WO2010050955A1 - Compositions et procédés microbicides et spermicides à large spectre - Google Patents

Compositions et procédés microbicides et spermicides à large spectre Download PDF

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Publication number
WO2010050955A1
WO2010050955A1 PCT/US2008/081795 US2008081795W WO2010050955A1 WO 2010050955 A1 WO2010050955 A1 WO 2010050955A1 US 2008081795 W US2008081795 W US 2008081795W WO 2010050955 A1 WO2010050955 A1 WO 2010050955A1
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composition
testing
microbicidal
water
amino acid
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PCT/US2008/081795
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English (en)
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Kewang Lu
Qionggong Ning
Lei Zhang
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Esawtech, Ltd.
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Priority to PCT/US2008/081795 priority Critical patent/WO2010050955A1/fr
Publication of WO2010050955A1 publication Critical patent/WO2010050955A1/fr

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    • 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
    • A61K9/0031—Rectum, anus
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets

Definitions

  • compositions containing N-cocoyl amino acid pyrrolidone salts for preventing or reducing the transmission of sexually transmitted diseases (STDs). Also provided are compositions and methods for preventing conception and/or reducing the risk of conception. Also provided are methods of inhibiting the activity of pathogens whose mode of transmission is nonsexual. Also provided are compositions effective in the inhibition of bacteria and fungi, which coexist with viruses or viral infections.
  • Sexually transmitted diseases are among the most prevalent and communicable diseases, and continue to be a significant public health problem. It is estimated that more than 250 million people worldwide, and close to 3 million people in the United States, are infected annually by gonorrhea. Annual worldwide incidence of syphilis is estimated at 50 million people, with 400,000 in the United States annually needing treatment.
  • the human immunodeficiency virus (HIV) resulting in fatal acquired immunodeficiency syndrome (AIDS), has spread rapidly in both homosexual and heterosexual groups.
  • HIV human immunodeficiency virus
  • AIDS fatal acquired immunodeficiency syndrome
  • vaccines do not exist, and therapeutic agents are only partially effective, expensive, and difficult to distribute.
  • female partners in many relationships do not control pregnancy or STI .
  • HIV may not be the sole agent responsible for AIDS ( Duesberg, P. H. (1991) Proc. Natl. Acad. Sci. 88:1575-1579; Lemaitre, M., Guetard, D., Henin, Y., Montagnier, L. and Zerial, A. (1990). Res. Virol. 141 :5-16).
  • antimicrobial agents such as those described in this invention, with a broad spectrum of activities against viruses, bacteria, and yeasts may be of particular value in the prevention and treatment of Acquired Immune Deficiency Syndrome (AIDS).
  • STD sexually transmitted disease
  • a microbicidal composition comprising 0.003 to 3 weight percent N-cocoyl amino acid pyrrolidone salts and 10 to 99.997 weight percent solvent.
  • the solvent comprises a member selected from the group consisting of water, glycerin, glycerol- gelatin, ethanol, propylene glycol, polyethylene glycol, a water and glycerin mixture, a water and glycerol-gelatin mixture, a water and ethanol mixture, a water and propylene glycol mixture, and a water and polyethylene glycol mixture.
  • FIG. 1 is the formula for N-cocoyl amino acid pyrrolidone salts in which A is an amino acid residue and R is a C. sub.10 -C. sub.14 fatty acid residue.
  • compositions and methods for the prevention and control of sexually transmitted diseases and for the prevention of pregnancy also relate to treatment of viral infections. More particularly, provided is a method for inhibiting the development of diseases and infections caused by viruses and some sexually transmitted pathogens whose major mode of transmission is sexual. Certain embodiments relate to methods of inhibiting the activity of enveloped viruses and other pathogens whose mode of transmission is nonsexual. Certain embodiments are effective in the inhibition of bacteria and fungi, which coexist with viruses or viral infections. Certain embodiments relate to prevention or treatment for virus related diseases, particularly sexually transmitted diseases related to AIDS, and to diseases related to this and other opportunistic infections of the immune-compromised host.
  • compositions described may be useful to inactivate viruses, including vaccinia, varicella, herpes zoster, cytomegalovirus, influenza, mumps and measles.
