WO2007074478A1 - Spermicide et dispositif contraceptif anti-infectieux innovants - Google Patents

Spermicide et dispositif contraceptif anti-infectieux innovants Download PDF

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WO2007074478A1
WO2007074478A1 PCT/IN2006/000506 IN2006000506W WO2007074478A1 WO 2007074478 A1 WO2007074478 A1 WO 2007074478A1 IN 2006000506 W IN2006000506 W IN 2006000506W WO 2007074478 A1 WO2007074478 A1 WO 2007074478A1
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spermicidal
infective
contraceptive device
novel
extract
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PCT/IN2006/000506
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English (en)
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Rajesh Jain
Kour Chand Jindal
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Panacea Biotec Ltd
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    • 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
    • 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
    • A61F6/06—Contraceptive devices; Pessaries; Applicators therefor for use by females
    • 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
    • A61F6/06—Contraceptive devices; Pessaries; Applicators therefor for use by females
    • A61F6/08—Pessaries, i.e. devices worn in the vagina to support the uterus, remedy a malposition or prevent conception, 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
    • 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)
    • A61K36/58—Meliaceae (Chinaberry or Mahogany family), e.g. Azadirachta (neem)
    • 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

Definitions

  • the present invention relates to novel spermicidal and anti-infective devices which are highly useful as a contraceptive method for prevention of unwanted pregnancy besides providing effective protection against microbes.
  • the present invention also describes process for preparation of such novel devices and method of using them.
  • the novel devices of the present invention can be used by males or females or both. Also, the devices are safe and easy to formulate and provides effective protection particularly against sexually transmitted diseases (STDs) and human immunodeficiency virus
  • HIV infection is a worldwide epidemic affecting people everywhere. The spread of HIV infection has occurred on such a scale, and the impact of the disease is potentially so devastating to world health, that only a concerted, global response is appropriate. There are approximately 16,000 new HIV-I infections per day, 90% of which occur in developing countries. At the end of 2004, it was estimated that nearly 40 million people were currently living with HIV infection. HIV is transmitted through direct contact of a mucus membrane with a bodily fluid such as blood, semen, vaginal fluid or breast milk.
  • a bodily fluid such as blood, semen, vaginal fluid or breast milk.
  • This transmission can come in the form of: penetrative (anal or vaginal) sex; oral sex; blood transfusion; contaminated needles; exchange between mother and infant, during pregnancy, childbirth and breastfeeding; or other exposure to one of the above bodily fluids.
  • penetrative (anal or vaginal) sex The majority of HIV infections are acquired through unprotected sexual relations. Sexual transmission occur when there is contact between sexual secretions of one partner with the rectal, genital or mouth mucous membranes of another. Results of multiple studies suggest that the presence of other STDs can greatly increase transmission of HIV. From a public health perspective, the need for contraception has never been greater. Although the existing male-specific methods such as withdrawal, condoms, and vasectomy are safe and effective, increasing male options for fertility control could improve family planning.
  • 'Coitus interruptus' does not require any devices, chemicals, or hormonal treatments, but the same provides no protection from lesions on skin or mucus membranes, and fluid from the pre-ejaculate that may contain pathogens such as gonorrhea and HIV.
  • Vasectomy involves the surgical isolation and division, electrocauterization, or occlusion (with clips) of the paired vas deferentia and provides long-lasting benefit, but initial costs are high and there are concerns about possible elevated risk of heart disease and prostate cancer.
  • Contraceptive methods for female includes herbal methods such as consumption of wild yam and application of neem oil on the cervix, inserting a film or a sponge or jellies or foam containing a spermicide into vagina and depositing over the cervix or use of an inter uterine device (IUD).
  • IUD inter uterine device
  • Such methods often cause lower abdominal pain, allergic reactions such as vaginal burning, itching, redness and rashes, etc. and do not offer any protection from STDs or HIV and instead may increase opportunity for infections.
  • Condoms are by far the best available methods for contraception.
  • a condom can be described as a protective sheath used as a contraceptive or to protect against sexually transmitted diseases. They are primarily of three types: (i) 'Latex condoms' are by far the most abundant on the market. They are relatively inexpensive, thin, flexible, and extremely effective against pregnancy and STDs including AIDS. The only drawbacks include possible allergies to latex and bad odour of the latex rubber. Oil based lubricants such as petroleum jelly and cold cream will break down latex rubber, hence water based lubricant needs to be used, (ii) 'Polyurethane condoms' are made from polyurethane which is a plastic-like material.
  • Plastic (polyurethane) condoms provide an alternative in cases in which allergy or other factors prevent the use of latex. Although in one randomized crossover trial a majority of male subjects preferred the sensitivity of plastic over latex condoms, the clinical failure rates (breakage or slippage) were significantly increased for polyurethane models. Another randomized trial found a lower condom-related dropout rate and greater overall satisfaction among men assigned to the latex condom group. Perfect use of male condoms is associated with a 3% probability of pregnancy, whereas typical use increases the risk to 14%. The addition of spermicidal lubricants to condoms may further reduce the risk of pregnancy for all types of condoms.
  • lubricants do not affect the transmission of STDs, and may increase the risk of urinary tract infections in female partners.
  • Oil-based lubricants such as petroleum jelly should never be used with latex condoms because they degrade the latex and therefore increase the risk of breakage.
