CN1314152A - Application of nifedipine as spermicide - Google Patents
Application of nifedipine as spermicide Download PDFInfo
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- CN1314152A CN1314152A CN 01106969 CN01106969A CN1314152A CN 1314152 A CN1314152 A CN 1314152A CN 01106969 CN01106969 CN 01106969 CN 01106969 A CN01106969 A CN 01106969A CN 1314152 A CN1314152 A CN 1314152A
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- Prior art keywords
- niphesamide
- spermicide
- killing
- test
- contraceptive
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- 239000000934 spermatocidal agent Substances 0.000 title claims abstract description 16
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 title abstract 2
- 229960001597 nifedipine Drugs 0.000 title abstract 2
- 239000003433 contraceptive agent Substances 0.000 claims abstract description 16
- 230000002254 contraceptive effect Effects 0.000 claims abstract description 15
- 241000588653 Neisseria Species 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000000843 anti-fungal effect Effects 0.000 claims 1
- 229940121375 antifungal agent Drugs 0.000 claims 1
- 230000002147 killing effect Effects 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 14
- 210000004877 mucosa Anatomy 0.000 abstract description 6
- 230000007794 irritation Effects 0.000 abstract description 3
- 229920004918 nonoxynol-9 Polymers 0.000 abstract description 3
- 229940087419 nonoxynol-9 Drugs 0.000 abstract description 3
- FBWNMEQMRUMQSO-UHFFFAOYSA-N tergitol NP-9 Chemical compound CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 FBWNMEQMRUMQSO-UHFFFAOYSA-N 0.000 abstract description 3
- 208000005623 Carcinogenesis Diseases 0.000 abstract description 2
- 208000031320 Teratogenesis Diseases 0.000 abstract description 2
- 230000036952 cancer formation Effects 0.000 abstract description 2
- 231100000504 carcinogenesis Toxicity 0.000 abstract description 2
- 241001502500 Trichomonadida Species 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 230000035772 mutation Effects 0.000 abstract 1
- 229920000847 nonoxynol Polymers 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 24
- 238000000034 method Methods 0.000 description 9
- 241000283973 Oryctolagus cuniculus Species 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 7
- 210000004379 membrane Anatomy 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 210000000582 semen Anatomy 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- NKBASRXWGAGQDP-UHFFFAOYSA-N 5-chlorosalicylic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1O NKBASRXWGAGQDP-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 230000007674 genetic toxicity Effects 0.000 description 4
- 231100000025 genetic toxicology Toxicity 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 208000031404 Chromosome Aberrations Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 231100000005 chromosome aberration Toxicity 0.000 description 3
- 210000000795 conjunctiva Anatomy 0.000 description 3
- 239000002085 irritant Substances 0.000 description 3
- 231100000021 irritant Toxicity 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 210000001215 vagina Anatomy 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004820 blood count Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000002124 endocrine Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940093181 glucose injection Drugs 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 231100000350 mutagenesis Toxicity 0.000 description 2
- 238000002703 mutagenesis Methods 0.000 description 2
- 229940127234 oral contraceptive Drugs 0.000 description 2
- 239000003539 oral contraceptive agent Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- LAOOXBLMIJHMFO-UHFFFAOYSA-N 1-[2-(diethylamino)ethylamino]-4-methylthioxanthen-9-one;hydron;chloride Chemical compound Cl.S1C2=CC=CC=C2C(=O)C2=C1C(C)=CC=C2NCCN(CC)CC LAOOXBLMIJHMFO-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 241000565675 Oncomelania Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 231100000460 acute oral toxicity Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- -1 dimethyl sulfoxine Chemical compound 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 206010023683 lagophthalmos Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 231100001225 mammalian toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003750 molluscacide Substances 0.000 description 1
- 230000002013 molluscicidal effect Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 231100000299 mutagenicity Toxicity 0.000 description 1
- 230000007886 mutagenicity Effects 0.000 description 1
- 210000004083 nasolacrimal duct Anatomy 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- RJMUSRYZPJIFPJ-UHFFFAOYSA-N niclosamide Chemical compound OC1=CC=C(Cl)C=C1C(=O)NC1=CC=C([N+]([O-])=O)C=C1Cl RJMUSRYZPJIFPJ-UHFFFAOYSA-N 0.000 description 1
- 229960001920 niclosamide Drugs 0.000 description 1
- LIXVMPBOGDCSRM-UHFFFAOYSA-N nonylbenzene Chemical compound CCCCCCCCCC1=CC=CC=C1 LIXVMPBOGDCSRM-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000004409 osteocyte Anatomy 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960000581 salicylamide Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000001843 schistosomicidal effect Effects 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses the application of nifedipine as spermicide, especially in preparing contraceptive for external use, it has quite strong killing action to human sperm in extremely low concentration of 2.5mg/L in extremely short time, the killing rate is 100%, its effect is 20 times of that of nonoxynol-9 of spermicide currently used, there is no irritation to mucosa, there is no three-cause action (teratogenesis, carcinogenesis, mutation), it is a high-efficient, safe (LD)501420.21mg/kg), low cost, convenient use, and capability of killing and inhibiting mold, gonococcus and trichomonad, and can be used for preparing contraceptive for external use instead of nonoxynol.