  • viruses including vaccinia, varicella, herpes zoster, cytomegalovirus, influenza, mumps and measles.
  • the compositions prevent and/or treat certain skin diseases, such as, without limitation, ringworm and other fungi infectious skin diseases.
  • the compositions provides a broad spectrum and highly efficient microbicides useful for reducing the risk of transmission of STD-causing organisms to health care providers, laboratory personnel, or other persons who may come in contact with biological samples, specimens, or material.
  • the compositions can also be used as spermicides.
  • spermicidal compositions can be used alone, or with other known spermicides, or with or incorporated into contraceptive devices such as condoms, sponges, vaginal inserts, contraceptive films, diaphragms, suppositories, contraceptive patches or sustained release devices.
  • the compositions can be incorporated into douches or wipes.
  • composition can also be used in or on animals as disinfecting or antiseptic agents.
  • compositions can be formulated in the form of a gel, liquid, aerosol, mist, sponge, spray, foam, gel, cream, salve, jelly, suppository and film.
  • compositions can be applied to the external genital organs, vagina, anorectic region and rectum in different dosage forms with appropriate apparatus.
  • the composition as a gel could be applied to vagina or rectum through an applicator or syringe.
  • a microbicidal composition may be prepared comprising an amino acid derivative modified with a C. sub.10-14 alkyl group at the N-terminus.
  • a N-cocoyl group is included.
  • the amino acid residue bears a positive charge and the negative counter ion is an organic molecule.
  • the negative counter ion is pyrrolidone salts. There are no halogen elements, such as chloride or bromide, in the structure of the amino acid compound.
  • a non-limiting example is an amino acid ethyl ester acylated at the N-terminus with a coconut oil fatty acid residue, and having DL-pyrrolidone carboxylic acid added thereto.
  • N-cocoyl amino acid pyrrolidone salts are represented by the formula:
  • A is an amino acid residue and R is a C.sub.10 -C. sub.14 fatty acid residue.
  • the amino acid residue could be from that of an arginine, lysine, histidine, homolysine, an unnatural amino acid residue bearing a positive charge, a di-peptide bearing a positive charge group, or a tri-peptide bearing a positive charge group.
  • N-cocoyl Arginine pyrrolidone salts may be prepared as follows:
  • Solution A may be prepared by: mixing 1.2 equivalent N, N'-Dicyclohexylcarbodiimide (DCC) with 1 equivalent myristic acid (CH 3 (CH 2 ) 10 COOH) in DMF and stir for 45 minute to 2 hours; adding 1.2 equivalent N-Hydroxylsuccinimide (NHS) dissolved in CH 2 CI 2 ; stirring until a dicyclohexane urea precipitate forms; and filtering the reaction mixture to remove the dicyclohexane urea precipitate.
  • DCC N, N'-Dicyclohexylcarbodiimide
  • NHS N-Hydroxylsuccinimide
  • Solution B may be prepared by: mixing L-Arginine ethyl ester dihydrochloride and 1 equivalent of NaOH at O degree C in DMF or CH 2 CI 2 for 30 minutes; adding 1.3 equivalent of triethyl amine (Et 3 N); and mixing to form a homogeneous solution.
  • the amino salt may be prepared by: mixing together solution A and solution B at room temperature for two hours; removing most of the solvent by vacuum; dissolving the product in methanol; adding one equivalent of NaOH extracting the product with a mixture of water and ether or a mixture of water and EtOAc; drying the organic phase under vacuum; re-precipitating the product by using solvent hexane, or water, or methanol, or a mixture of methanol and water; re-dissolving the product in methanol; adding one equivalent of DL-pyrrolidone carboxylic acid; and removing the methanol under vacuum to obtain the final product.
  • the N-cocoyl amino acid pyrrolidone salts is contained in a proportion of from 0.003 to 3 weight percent.
  • N-cocoyl amino acid pyrrolidone salts are soluble in water, highly safe with respect to acute toxicity (LD. sub.50), have no substantial irritation to skin or ophthalmic mucosa, have good biodegradable characteristics, and can rapidly be decomposed in wastewaters.
  • microbicide compositions comprise natural plant polysaccharides.