  • One of the cornerstones of safer sex programs is correct condom use to prevent both unplanned pregnancies and the spread of sexually transmissible infections, including HI V/ AID S.
  • many people are unaware that commonly used products may have an adverse effect on the protective properties of barrier contraceptives made of latex.
  • lubricants spermicidal preparations, personal hygiene products, hormonal preparations, acidifying agents, and preparations used for treatment of common vaginal infections, especially Candida. It is possible that any dermatological product used on the genital area in both sexes, may have an effect on latex rubber.
  • Research strategies on hormonal methods of male contraception include weekly or long-acting intramuscular injections, and implantable, oral, or transdermal testosterone delivery systems. In an effort to boost the rates of azoospermia, combination regimens involving gonadotropin-releasing hormone analogues and progestins have also been studied. The efficacy of male hormonal methods depends on the degree of suppression of spermatogenesis. Concerns regarding hepatotoxicity and short half-life limit the potential use of currently available oral testosterone as a contraceptive.
  • nonoxynol-9 (N-9) tested the effect of nonoxynol-9 (N-9) in condom lubrication on the risk of acquiring STD and genital discomfort. They concluded that plain silicone lubricated condoms are as effective as N-9 lubricated condoms, cost effective, have longer expected shelf life, and therefore may be the better condom to provide.
  • nonoxynol-9 (N-9) is the most widely used lubricant along with condoms that claims protection from transmission of STDs. While the effectiveness of nonoxynol-9 as a spermicide is well known, its usefulness as a microbicide has been questioned, and in fact recent data indicate that nonoxynol-9 may actually increase the risk of HIV transmission.
  • nonoxynol-9 can induce lesions and ulcerations to genital mucosa, thereby increasing the probability of transmitting infectious agents.
  • US5778886 discloses the use of nonoxynol-9 and hydrogen peroxide in vaginal compositions for the prevention of conception and the transmission of STD.
  • US6624198 discloses a spermicidal lubricant composition, which includes chlorhexidine salt as an active ingredient against HIV and other viruses.
  • Patents have been granted for coating of condoms with a lubricant, with additional anti-microbial property.
  • Patents have been granted for anti-microbial preparations of trioxolane or diperoxide derivatives [US5364879], antiviral protein preparation of a particular sequence [US6420336], Lactic acid bacteria containing compositions [US 6,892,732], beta-cyclodextrin containing compositions [US6835717], chlorhexidine and paraben containing compositions [US6624198] and butylurea in combination with Nonoxynol-9 and benzalkonium chloride, which may be incorporated into condom lubricants.
  • WO 200682596 describes a stable non-synthetic herbal anti-fertility composition having high spermicidal activity for intra vaginal administration comprising neem oil and pharmaceutically acceptable excipients in suitably formulated dosage form for vaginal administration; however no disclosure is provided on making a spermicidal device with herbal product which is also effective against microbes and STDs.
  • US Patent no. 6333058 describes a process for preparing a spermicidal agent from neem oil.
  • European patent no. EP472791 discloses the use of neem oil or its components in the manufacture of a medicament for the reversible blocking of fertility in a female.
  • 5196197 describes an antifertility agent comprising neem oil and a reetha extract wherein the neem oil is present in a concentration of about 10%-25% w/w and the concentration of the reetha extract is about 0.5-1% w/w. But none of them disclose a device along with plant derived substance for use as spermicidal and anti-infective. Since the work of Henshaw in 1953, there has been a steady accumulation of information regarding the screening of plants having antifertility efficacy (Chopra et al, 1956, 1958; Casey, 1960; Choudhury, 1966; Bhakuni et al, 1969; Farnsworth et ctl., 1975).
  • An ideal male contraceptive should be safe, effective and reversible, and not have an effect on the libido. Suppression of spermatogenesis by sex steroids has been considered as a reversible chemical method of male contraception for a long time despite the side effects associated with hormonal methods. Androgens alone, or progestogens combined with androgens, were effective in inducing azoospermia in Caucasian men (Schearer et al, 1978). These were found to be effective in suppression of spermatogenesis but their treatment caused unacceptable side effects with long-term use, hence the search for alternatives preferably natural/herbal products.
  • Neem (Azadirachta indicd), an esteemed evergreen plant, is native to the Indian subcontinent. Neem seed oil is a traditionally known anti-microbial agent with documented potent anti-bacterial, anti-fungal and anti-viral activities along with spermicidal properties. Several diverse chemical compounds and their derivatives like azadirachtin and nimbicidin have been isolated from neem products. Such compounds possess varied biological properties and impart bitterness to neem. Bitter compounds exhibit repellent, sterilising, and antifertility effects in insects, and are hence employed in the manufacture of pesticides.
  • neem derivatives Hypoglycaemic, anti-inflammatory, anti-infective, and antinematodal effects of neem derivatives are well documented. Aqueous extracts of neem seeds, bark, or leaves exhibit potent immunostimulant activity through both humoral and cell-mediated response. Nimbin and Nimbidin which have been shown to be potent anti-viral agents along with other triterpenoids present in neem, occur predominantly in the oil extracted from the kernels [Verma, Acta Microbiol Pol B. 1974; 6(1): 9-13].
  • NIM-76 The volatile, odourous fraction of neem oil coded as NIM-76 obtained by steam distillation was investigated for in-vitro spermicidal activity and was found to inhibit spermatozoal motility at minimum concentrations of 0.25 mg/ml for rat and 25 mg/ml for human spermatozoa [Riar et al. Contraception. 1990 Oct; 42(4): 479- 87].
