includes administering to the animal an effective amount of a contraceptive composition which composition includes an effective amount of a dendrimer compound including one or more naphthyl disulphonic acid surface groups, or a pharmaceutically acceptable salt or solvate of the dendrimer compound; and a pharmaceutically acceptable carrier, excipient and/or diluent therefor.
• the STIs that are prevented are viral STIs, including HIV, HSV, HBV, HCV, HPV and CMV infections.
• the dendrimer compounds described above may also be used for the manufacture of a medicament for selectively reducing or preventing conception in a female animal, and preventing one or more sexually transmitted infections.
• the contraceptive composition may be carried on a surface of a prophylactic device with which it is compatible. Accordingly, there is provided a method of selectively reducing or preventing conception in a female animal, including a human, which method includes providing: an effective amount of a contraceptivetcemaosuiQn+including a dendrimer compound including one or more naphthyl sulphonic acid surface groups, or a pharmaceutically acceptable salt or solvate of the dendrimer compound; and a pharmaceutically acceptable carrier, excipient and/or diluent therefor; and a prophylactic device; the contraceptive composition being carried on a surface of the prophylactic device and being compatible therewith.
• the prophylactic device may be of any suitable type.
• a condom, cervical cap, contraceptive diaphragm, vaginal sponge, intrauterine device, pessary or the like may be used.
• a condom is preferred.
• the dendrimer compound may contact a surface of the prophylactic device in any suitable manner.
• the dendrimer compound may be coated on, or impregnated into, one or more surfaces of the prophylactic device.
• the dendrimer compound may be covalently bound to one or more surfaces of the prophylactic device.
• the dendrimer compound according to the method of the present invention may be administered in an amount sufficient to prevent pregnancy.
• the amount of dendrimer compound included in the contraceptive composition of the present invention may be in the range of 0.5 to 70% by weight based on the total weight of the composition.
• the amount of contraceptive composition administered may be in the range of from 0.1 to 10 g, preferably 0.5 to 8 g, most preferably 1 to 5 g.
• the contraceptive composition used in the method described above may also exhibit antimicrobial activity as described above.
• Example 1 Preparation of contraceptive composition (3% w/w active).
• Protocol i The equipment is sanitised and rinsed prior to manufacture.
• ii. In a stainless steel jug, Sodium Hydroxide, NF, is dissolved in purified water.
• iii. In a stainless steel vessel, EDTA Disodium Dihydrate, USP, is added to purified water and stirred with a high shear mixer until dissolved.
• Methyl- and Propyl- paraben, NF are added one at a time and mixed until fully dispersed, v. Carbopol ® 971 P, NF, is added slowly and the mixture stirred until the Carbopol ® 971 P,
• NF is fully dispersed and a smooth gel is formed.
• Propylene glycol, USP, and Glycerin, USP are added to the vessel and the solution mixed until the contents are fully dispersed.
• Sodium Hydroxide solution from Step ii. is added until the pH is greater than 4.0.
• SPL7013 is added in appropriate quantity calculated to give a 3% w/w gel.
• Sodium Hydroxide solution from Step ii. is added until the desired pH is reached, e.g. pH
• a modified Sander-Cramer Assay was conducted to assess the spermicidal activity of the contraceptive composition of the present invention. This assay determines the sperm- immobilising minimum effective concentration (MEC).
• composition of the present invention was labelled "failed" and a MEC was not established.
• the contraceptive activity of the composition of the present invention is not as a result of spermicidal activity.
• the spermicidal activity of the control agent N9 is due to the cytotoxic properties of this agent. Therefore, the spermicidal inactivity of the contraceptive composition suggests that it is different to N9 and that it will not be cytotoxic in humans.
• the typical ejaculate of the New Zealand White rabbit contains about 2-3x10 8 sperm, which, if delivered by a cannula to the cervicovagina, delivers about 5000 Fertilizing Dosesso (FD 50 ).
• One fertilizing doses 50 as used here ⁇ gjgfg ⁇ d ⁇ to be the quantity of sperm that will lead to 50% of a given population of rabbits becoming pregnant.
• the human ejaculate delivers less than 1 FD 50 .
• both the test agent and sperm should be delivered to the cervico- vagina, and the total number of sperm delivered should be reduced.
• the rabbit protocol was used to test a number of formulations, including a hydroxylcellulose (HEC) placebo gel.
• the test subjects were divided as shown in Table 2.
• the test formulation (2 ml) was deposited in the cervico-vagina of the rabbits using a flexible cannula of Tygon tubing attached to a 5 ml syringe.
• Fresh rabbit sperm collected from 2 male rabbits was pooled and diluted 5-fold with rabbit seminal plasma.