  • microbicide compositions comprise a natural plant polysaccharides to enhance antibacterial effects and to protect the epithelium tissues.
  • plant polysaccharides comprise Aloe Vera polysaccharides.
  • plant polysaccharides may comprise powder of freeze dried Aloe Vera gel.
  • microbicide compositions comprise an ampholytic surfactant.
  • ampholytic surfactants comprise amine oxide such as alkyl dimethyl amine oxide.
  • microbicide compositions comprise conventional additive components in conventional amounts.
  • conventional additive components comprise natural polysaccharides, natural plant acid and their salts, fragrance, colorant, flavor, plasticizer, stabilizing agent, emulsifier, moisturizer, and combinations thereof.
  • a liquid microbicide composition is prepared by adding and incorporating the active ingredients in proper amounts into an aqueous medium in an optional order in a conventional method.
  • a liquid microbicide composition may be prepared by mixing the following ingredients by weight percentages in the provided ranges to obtain a homogeneous solution:
  • N-cocoyl amino acid pyrrolidone salts 0.003 - 3 weight percent
  • a microbicide composition comprising plant polysaccharides.
  • a microbicide composition comprising plant polysaccharides may be prepared by mixing the following ingredients by weight percentages in the provided ranges to obtain a homogeneous solution:
  • Plant polysaccharides 0.001 - 4 weight percent
  • N-cocoyl amino acid pyrrolidone salts 0.003 - 3 weight percent
  • a microbicide composition is prepared as a gel.
  • a gel microbicide composition may be prepared as described in the steps that follow.
  • Ampholytic surfactant 0.0016 - 3 weight percent
  • step B Add Hydroxypropyl ethyl cellulose 0.010 - 5.0 weight percent to the 60° C - 95°C homogeneous solution from step A; stir for more than 30 minutes; stop heating and slowly reduce the temperature to 50° C.
  • step C Add N-cocoyl amino acid pyrrolidone salts 0.003 - 3.0 to the solution from step B; stir until the temperature of the solution drops to room temperature to obtain a colorless transparent gel.
  • the gel microbicide composition may be stored or applied with a syringe.
  • a syringe is filled with 3-5 ml of the gel microbicide composition; the filled syringe is sealed within an aluminum foil bag; and, at use, the user opens the foil bag and inserts the syringe into the vagina or the rectum to apply the material.
  • Table 1 lists 37 formulations prepared following the above procedures to make liquid or gel preparations. Abbreviations used in Table 1 and hereafter are: Freeze dried Aloe Vera gel powder (AV); Alkyldimethylamine oxide (C1); Water (H 2 O); N-cocoyl amino acid pyrrolidone salts (CAPS); Hydroxypropyl methyl cellulose (HP). TABLE 1. FORMULATIONS OF MICROBICIDES
  • a microbicide composition is prepared as a suppository.
  • a microbicide composition is prepared as a suppository comprised of the ingredients in the quantities listed in TABLE 2 by the following method.
  • a microbicide composition is prepared as a spray or mist.
  • a microbicide composition is prepared as a spray comprised of the ingredients in the quantities listed in TABLE 3 by the following method.
  • a microbicide composition is prepared as a mist comprised of the ingredients in the quantities listed in TABLE 3 by the following method.
  • a microbicide composition is prepared as a film.
  • a microbicide composition is prepared as a file comprised of the ingredients in the quantities listed in TABLE 4 by the following method. Triturating Gelatin with Hydroxyethyl cellulose and glycerin and mixing thoroughly to form a slurry; dissolving CAPS in warm water to obtain a homogeneous solution; adding the solution to the slurry to form a mixture; heating the mixture at 40 0 C and mixing until the cellulose and the gelatin are completely hydrated; casting a film of about 2 mm thick by pouring the mixture onto a polyethylene sheet and cooling the mixture; and cutting the film.
  • the film is cut into 3.9X3.9 cm squares.
  • the microbicide was tested on Ureaplasma Urealyticum. The details of the test were as follows.
  • the testing strain was a Ureaplasma Urealyticum clinical strain.
  • the culture medium was a high efficiency Ureaplasma culture medium.
  • the testing sample was the microbicide solution prepared per Example 1 , formulation 3.