  • the NIM-76 preparation inhibited growth of various pathogens including Escherichia coli and Klebsiella pneumoniae, which were not affected by the whole neem oil. NIM-76 also exhibited antifungal activity against Candida albicans and antiviral activity against Poliovirus replication in vero cell lines.
  • mice from systemic candidiasis as revealed by enhanced % survival and reduced colony forming units of C. albicans in various tissues.
  • NIM-76 has a potent broad-spectrum anti-microbial activity [Sairam et al., J Ethnopharmacol. 2000 Aug; 71(3): 377-82].
  • a polyherbal pessary formulated with purified ingredients from Neem, Sapindus mukorossi and Mentha citrata oil was tested for spermicidal action on human sperm by Sander-Cramer slide test in-vitro and by post coital tests in-vivo in rabbits.
  • Garg et al J. Ethnopharmacol. 1994 oct;44(2): 87-92 has reported that Azadirachta indica (neem) seed extracts are known to activate the local cell-mediated immune reactions after a single intrauterine administration, leading to a long term reversible block of fertility.
  • neem seeds were extracted by both mechanical expression and solvent extraction using a range of polar to non-polar solvents which yielded three broad fractions.
  • the mechanically expressed oil was fractionated using different approaches and studied for antifertility activity.
  • the hexane extract and a corresponding column fraction showed potent and reproducible antifertility activity. Other fractions were less stable with regard to reproducibility of effects and composition. It was concluded that for subsequent fractionation to reach the last active fraction, the hexane extract is the most useful starting material. Parida et al (J. Ethnopharmacol.
  • Gossypol is a natural polyphenols compound, derived mainly from cottonseed oil, that causes antifertility and antisteroidogenic activities in both males and females. It reportedly induces disturbances of the hypothalamic-pituitary axis, disruption of spermatogenesis in the testes, and inhibition of post ejaculatory spermatozoa motility.
  • a study conducted by Gu et al (Asian J. Androl. 2000 Dec; 2(4):283-7) to ascertain whether the side effects of gossypol, hypokalemia and irreversibility, could be avoided on dose reduction.
  • a regimen with 10 or 12.5 mg of gossypol as the daily loading dose and 35 or 43.75 mg as the weekly maintenance dose could induce infertility in male volunteers without developing hypokalemia or irreversibility.
  • Papaya (Carica papaya) seed has been traditionally known as an orally active contraceptive.
  • Several animal studies have confirmed that purified fractions of Papaya seed extract are effective oral male contraceptives [Lohiya et al, Reprod Toxicol. 2005 May-Jun; 20(l):135-48; Asian J Androl. 2002 Mar; 4(l):17-26].
  • a complete loss of fertility has been reported in male rabbits, rats and monkeys fed an chloroform extract of papaya seeds (Lohiya et al. 1999; Pathak et al. 2000; Lohiya et al. 2002), suggesting that ingestion of papaya seeds may adversely affect the fertility of human males or other male mammals.
  • Papaya seed extract purified fraction showed a dose-dependent spermicidal effect showing an instant fall in the sperm motility to less than 20% at 2% concentration when applied in-vitro on human sperms. Only 250 microliters of the 2% solution of the extract was able to cause total immobilization of human sperms within 20-25 minutes [Lohiya et al. Asian J Androl. 2000 Jun; 2(2): 103-9].
  • An oral dose of crude ripe pawpaw ⁇ Carica papaya) seeds in male albino rats caused degeneration of the germinal epithelium and germ cells, reduction in the number of Leydig cells and vacuoles in the tubules (Udoh and Kehinde, 1999).
  • Lohiya et al (Asian J. Androl. 2002 Mar; 4(1): 17-26) evaluated the antifertility activity of the chloroform extract of Carica papaya seeds by oral administration in langur monkey. It was concluded that Carica papaya seed extract may selectively act on the developing germ cells, possibly mediated via Sertoli cells, leading to azoospermia.
  • Manivannan et al (Phytother. Res. 2004 Apr;18(4):285-9) has shown that the benzene chromatographic fraction of the chloroform extract of the seeds of Carica papaya at a dose of 10 mg/rat/day for 150 days provides a total inhibition of motility and reduced sperm count and infertility.
  • One triptolide was chosen for further pharmacological studies and was found to induce complete infertility in male rats acting primarily on epididymal sperm with minimal effects on the testis (Lue et al, 1998).
  • Coconut oil is unusually rich in short and medium chain fatty acids.
  • Laurie acid the major fatty acid from the fat of the coconut, has been recognized for its unique properties in foods which are related to its antibacterial, antiviral and antiprotozoal functions.
  • Being acid is a medium-chain fatty acid, which has the additional beneficial function of being transformed into a substance called "monolaurin" in the human body.
  • Monolaurin is an antibacterial, antiviral and antiprotozoal substance used by the human body to destroy lipid-coated viruses such as HIV, herpes, influenza, various pathogenic bacteria and protozoa such as Giardia lamblia.
  • Capric acid another one of coconut's medium-chain fatty acids has been added to the list of coconut's antimicrobial components.
  • Capric acid is found in large amounts in coconuts and it has a similar beneficial function when it is transformed into "monocaprin" in the human body.