• Contraceptive efficacy was determined by sacrificing the animals 15 days post insemination, dissecting out the uterine horns to determine whether or not the animal became pregnant, and for the pregnant animals, counting the number of implanted embryos.
• the active in HEC or the formulation of Example 1 demonstrated significant contraceptive effects in the rabbit model when compared to the HEC placebo gel.
• the comparative contraceptive effects of the active in HEC or the formulation of Example 1 did not differ significantly.
• composition of the present invention formulated in either HEC or according to Example 1 , demonstrates significant contraceptive effects in the rabbit model when delivered 5 minutes prior to artificial insemination (Table 3) and also when delivered ⁇ 24 hours prior to insemination (Table 4).
• HSV-2 herpes simplex virus type 2
• the mouse HSV-2 vaginal transmission model is used by Richard Cone at Johns Hopkins University, Baltimore, USA, to assess toxicities associated with spermicides and other contraceptive compositions that could lead to susceptibility to pathogens such as HSV-2.
• mice Prior to the susceptibility assessment, female CF-1 mice (Harlan, Indianapolis, IN, USA) 6-8 weeks old are progestin treated (Depo Provera®, medroxyprogesterone acetate) to increase HSV-2 susceptibility, and to make the mice more uniform in terms of susceptibility than mice at different stages of the oestrous cycle.
• progestin treated Depo Provera®, medroxyprogesterone acetate
• a contraceptive composition according to the present invention was administered to the vagina followed 12 hours later by administration of a low-dose inoculum of HSV-2 (0.1 ID 50 ) delivered in 10 ⁇ l_ of Bartels medium. Control animals received 20 ⁇ l_ of PBS instead of test product.
• mice were treated with PBS for every group of mice treated with test product.
• One control group was inoculated with 0.1 ID 50 , while the other was inoculated with 10 ID 50 .
• the fraction of animals infected in each control group was then used to construct a dose-response graph (fraction infected vs. log ID), drawing a linear interpolation between the low and high dose points.
• the fraction of mice infected in the test group was then plotted on this graph to determine the effective ID of the low-dose inoculum in this test group.
• Relative susceptibility was defined as the effective ID the low-dose inoculum delivered to the test mice divided by the ID it delivered to the control animals.
• mice treated with N9 were 29.7 times more susceptible to HSV-2 infection than the control animals (P ⁇ 0.001, Fishers exact two-sided t-test), while animals treated with spermicidal ingredients 1 and 2 were 29.1 (PO.001) and 17.5 (PO.001) times more susceptible, respectively.
• the contraceptive composition according to the present invention does not appear to lead to increased susceptibility in the mouse-model of HSV-2 infection. This study indicates that the contraceptive composition is non-cytotoxic and suggests that it will be safe for use in humans. N9 and other spermicidal microbicides may lead to increased susceptibility. (Reference: Cone RA, Hoen TE, Wang XX & Moench TR. Microbicidal Detergents Increase HSV Susceptibility in Mice Without Causing Visible Epithelial Defects. Abstract # 02421, "Microbicides 2004" Conference, London, UK; March 2004).
• Example 5 Condom Compatability Study of 3% w/w of active in Carbopol ® gel.
• Certain ingredients in vaginal formulations may compromise condom integrity. This method was used to determine the effect of the composition of the present invention on condoms.
• condoms were removed from their individual packages and unrolled. Using a soft brush, the entire length of each condom was coated with a gel formulation of the composition of the present invention. Individual condoms were laid on a lined tray, and incubated at 37 0 C and 90% relative humidity for not less than one hour. Following each incubation period, and prior to testing, excess gel was removed from the condoms using a dry, non-abrasive cloth. Each treated condom was tested in sequential order for airburst pressure and volume. For comparison, baseline data was obtained by perfoming analogous testing on untreated condoms and condoms treated with placebo gel lacking any active pharmaceutical ingredients.
• Table 5 Airburst pressures and volumes of latex condoms following exposure to the contraceptive composition for not less than one hour.
• the tensile strength of condoms following treatment with a gel formulation of the composition of the present invention was investigated.
• condoms were removed from their individual packages and unrolled.
• Test pieces of the condom material were cut out of the condom in accordance with ISO 4074:2002 and these pieces placed on a lined tray.
• the cut out test pieces of condom were all coated test pieces with the gel, placed on a lined tray and incubatee at 37 0 C and 90% relative humidity for not less than one hour.
• excess lubricant was removed from sample pieces with isopropyl alcohol and the test pieces allowed to completely dry.
• the tensile strength of test pieces was determined in accordance with the procedure specified in ISO 4074:2002.
• Table 6 Tensile strength and elongation properties of condom latex text pieces following exposure to the contraceptive composition for not less than one hour.

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• 2007
  • 2007-03-21 US US12/294,024 patent/US8193248B2/en not_active Expired - Fee Related
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