  • the testing methods and standards followed the standards issued by The Health Department of China in the 2002 Edition of Technical Standards for Disinfection (The Standard).
  • the tests followed the "Standard" with consideration of the characteristics of Ureaplasma Urealyticum.
  • the testing temperature was in the range of 20°C - 25°C.
  • the sample dilutions ratios tested were: 1 :100; 1 :200; 1 :500; and 1 :1000.
  • the concentration of Ureaplasma Urealyticum was 10 ⁇ 7.
  • the treatment used a Ureaplasma Urealyticum suspension and sample diluted in a ratio of 1 : 9.
  • the reaction times were 1 minute, 3 minutes, and 5 minutes. Diluting methods were used to remove the residue of the sample. Tests were repeated two times.
  • testing results showed that the testing sample diluted for 100 times and reacted with a Ureaplasma Urealyticum suspension for 1 minute killed Ureaplasma Urealyticum.
  • the microbicide was tested on Neisseria Gonorrhoeae.
  • the details of the test were as follows.
  • the testing strain was a Neisseria Gonorrhoeae clinical strain.
  • the culture medium was a 10% blood dish.
  • the testing sample was the microbicide solution prepared per Example 1 , formulation 3.
  • the testing methods and standards followed the standards issued by The Health Department of China in the 2002 Edition of Technical Standards for Disinfection (The Standard). The tests followed the "Standard" with consideration of the characteristics of Neisseria gonorrhoeae.
  • the testing temperature was in the range of 25 0 C - 28°C.
  • the sample dilutions ratios tested were: 1 :25; 1 :50; and 1 :100.
  • the concentration of Neisseria gonorrhoeae was 10 ⁇ 7.
  • the treatment used a Neisseria gonorrhoeae suspension and sample diluted in a ratio of 1 :1. The reaction times were 1 minute, 3 minutes, and 5 minutes.
  • testing results showed that the testing sample diluted for 100 times and reacted with a Neisseria gonorrhoeae suspension for 1 minute killed Neisseria gonorrhoeae. TEST ON TRICHOMONAS VAGINALIS
  • the microbicide was tested on Trichomonas vaginalis. The details of the test were as follows.
  • the testing strain was a clinically isolated Trichomonas vaginalis strain.
  • the culture medium was a liver infusion medium.
  • the testing sample was the microbicide solution prepared per Example 1 , formulation 3.
  • TABLE 7 The results of the testing the samples on Trichomonas vaginalis are shown in TABLE 7.
  • a "+” indicates that Trichomonas vaginalis was active, and a "-” indicates that Trichomonas vaginalis were not active and were dissolved.
  • the testing results showed that the testing sample diluted for 100 times and reacted with Trichomonas vaginalis suspension for 1 minute killed Trichomonas vaginalis.
  • the microbicide was tested on HIV-1.
  • the details of the test were as follows.
  • the testing strain was Human Immunodeficiency Virus: HIV-1 IMB strain.
  • the cell was an MT 4 cell.
  • the testing sample was the microbicide solution prepared per Example 1 , formulation 2.
  • Testing samples were diluted to 1 :20; 1 :40; 1 :80 and 1 :160 solutions with distilled water. For each testing sample, 0.9 ml of testing sample was mixed to 0.1 ml HIV suspension solution. The resulting mixtures were each reacted for 1 min.; 3 min.; 5 min. at room temperature. 0.1 ml of each mixture was diluted with culture fluid to 1 :1000. The virus concentrations were titrated (96 well plate, each well contains 0.1 ml of 50000/ml MT4 cell). The titrated mixtures were incubated for 7 days at 37 0 C and 5% CO2. 7) 0.1 ml of fresh culture fluid was added to each titrated mixture at the third day. Observation for cell growth was made everyday. Existence of Virus with
  • the experimental groups were: Testing group; Drug (sample) removed control group (1000 times diluted Virus + 1000 times diluted sample); Normal cell control group; and Virus control group (Virus + culture fluid).
  • HIV-1 titration was 10 7 TCID 50 .
  • the "drug removed control group" showed that the dilution could stop the effect of sample to the virus.