  • Monocaprin has been shown to have antiviral effects against HIV and is being tested for its antiviral effects against herpes simplex and antibacterial effects against chlamydia and other sexually transmitted diseases.
  • Embelin (2,5-dihydroxy-3-undicyl-l,4-benzoquinone) isolated from Embelia ribes berries showed spermicidal activity by inhibition of sperm count and activity of enzymes of energy metabolism.
  • Purandare et al. (1979) studied the spermicidal activity of berries of E. ribes in male bonnet monkeys ⁇ Macaca radiatd).
  • Agarwal et al. (1986) found that embelin altered testicular histology in male rats. The compound is suggested to possess antiandrogenic properties.
  • Solasodine a steroidal alkaloid of Solarium xanthocarpum caused disruptive changes in the acrosomal membrane of sperm and arrest of spermatozoal motility (Kanwar et ah, 1988). Oral administration of solasodine to intact dogs significantly decreased the epithelial cell height of the cauda epididymides. Concurrent treatment of solasodine along with testosterone propionate was unable to restore the normal epithelial lumen parameters (Gupta and Dixit, 2002). A peculiar antispermatogenic effect o ⁇ Echallium ellaterum has been reported in the US Patent No. 4148892 (Nassar, 1979).
  • spermicidal agents are chemical compounds possessing varied quantum of side effects.
  • a major problem is that in case if the condom slips down during a decreased erection then the pathogens of STDs can cause an infection either by getting into the inner part of the condom or by getting out of it. Also, a frequent cause for tearing the condoms is that they are hurt by the nails of users trying to retain them on their place when they are felt slipping down.
  • STDs sexually transmitted diseases
  • HSV human immunodeficiency virus
  • compositions comprising one or more spermicidal and anti-infective plant derived substance in the form of spray coat, gel, lubricant cream or the like intended for application on a contraceptive device such as a condom by at least one of the individuals involved in intercourse.
  • It is a further objective of the present invention to provide process for preparation of such novel devices comprising the following steps: i) obtaining the spermicidal and anti-infective extract from plant source(s), ii) applying the extract either inside or outside or on both sides of the contraceptive device.
  • It is a still further objective of the present invention to provide process for preparation of such novel devices comprising the following steps: i) obtaining the spermicidal and anti-infective extract from plant source(s), ii) formulating the said extract into a suitable composition along with one or more carrier(s) or excipient(s). iii) providing the said composition along with a contraceptive device either as a single pack or separately, wherein the composition is applied either inside or outside or on both sides of the contraceptive device.
  • the present invention provides novel spermicidal and anti-infective contraceptive devices comprising at least one plant derived substance which are effective as a contraceptive method for prevention of unwanted pregnancy besides providing effective protection against microbes and optionally against fungal infections.
  • the device particularly provides effective protection against microbes particularly against sexually transmitted diseases (STDs) and human immunodeficiency virus (HIV), and/or against fungal infections.
  • the contraceptive device of the present invention to which at least one spermicidal and anti-infective plant derived substance is applied either inside or outside or on both sides, is a condom.
  • a condom is effective as a contraceptive method for prevention of unwanted pregnancy besides providing effective protection against microbes and optionally against fungal infections.
  • the spermicidal and anti-infective plant derived substance or composition comprising such substance formulated optionally with one or more carrier(s) or excipient(s), applied to the condom is an extract obtained from the plant Azadirachta indica optionally comprising another spermicidal and/or anti-infective plant derived substance, which is effective as a contraceptive method for prevention of unwanted pregnancy besides providing effective protection against microbes and optionally against fungal infections.
  • another spermicidal plant derived substance is an extract obtained from the plant Carica papaya
  • a composition comprising one or more spermicidal and anti-infective plant derived substance in the form of spray coat, gel, lubricant cream or the like intended for application on a contraceptive device such as a condom by at least one of the individuals involved in intercourse.
  • a novel spermicidal and anti- infective contraceptive devices comprising at least one plant derived substance, wherein the plant derived substance is applied either inside or outside or on both sides.
  • the contraceptive device of the present invention comprises of at least one plant derived spermicidal and at least one anti-infective substance alongwith acceptable carriers or excipients which are useful in preventing bacterial, viral and fungal infections.
  • the anti-infective substance(s) is obtained from a plant selected from but not limited to a group comprising Azadirachta indica, reetha saponins, quinine hydrochloride (obtained from Cinchona), gossypol, coconut oil, and the like or mixtures thereof.
  • the plant derived spermicidal substance(s) is obtained from the plant selected from but not limited to a group comprising Aristolochia indica; Neem ⁇ Azadirachta indica); Balanites roxburghii; Calotropis procera; Papaya ⁇ Carica papaya); Catharanthus roseus; Dieffenbachia seguine; Ecballium elaterium; Gossypium species; Hibiscus rosa-sinensis; Hippophae salicifolia; Leucaena glauca; Lonicera ciliosa; Lupinus tennis; Malvaviscus conzattii; Momordica charantia; Ocimum sanctum; Prunus emarginata; Withania somnifera; Embelia ribes; Solanum xanthocarpum; Vinca rosea; Karanj ⁇ Pongamia pinnata), carrageenan, reetha sapon
  • the spermicidal and anti-infective plant derived substance applied to the condom is an extract obtained from the plant Azadirachta indica.