  • 1 :20 and 1 :40 dilutions were reacted with HIV-1 for 1 minute, titrated and cultured with MT4 cell, no cell abnormality were observed.
  • 1 :80 dilutions were reacted with HIV-1 for 3 minutes, titrated and cultured with MT4 cell, no cell abnormality were observed.
  • the microbicide was tested on Candida albicans. The details of the test were as follows.
  • the testing strain was Candida albicans ATCC 10231 , 4th generation.
  • the culture medium was a 10% blood dish.
  • the testing sample was the microbicide solution prepared per example 1 , formulation 2.
  • the testing method used a nutrient broth dilution method at a temperature of 21 +/- 1 0 C .
  • the microbicide was tested on HIV-1. The details of the test were as follows.
  • the testing strain was Human Immunodeficiency Virus: HIV-1 IMB strain.
  • the cell was an MT 4 cell.
  • the testing sample was the microbicide solution prepared per Example 1 , formulation 5.
  • HIV Virus deactivation Tests Page: 38. Testing samples were diluted to 1 :20; 1 :40; and 1 :80 solutions with distilled water. For each testing sample, 0.9 ml of testing sample was mixed to 0.1 ml HIV suspension solution. The resulting mixtures were each reacted for 1 minute; 3 minutes; 5 minutes; and 10 minutes at room temperature. 0.1 ml of each mixture was diluted with culture fluid to 1 :1000. The virus concentrations were titrated (96 well plate, each well contains 0.1 ml of 50000/ml MT4 cell). The titrated mixtures were incubated for 7 days at 37 0 C and 5% CO2. 0.1 ml of fresh culture fluid was added to each titrated mixture at the third day. Observation for cell growth was made everyday. Existence of Virus with CPE was evaluated.
  • the experimental groups were: Testing group; Drug (sample) removed control group (1000 times diluted Virus + 1000 times diluted sample); Normal cell control group; and Virus control group (Virus + culture fluid).
  • HIV-1 titration was 10 7 TCID 50 .
  • the "drug removed control group" showed that the dilution could stop the effect of sample to the virus.
  • 1 :20 and 1 :40 dilutions were reacted with HIV-1 for 1 minute, titrated and cultured with MT4 cell, no cell abnormality were observed.
  • 1 :80 dilutions were reacted with HIV-1 for 3 minutes, titrated and cultured with MT4 cell, no cell abnormality were observed.
  • the microbicide was tested on Treponema Pallidum. The details of the test were as follows.
  • the testing strain was Treponema Pallidum, Nichols strain.
  • the testing sample was the microbicide gel prepared per example 1 , formulation 5.
  • the testing methods and standards followed the "Guidelines for Pre-clinical and Clinical Research of New Drugs" in the 1993 Edition of The Experimental Methods and Procedures for Anti-Treponema Pallidum.
  • the testing temperature was in the range of 20 0 C - 25°C.
  • the sample dilutions ratios tested were: 1 :5; 1 :10; 1 :20; 1 :40; 1 :80; and 1 :100. 5) Samples were diluted with distilled water.
  • Treponema Pallidum Suspension each field >30 Treponema Pallidum.
  • the reaction times were 1 minute, 3 minutes, 5 minutes, and 10 minutes. No terminating agent was employed in the tests.
  • the deactivating effects for Treponema Pallidum were recorded at different time intervals. The tests were repeated two times.
  • the microbicide was tested on Chlamydia trachomatis. The details of the test were as follows.
  • the testing strain was Chlamydia trachomatis, E Bour type, 10 th generation, provided by CDC of USA.
  • the cells were McCoy cells.
  • the culture medium was RPMI- 1640 culture medium.
  • the testing sample was the microbicide gel prepared per example 1 , formulation 5. Diluting neutralizing methods were employed, the diluent was 1640 medium with 10% bovine serum.
  • the testing methods and standards followed the standards issued by The Health Department of China in the 2002 Edition of Technical Standards for Disinfection (The Standard). The tests followed the "Standard" with consideration of the characteristics of Chlamydia trachomatis.
  • the testing temperature was 25°C.
  • the microbicide concentrations tested were: 1 :20; 1 :50; 1 :100; 1 :200; and 1 :500.
  • the concentration of Chlamydia trachomatis suspension was 10 5 .
  • the reaction times were 1 minute, 3 minutes, 5 minutes, and 10 minutes. Diluting methods were used to remove the residue of sample.
  • Example 1 Testing sample diluted at 1 :50 (example 1 , formulation 9) and reacted with Chlamydia trachomatis suspension for 1 minute killed Chlamydia trachomatis.
  • the microbicide was tested on Ureaplasma Urealyticum. The details of the test were as follows.
  • the testing strain was Ureaplasma Urealyticum, international standard strain, 6 th generation.
  • the culture medium was High efficiency Ureaplasma culture medium.
  • the testing sample was the microbicide gel prepared per example 1 , formulation 5.
  • the testing methods and standards followed the standards issued by The Health Department of China in the 2002 Edition of Technical Standards for Disinfection (The Standard).
  • the tests followed the "Standard" with consideration of the characteristics of Ureaplasma Urealyticum.
  • the testing temperature was 25°C- 28°C.
  • the microbicide concentrations tested were: 1 :100; 1 :200; 1 :500; and 1 :1000.
  • the concentration of Ureaplasma Urealyticum was 10 7 .
  • the reaction times were 1 minute, 3 minutes, 5 minutes, and 10 minutes.
  • the treatment used a Ureaplasma Urealyticum suspension in a diluted sample at a ratio of 1 :9. Diluting methods were used to remove the residue of drug.
  • the test was repeated two times.
  • testing results showed that a testing sample diluted 200 times (Example 1 , formulation 4) and reacted with Ureaplasma Urealyticum suspension for 1 minute, killed Ureaplasma Urealyticum.
  • the microbicide was tested on Neisseria gonorrhoeae.
  • the details of the test were as follows.
  • the testing strain was Neisseria gonorrhoeae, Standard strain G, provided by WHO.
  • the culture medium was 10% blood dish.
  • the testing sample was the microbicide gel prepared per example 1 , formulation 5.
  • the testing methods and standards followed the standards issued by The Health Department of China in the 2002 Edition of Technical Standards for Disinfection (The Standard). The tests followed the "Standard" with consideration of the characteristics of Neisseria gonorrhoeae.
  • the testing temperature was 25°C- 28 0 C.
  • the microbicide concentrations tested were: 1 :25; 1 :50; 1 : 100; 1 :250; and 1 :500.
  • the concentration of Neisseria gonorrhoeae suspension was 10 7 .
  • the treatment times were 1 minute, 3 minutes, 5 minutes, and 10 minutes.
  • the treatment used a Neisseria gonorrhoeae suspension diluted in 1 :1 ratio. Diluting methods were used to remove the residue of drug.
  • the test was repeated three times.
  • testing results showed that a testing sample diluted for 100 times (example 1 , formulation 8) and reacted with Neisseria gonorrhoeae suspension for 1 minute, killed Neisseria gonorrhoeae. TEST ON TRICHOMONAS VAGINALIS
  • the microbicide was tested on Trichomonas vaginalis. The details of the test were as follows.
  • the testing strain was clinically isolated Trichomonas vaginalis.
  • the culture medium was liver infusion medium.
  • the testing sample was the microbicide gel prepared per example 1 , formulation 5.
  • the testing temperature was 20 0 C- 25°C.
  • the microbicide concentrations tested were: 1 :50; 1 : 100; 1 :200.
  • the concentration of Trichomonas vaginalis suspension was 10 5 /ml.
  • the treatment times were 1 minute, 3 minutes, 5 minutes, and 10 minutes.
  • the treatment used a Trichomonas vaginalis suspension diluted in 1 :1 ratio. Diluting methods were used to remove the residue of drug. The test was repeated two times.
  • TABLE 13 The results of the testing the samples on Trichomonas vaginalis are shown in TABLE 13.
  • a "+” indicates active Trichomonas vaginalis
  • a " ⁇ ” indicates most Trichomonas vaginalis were killed, a few active were left
  • a "-” indicates that Trichomonas vaginalis were not active and were dissolved.
  • testing results showed that a testing sample diluted for 100 times (example 1 , formulation 8) and reacted with Trichomonas vaginalis suspension for 1 minute, killed Trichomonas vaginalis.