  • the device comprises another spermicidal and/or anti-infective plant derived substance which is preferably an extract obtained from the plant Carica papaya, optionally with one or more acceptable carriers.
  • the plant based spermicidal or anti-infective substance(s) of the present invention may be extracted by using any one or combination of the following techniques:
  • the process of extraction of the spermicidal agent generally comprises the following steps: i) Extraction of dried and powdered plant or part(s) of plant with either medium polar solvents selected from but not limited to dichloromethane, chloroform, ethyl acetate and like used either alone or in combination thereof, or, polar solvents selected from but not limited to isopropanol, ethanol, methanol and like used either alone or in combination thereof, ii) Filtration of extract optionally using a filter aid, iii) Distillation of the extract to remove the solvent, iv) Optionally, fractionation of the residue obtained, after extraction with medium polar solvent, with a polar solvent selected from but not limited to isopropanol, ethanol, methanol and like used either alone or in combination thereof, v) Optionally, fractionation of the residue obtained, after extraction with polar solvent, with a medium polar solvent selected from but not limited to dichloromethane, chloroform,
  • the process of extraction of the spermicidal agent from Azadirachta indica comprises the following steps: i) Extraction of oil with polar solvents selected from but not limited to a group comprising acetone, isopropanol, ethanol, methanol, water, and the like, used either alone or in combination thereof, ii) Distillation of the extract to remove the solvent partly or completely, iii) Optionally, washing the residue obtained with a non-polar solvent selected from but not limited to a group comprising heptane, hexane, petroleum ether, benzene, toluene, and like, used either alone or in combination thereof.
  • polar solvents selected from but not limited to a group comprising acetone, isopropanol, ethanol, methanol, water, and the like, used either alone or in combination thereof
  • polar solvents selected from but not limited to a group comprising acetone, isopropanol, ethanol, methanol, water, and
  • the process of extraction from Azadirachta indica can be carried out by any of the following methods:
  • Neem oil (5 kg) was extracted by stirring at room temperature four times with methanol (4 ⁇ 20L) for 1 hour each time. The mixture was allowed to stand every time in a separating funnel for 1 hour so that the oil and methanol layers get separated. The methanol extracts obtained were pooled and dried under vacuum in a distillation assembly (10OL capacity). The waxy material (Yield - 1.5 kg) was obtained.
  • Neem oil (5 kg) was extracted by stirring at room temperature four times with 80% ethanol (4 ⁇ 20L) for 1 hour each time. The mixture was allowed to stand every time in a separating funnel for 1 hour so that the oil and ethanol layers get separated. The aqueous ethanolic extracts obtained were pooled and dried under vacuum in a distillation assembly (10OL capacity). The waxy material (Yield - 1.1 kg) was obtained.
  • Neem oil (5 kg) was extracted by stirring at room temperature four times with 80% methanol (4*20L) for 1 hour each time. The mixture was allowed to stand every time in a separating funnel for 1 hour so that the oil and methanol layers get separated.
  • Aqueous niethanolic extracts obtained were pooled and concentrated to half of its volume under vacuum in a distillation assembly (10OL capacity). This was washed by stirring twice with hexane (2> ⁇ 20L) for 15 minutes each time in extraction assembly (10OL capacity) attached with stirrer.
  • Aqueous methanolic layer was collected and concentrated to semisolid under vacuum in a distillation assembly (10OL capacity). The residue was finally dried under vacuum on a rotavapour to get dried solid material (Yield - 500 g).
  • neem seeds were expressed in a roller mill and filtered to obtain about 850 g neem oil.
  • the neem oil was optionally further extracted with a polar solvent selected from but not limited to 2-propanol, ethanol, methanol, water, and the like, used either alone or in combination thereof.
  • the polar solvent extract was distilled to remove the solvent and to yield an oily extract (280 g).
  • 5 kg neem seeds were powdered and extracted with a medium polar to polar solvent selected from but not limited to chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, water and the like, used either alone or in combination thereof.
  • the solvent extract was distilled to remove solvent yielding an oily extract (365 g).
  • 3 kg neem seeds were powdered and steam distilled along with 1OL of water.
  • the volatile oil (3 ml) obtained was collected in a Clavenger Apparatus.
  • 4 kg neem seeds were expressed in a roller mill and filtered to obtain about 850 g neem oil.
  • the neem oil was optionally steam distilled along with 5 L of water.
  • the volatile oil (4 ml) obtained was collected in a Clavenger Apparatus.
  • the process of extraction from Carica papaya can be carried out by any of the following methods: 1. Powdered seeds of Carica papaya (5 kg) were extracted by refluxing four times with methanol (4 ⁇ 30L) for 2 hours each time. Methanol extracts obtained were pooled and filtered through buchner's funnel using celite as filter aid. The methanol was removed under vacuum in a distillation assembly (10OL capacity). The oily material (Yield - 848 g) obtained was shaken with 2.5L chloroform in a
  • Papaya seeds were powdered and extracted with a medium polar to polar solvent selected from but not limited to chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, water and the like, used either alone or in combination thereof.
  • the solvent extract was distilled to remove the solvent and to yield an oily extract (365 g).
  • the papaya seed extract was loaded on a column packed with a polar stationary phase selected from but not limited to silica gel, kieselgurh, aluminium oxide, magnesium silicate and the like, used either alone or in combination thereof.