  • microbicide was tested on Herpes Simplex Virus. The details of the test were as follows.
  • the testing strain was Herpes Simplex type Il strain, standard international strain, provided by the Drug and bio-product office of the Health Department of China.
  • the culture medium 1640 culture medium.
  • the cell was Vero cell strain, introduced by the Cell biology Institute of Shanghai.
  • the testing sample was the microbicide gel prepared per example 1 , formulation 5.
  • the virus suspension was 5x10M/ml.
  • the microbicide concentrations tested were 1 :20; 1 :40; and 1 :50.
  • the reaction times were 1 minute, 3 minutes, 5 minutes, and 10 minutes.
  • the testing temperature was 20 0 C- 25 0 C. Diluting methods were used to remove the residue of drug (2% bovine serum culture medium as diluents). The test was repeated two times.
  • testing results showed that in a testing sample diluted for 20 times (Example 1 , formulation 7) and reacted with Herpes Simplex Virus, Herpes Simplex Virus was killed with 20 times dilution of the sample in 1 minute.
  • the microbicide was tested on Staphylococcus aureus. The details of the test were as follows.
  • the testing strain was Staphylococcus aureus ATCC6538, 5-6th generations, provided by the reserve center of China microbial reservation committee.
  • the testing medium carrier was sterilized filter paper.
  • the testing sample was the microbicide gel prepared per example 1 , formulation 5.
  • Example 1 Testing sample (Example 1 , formulation 5) reacted with Staphylococcus aureus for 1 minute; the average bactericide rate was 95.70%.
  • the microbicide was tested on Candida albicans. The details of the test were as follows.
  • the testing strain was Candida albicans, ATCC 10231 , the 5-6 generation as provided by the "Reserve Center of Chinese Microbial Reservation Committee".
  • the testing sample was the microbicide gel prepared per example 1 , formulation 5.
  • the bactericide effect of the testing sample to Candida albicans ATCCI0231 at 20 ⁇ 1 °C temperature with three repeated tests showed that for testing material reacted with Candida albicans ATCCI0231 for 1 minute, the average bactericide rate was 95.47%.
  • the Microbicidal Gel has bactericide effect on Candida albicans.
  • microbicide was tested on Eschetichia coli.
  • the details of the test were as follows.
  • the testing strain was Eschetichia coli 8099, the 5-6 generation as provided by the "Reserve Center of Chinese Microbial Reservation Committee".
  • the testing sample was the microbicide gel prepared per example 1 , formulation 5.
  • the bactericide effect of the testing sample to Eschetichia coli at 20 ⁇ 1 °C temperature with three repeated tests showed that for sample gel reacted with Eschetichia coli for 1 minute, the average bactericide rate was 99.97%.
  • the average bactericide rate was 99.97%.
  • microbicide was tested on human sperm. The details of the test were as follows.
  • the human sperm was normal sperm obtained from three healthy adults.
  • the testing sample was the microbicide solution prepared per example 1 , formulation 37.
  • the method followed was: mix the diluted samples with equal volume of fresh sperm (0.5 ml sample and 0.5 ml sperm); determine the minimum concentration and time of demobilize all the sperms; use saline as negative control; repeat the tests for three times.
  • Active rate ( % ) 75 73 The undiluted solution reacted with equal volume sperm for 30 seconds, 1 minute, 2 minutes, 3 minutes. The sperm survival rate was zero. The spermicidal rate of testing microbicide solution was 100% in 30 seconds (in vitro). For saline reacted with equal volume sperm, the sperm count and active rate was not influenced.
  • the spermicidal rate of testing sample was 100% in 30 seconds (in vitro).
  • microbicide was tested on human sperm. The details of the test were as follows.
  • the human sperm was normal sperm obtained from three healthy adults.
  • the testing sample was the microbicide gel prepared per example 1 , formulation 5.
  • the method followed was: dilute the Testing sample to different concentrations (1 :10, 1 :5, 1 :1); mix the diluted samples with equal volume fresh sperm (0.5 ml sample and 0.5 ml sperm); determine the minimum concentration and time of demobilize all the sperms; use saline as negative control; repeat the tests for three times.
  • the gel was diluted at 1 :1 , 1 :5 and reacted with equal volume sperm for 30 seconds, 1 minute, 2 minutes, and 3 minutes.
  • the sperm survival rate was zero.
  • the sperm survive rate was 10%.
  • the 1 :10 gel dilution reacted with sperm for 1 minute, 2 minutes, and 3 minutes, respectively; the sperm survive rate was zero.
  • Results are shown in Tables 21 , 22, and 23.
  • the spermicidal rate in testing microbicide gel was 100% in 30 seconds (in vitro), the minimum effective dilution was 1 :5.
  • the spermicidal rate in testing microbicidal gel was 100% in 60 seconds (in vitro), the minimum effective dilution was 1 :10.

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Abstract

La présente invention concerne des compositions, des procédés et des compositions pharmaceutiques topiques microbicides et spermicides contenant des carboxylates de pyrrolidone-N-cocoyl-acide aminé (sels de pyrrolidone-N-cocoyl-acide aminé, CAPS) comme principes actifs. L'invention vise à la prévention et à la suppression des maladies sexuellement transmissibles et à la prévention de la grossesse. Le spectre microbicide de l'invention comprend divers pathogènes de MST, des virus VIH, ainsi que des bactéries gram-positives et gram-négatives et des levures. L'invention concerne également des barrières spermicides contenant les compositions. Les sels de pyrrolidone-N-cocoyl-acide aminé sont représentés par la formule : dans laquelle A représente un acide aminé et R représente un résidu d'acide gras en C10-C14.
PCT/US2008/081795 2008-10-30 2008-10-30 Compositions et procédés microbicides et spermicides à large spectre WO2010050955A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1352420A (en) * 1971-06-18 1974-05-08 Ajinomoto Kk Arginine derivatives their production and their use
US4424232A (en) * 1982-05-19 1984-01-03 Parkinson Richard W Treatment of herpes simplex
WO1994019027A1 (fr) * 1993-02-26 1994-09-01 Wesley-Jessen Corporation Composition de desinfection des verres de contact et mode d'emploi
US20040258629A1 (en) * 2003-06-23 2004-12-23 Boyd Thomas J. Antiplaque confectionery dental composition
US7037513B1 (en) * 2005-01-31 2006-05-02 Aquea Scientific Corporation Bodywash additives
EP1693067A1 (fr) * 2003-10-30 2006-08-23 Obschestvo S Ogranichennoi Otvetstvennostyu "Rusgen" Composition pharmaceutique anti-herpetique, procede de production d'une forme medicamenteuse a partir de cette composition et procede d'utilisation correspondant
EP1844773A1 (fr) * 2005-02-03 2007-10-17 Kyorin Pharmaceutical Co., Ltd. Preparation pour absorption percutanee
CN101099735A (zh) * 2007-07-24 2008-01-09 艾硕特生物科技（昆明）有限公司 一种广谱、高效的微生物杀灭剂

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1352420A (en) * 1971-06-18 1974-05-08 Ajinomoto Kk Arginine derivatives their production and their use
US4424232A (en) * 1982-05-19 1984-01-03 Parkinson Richard W Treatment of herpes simplex
WO1994019027A1 (fr) * 1993-02-26 1994-09-01 Wesley-Jessen Corporation Composition de desinfection des verres de contact et mode d'emploi
US20040258629A1 (en) * 2003-06-23 2004-12-23 Boyd Thomas J. Antiplaque confectionery dental composition
EP1693067A1 (fr) * 2003-10-30 2006-08-23 Obschestvo S Ogranichennoi Otvetstvennostyu "Rusgen" Composition pharmaceutique anti-herpetique, procede de production d'une forme medicamenteuse a partir de cette composition et procede d'utilisation correspondant
US7037513B1 (en) * 2005-01-31 2006-05-02 Aquea Scientific Corporation Bodywash additives
EP1844773A1 (fr) * 2005-02-03 2007-10-17 Kyorin Pharmaceutical Co., Ltd. Preparation pour absorption percutanee
CN101099735A (zh) * 2007-07-24 2008-01-09 艾硕特生物科技（昆明）有限公司 一种广谱、高效的微生物杀灭剂

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