  • the column was washed with a non-polar solvent selected from but not limited to petroleum ether, hexane, pentane, cyclohexane and the like, used either alone or in combination thereof. Then the column was eluted with a medium polar solvent selected from but not limited to chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, and the like, used either alone or in combination thereof. The solvent elute was then dried to yield an oily substance (650 mg).
  • a non-polar solvent selected from but not limited to petroleum ether, hexane, pentane, cyclohexane and the like, used either alone or in combination thereof.
  • a medium polar solvent selected from but not limited to chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, and the like, used either alone or in combination thereof.
  • the solvent elute was then dried to yield an oily
  • the plant derived spermicidal substance(s) are selected such that preferably a positive synergistic effect in the spermicidal activity is obtained which implies the use of reduced concentrations of each agent to bring about the desired action.
  • the spermicidal and anti-infective contraceptive device of the present invention may be in the form of a condom spray coated with an aqueous or oily extract of one or more plant derived spermicidal and anti-infective substance(s), or in the form of a cream, gel or a pessary intended to be applied to the contraceptive device such as condom prior to use.
  • the condom may be made synthetically from plastics, polymers, nitrile, latex or polyurethane or a natural membrane obtained from a natural source such as sheep skin or lamb cecum.
  • the condoms are either for male or female use.
  • the addition of one or more plant derived spermicidal and anti-infective substance(s) to condoms further reduces the risk of pregnancy and/or alleviates or reduces genital discomfort and/or prevents lesions and ulcerations to genital mucosa, thereby minimizing the probability of transmitting infectious agents.
  • the contraceptive device is a male contraceptive that is safe, effective and reversible, and does not have an effect on the libido.
  • the plant derived substance useful in the present invention obtained from Azadirachta indica may be the neem oil or fraction thereof that inhibits human spermatozoal motility in at minimum concentrations of about 25 mg/ml.
  • the oil extract obtained from Azadirachta indica in the present invention inhibited growth of various pathogens including Escherichia coli and Klebsiella pneumoniae, and also exhibited antifungal activity against Candida albicans and Chlamydia, and antiviral activity against Poliovirus. Also it reduces the risk of gonorrhoea and HIV transmission.
  • aqueous/alcoholic extract of neem leaves or seeds and pure neem compound are highly effective in inhibiting viral infection.
  • plant derived substance useful in the present invention obtained from Carica papaya in the form of aqueous or alcoholic seed extract are effective is highly effective as spermicidal.
  • Papaya seed extract showed a dose-dependent spermicidal effect showing an instant fall in the sperm motility to less than 20% at about 2% concentration when applied in-vitro on human sperms.
  • the plant derived substance may be combined with one or more other spermicidal or anti-infective agents known to the art such as hormones e.g. danazol, depot medroxy progesterone acetate (DMPA), cyproterone acetate, melatonin, levonorgestrel, Ru-486, testosterone buciclate and other androgen esters.
  • hormones e.g. danazol, depot medroxy progester
  • Plant derived substance such as an extract obtained from the plant Azadirachta indica although safe and effective had not been disclosed in the prior art for use as spermicidal and/or anti-infective along with a contraceptive device probably due to the unacceptable colour and/or odour of such product.
  • the device of the present invention removes such limitations of the art by providing extracts/compositions which have an acceptable colour and/or odour.
  • the acceptable carriers or excipients useful in formulating the devices of the present invention are preferably lubricants such as KY jelly (a lubricant produced by Johnson & Johnson), carboxymethyl cellulose, sodium alginate, EDTA, natural vegetable oils, propylene glycol, glycerin, low melting temperature triglyceride, mineral oil, aqueous solutions of high molecular weight polyethylene oxides, and the like or mixtures thereof.
  • lubricants such as KY jelly (a lubricant produced by Johnson & Johnson), carboxymethyl cellulose, sodium alginate, EDTA, natural vegetable oils, propylene glycol, glycerin, low melting temperature triglyceride, mineral oil, aqueous solutions of high molecular weight polyethylene oxides, and the like or mixtures thereof.
  • Polymers such as water soluble cellulose derivative (e.g.
  • methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose) or other water soluble polymers such as sodium alginate, polyvinyl pyrrolidone, polyvinyl alcohol or polymer of ethylene oxide, and the like can be used in the present invention.
  • Other optional substances that can be used in the present invention include anti- infectives such as methylparaben, chlorhexidine and the like.
  • the novel spermicidal and anti-infective contraceptive device of the present invention provide protection from transmission of STDs and HIV by virtue of the anti-infective substance(s), undesired pregnancy by virtue of spermicidal substance(s) and adequate lubrication for enhanced pleasure and ease of use.
  • the devices of the present invention optionally comprise natural sensation enhancers.
  • the contraceptive device is a condom and the effective preparation to be coated inside and/or outside the condom comprises a spermicidal and anti-infective substance(s) along with a carrier such as vegetable oil.
  • a carrier such as vegetable oil.
  • the vegetable oil useful in the present invention is selected from but not limited to a group comprising sunflower oil, soyabean oil, linseed oil, cottonseed oil, olive oil, palm oil, coconut oil and the like or mixtures thereof.
  • the hydrocarbon base comprises paraffins, waxes, petroleum jelly, lanolin, and the like or mixtures thereof. Although vegetable oils are compatible with latex condoms, polyurethane condoms are the preferred.
  • yohimbine selective competitive alpha2-adrenergic receptor antagonist for penile vasodilation
  • clove oil mimetics
  • arginine capillary blood circulation enhancer
  • the Azadirachta indica extract is present in the range of about 20 to 60% w/v and the Carica papaya extract is present in the range of about 1 to 5% w/v in the novel device of the present invention.
  • a volume of about 0.25 to 0.50 ml of the preparation is preferably used to make the coating inside and/or outside the condom.
  • a process for preparation of such novel devices comprising the following steps: i) obtaining the spermicidal and anti-infective extract from plant source(s), ii) applying the extract either inside or outside or on both sides of the contraceptive device.
  • a process for preparation of such novel devices comprising the following steps: i) obtaining the spermicidal and anti-infective extract from plant source(s), ii) formulating the said extract into a suitable composition along with one or more carrier(s) or excipient(s). iii) providing the said composition along with a contraceptive device either as a single pack or separately, wherein the composition is applied either inside or outside or on 5 both sides of the contraceptive device. i)
  • novel devices of the present invention preferably do not use lubricants such as nonoxynol-9 that is commonly used in most of the marketed condoms.
  • Nonoxynol-9 has been shown in several recent studies to actually increase the risk of HIV
  • the extract or composition of the plant derived substance used along with the contraceptive device besides acting as spermicidal and anti-infective, also functions as a lubricant.
  • the spermicidal and anti-infective contraceptive device is easy to
  • the plant derived extract or composition as active agent according to the present invention is useful for the prevention of STDs wherein said
  • STD virus is selected from the group consisting of HIV viruses, herpesviruses, hepatitis
  • influenza A viruses influenza A viruses
  • parainfluenza viruses parainfluenza viruses
  • human papilloma viruses 25 viruses, influenza A viruses, parainfluenza viruses, and human papilloma viruses.
  • B.No. 0580/090A Placebo
  • B.No. 0580/086A 2% Papaya extract.
  • the apparatus used for testing was Sperm Quality analyzer (SQA II C-P).
  • SQA Sperm Motility Index
  • Table 1 Average values over a period of 10 minutes after treatment of 50 ml of semen with 100 ml of spermicidal agent
  • a spermicidal, antimicrobial, cytocidal, or antibacterial effective amount of a natural or plant derived substance is applied with or without a carrier to the inner, outer or both surfaces of an appropriate contraceptive device such as a condom.
  • a condom or diaphram could be coated wholly or partially with dry or semisolid or liquid coating material containing an effective amount of the plant derived substance for spermicidal and anti-infective use according to the invention.
  • an effective amount of the natural substance of the invention can be applied in admixture with other antimicrobially, cytocidally, antibacterially, and/or spermicidally active ingredients prior to or during application to a condom or diaphram. Further, in some instances the natural substances of the invention could be applied, alone or in admixture with another spermicide, topically or vaginally.
  • the anti-infective use of the contraceptive device is intended as antimicrobial, cytocidal, antifungal, antiviral or antibacterial activity, particularly activity against sexually transmitted diseases and HIV.
  • sexually transmitted diseases include, but are not limited to, herpes, chlamydia, syphilis, gonorrhea, HIV, and other retroviruses, such as HTLV-I and HTLV-II.
  • Treatment or prevention could consist of topical or vaginal application of an effective amount of plant derived substance according to the invention, in or on a suitable carrier, for example, a condom, a diaphram, sponge, IUD, or other suitable device or substrate containing or having thereon an effective amount of the active ingredient, may be positioned intravaginally.
  • a suitable carrier for example, a condom, a diaphram, sponge, IUD, or other suitable device or substrate containing or having thereon an effective amount of the active ingredient, may be positioned intravaginally.
  • the spermicidal and anti-infective gel composition of the present invention may further contain a preservative, such as one or more members of parabens.
  • the gel can maintain its antiviral activity in dilutions of not less than 100 times.
  • the methods for preventing the transmission of HIV and other sexually transmitted viruses comprise applying the gel composition onto the contraceptive device such as a condom or a diaphragm before sexual intercourse.
  • the gel is capable of enhancing the risk-reducing effectiveness of condom and providing maximum protection for users.
  • the gel composition comprising the plant derived active substance(s) can be coated onto condoms during manufacture, and enclosed within conventional watertight plastic or foil packages that contain one condom per package, or it can be manually applied by a user to the inside and/or the outside of a condom, immediately before use.
  • the plant derived substance as active agent in the gel deactivates the viruses and prevents the infected person from transmitting the STD viruses to the non-infected person.
  • the coated extract or composition on the contraceptive device maintains its efficacy against secretion of bodily fluids thus providing the intended protection during sexual intercourse.
  • the coated extract or composition provides lubricity which further helps reduce the likelihood of transmitting the diseases by reducing the rupture of skins and/or blood vessels during sexual relationships.
  • the plant derived extract is formulated as a composition such as a gel or cream, the same may be packaged in any of the known forms, such in tubes, in bottles, in sachets or in capsules.
  • a preservative such as paraben(s) may be added to the composition.
  • the device coated with a plant derived extract per se or formulated into a composition is provided that can be used in acidic conditions that exist in the vagina and surrounding area without destabilization.
  • the present invention provides a kit for preventing sexually transmitted disease and infection and killing male sperm essentially comprising at least one preferably two plant derived active components, that can individually or collectively be loaded and/or preloaded into the contraceptive device such as condom.
  • the contraceptive device such as condom.
  • One of the major advantages of the spermicidal and anti-infective contraceptive device of the present invention is that it offers a unique method of protection against HIV, STDs and other microbial or fungal infection by using plant derived substance(s) as active agents which are highly effective, coupled with enhanced safety.
  • Azadirachta indica extract 30 2. Carica papaya extract 3
  • Example-3 Emulgel S. No. Ingredients Qry./100 gms
  • step (ii) and cooled it to 25° C.
  • Glycerine was added to the mixture of step (iii) and stirred to dissolve.
  • v) Glyceryl Monostearate and PEG 100 stearate were heated on heating mantle, vi) Neem Extract was added to the mixture of step (v) and heated to 75°C.
  • vii) The mixture of step (i) was heated to 75 0 C and the mixture of step (vi) was added to it under high stirring to form emulsion.
  • Mixture of step (iv) was added to the emulsion of step (vii) and pH was adjusted between 4.5-5.0 with triethanolamine.
  • the gel is applied on the outer side or inner side or on both sides of condom.
  • step (ii) and cooled it to 25° C.
  • Glycerine and Tween® 80 were added to the mixture of step (iii) and stirred to dissolve.
  • Neem Extract and Span® 80 were mixed together.
  • the mixture of step (i) was heated to 75 0 C and the mixture of step (v) was added to it under high stirring to form emulsion,
  • Mixture of step (iv) was added to the emulsion of step (vi) and pH was adjusted between 4.5-5.0 with triethanolamine.
  • the gel is applied on the outer side or inner side or on both sides of condom.
  • step (iv) and step (v) were added to the material of step (iii) and heated to 70°-75°C.
  • step (ii) and step 6 were mixed and cooled. vii ⁇ ) When the material of step (vii) attains a temperature of 50°-55°C, the material of step (i) was added to it. ix) The mixture was allowed to cool to room temperature to obtain the cream.
  • the mixture is applied on the cervix by inserting a film/sponge containing said mixture.
  • step (ii) The material of step (ii) was added to the material of step (iii) with stirring and the mixture was allowed to cool to 55°-60°C. v) The material of step (i) was added to the material of step (iv), stirred, and allowed to cool to room temperature to obtain the cream.
  • the cream is applied on to the vagina preferably by using a sponge.

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Abstract

La présente invention concerne un spermicide et des dispositifs anti-infectieux innovants qui sont utilisables en tant que procédé contraceptif et qui assurent en outre une protection efficace contre les microbes. L'invention concerne également le procédé de préparation de ces dispositifs innovants et leur procédé d'utilisation. Les dispositifs innovants de la présente invention qui peuvent être utilisés aussi bien par les hommes que par les femmes sont faciles à formuler et ils assurent en particulier une protection efficace contre les maladies transmissibles sexuellement (MTS) et le virus de l'immunodéficience humaine (VIH), ainsi que, éventuellement, contre les infections fongiques.
PCT/IN2006/000506 2005-12-28 2006-12-26 Spermicide et dispositif contraceptif anti-infectieux innovants WO2007074478A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9884049B2 (en) 2014-07-14 2018-02-06 Orion Biotechnology Canada Ltd. Microbicidal composition comprising an octoxynol and a quinolizidine alkaloid compound or a source thereof
WO2021247124A1 (fr) * 2020-06-01 2021-12-09 Corona Feed Additives, L.L.C. Composition, système et méthode de contraception de porc
WO2022076804A1 (fr) * 2020-10-08 2022-04-14 North Carolina State University Compositions de gel contraceptif multifonction et procédés d'utilisation associés

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2020107A (en) * 1934-08-06 1935-11-05 George A Cruickshank Combination pessary and vaginal suppository
US4004582A (en) * 1975-10-28 1977-01-25 Nakamura Robert M Intracervical contraceptive device
US6011013A (en) * 1997-06-20 2000-01-04 Oregon Health Sciences University Contraceptive compositions and methods
WO2006082596A2 (fr) * 2005-01-19 2006-08-10 Kamalinder Kaur Singh Preparations contraceptives a base d'herbes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2020107A (en) * 1934-08-06 1935-11-05 George A Cruickshank Combination pessary and vaginal suppository
US4004582A (en) * 1975-10-28 1977-01-25 Nakamura Robert M Intracervical contraceptive device
US6011013A (en) * 1997-06-20 2000-01-04 Oregon Health Sciences University Contraceptive compositions and methods
WO2006082596A2 (fr) * 2005-01-19 2006-08-10 Kamalinder Kaur Singh Preparations contraceptives a base d'herbes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SAIRAM M AT AL: "Anti-microbial activity of a new vaginal contraceptive NIM-76 from neem oil (Azadirachta indica)", JOURNAL OF ETHNOPHARMACOLOGY, vol. 71, 2000, Ireland, pages 377 - 382, XP009084019 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9884049B2 (en) 2014-07-14 2018-02-06 Orion Biotechnology Canada Ltd. Microbicidal composition comprising an octoxynol and a quinolizidine alkaloid compound or a source thereof
WO2021247124A1 (fr) * 2020-06-01 2021-12-09 Corona Feed Additives, L.L.C. Composition, système et méthode de contraception de porc
WO2022076804A1 (fr) * 2020-10-08 2022-04-14 North Carolina State University Compositions de gel contraceptif multifonction et procédés d'utilisation associés

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