Description
(chemical name is: new purposes N-(4-nitrobenzophenone)-5-chlorosamide) relates in particular to the new purposes in pharmaceutical field to the present invention relates to Niphesamide.
Present (lady's) contraception medicament mainly is divided into two kinds of vagina spermicide and oral contraceptives.Because oral contraceptive exist to disturb shortcomings such as human endocrine and toxic and side effects are bigger,, more and more be subject to people's attention so the vagina spermicide is applied widely with it, kill that essence is effective, toxic and side effects is little, do not disturb advantage such as endocrine.At present both at home and abroad the spermicide that uses has 6 kinds of nonoxynolums (NP-9) etc., and wherein nonoxynolum is the most frequently used.It is reported that it is minimum, and to kill smart concentration be 150mg/L (Americana report minimum kill smart concentration be 50mg/L), its major side effects is vaginal mucosa irritation symptom and burn feeling.After the also possible transvaginal mucosa of nonoxynolum is absorbed by the body, cause that transaminase SGOT obviously increases, and might cause liver injury.
For overcoming above-mentioned defective, a kind of new external applied contraceptive active component is provided, we study Niphesamide.Niphesamide is the salicylamide derivant, is a kind of noval chemical compound, its synthetic method, structural formula and as the existing report of the purposes of other medicines.The Yi Jianmin of this seminar etc. are at " Zhongnan Polytechnic Univ's journal "-99, reported the synthetic of Niphesamide on 30 (5)-519-521, Shi Tianyi etc. are in " fine chemistry industry "-98,15 (5)-14-16 have reported that " treating different things alike " method synthesizes Niphesamide, and CN1075137A discloses Snailicide (Niphesamide Niphensamide) and synthesis technique (number of patent application is 93110462.9) thereof; US4708953 discloses the salicylamide analog derivative and as the application of root nodule pathogenic bacteria agent for killing.
Show (novelty assessment report is attached) according to the project novelty assessment report of province Scientific and Technical Information Institute March 5 calendar year 2001, except that looking into the relevant paper that the member of seminar of new projects delivers, other does not see the bibliographical information identical with the technology of the present invention characteristics.
Its structural formula of Niphesamide of the present invention is:
Wherein, R
1=R
3=H, R
2=Cl works as R
2=R
3=H, R
1=Cl; R
1=R
2=Cl, R
3=H; R
1=H, R
2=R
3=Cl; R
1=R
2=R
3Then the derivant of Niphesamide during=Cl.The Niphesamide molecular formula is C
13H
9O
4N
2Cl, molecular weight 292,251～252 ℃ of fusing points, pale yellow powder, be insoluble to acid, atomic water-soluble, be slightly soluble in organic solvents such as ethanol, acetone, ether, benzene, chloroform, can be dissolved in pyridine, dimethyl sulfoxine, rare NaOH, KOH aqueous solution and the ammonia solution, in Reducing agent, be reduced and lose activity.Niphesamide produces the concentration of biological effect at 0.5～2mg.L, Zhang Yifu, Xu You, Shi Tianyi have reported " measuring the content of Niphesamide in the water with ultraviolet spectrophotometry " on " spectroscopy and spectrum analysis " 2000 the 20th the 2nd phases of volume, the detection effect of this detection method is more satisfactory.
The chemical compound Niphesamide can be synthetic by 5-chloro-salicylic acid, thionyl chloride, paranitroanilinum reaction, and synthetic method mainly contains that " method for the treatment of different things alike is " with " stepwise synthesis " two kinds.Knownly can and kill schistosomicide intermediate host---the molluscicide of oncomelania as plant root nodule pathogenic bacteria agent for killing.
The object of the present invention is to provide the new purposes of Niphesamide, promptly, also provide a kind of new active component simultaneously for external applied contraceptive as the new application of preparation spermicide.
For achieving the above object, we study as spermicide and the application in the preparation external applied contraceptive Niphesamide.The external animal toxicity test that kills smart test and send relevant department to carry out in smart test and the animal body that kills that carries out according to us, and killing and suppress experiment to mycete, gonococcus, infusorian, general pharmacological research and three tests of genetic toxicity show, Niphesamide can be used as a kind of new efficient, safe, inexpensive, easy to use and have the multi-pharmaceutics external use sperm killing agent of killing mould fungus inhibition, gonococcus, infusorian effect concurrently.
In order to understand essence of the present invention better, as the relevant test and the result of spermicide its new purposes in pharmaceutical field is described with Niphesamide below.Similarly, with niclosamide same pharmacological effect is arranged also, difference is the difference on use amount only.
Adopt the synthetic Niphesamide of the method for fractional steps, its basic step is:
(1) under the sodium hydroxide effect, generates t-butyl hypochlorate by the tert-butyl alcohol and chlorine earlier;
(2) again salicylic acid and first step product are reacted 5-chloro-salicylic acid (also can directly on market, buy the 5-chloro-salicylic acid);
(3) 5-chloro-salicylic acid and thionyl chloride effect are generated amide, back and paranitroanilinum react thick product;
(4) purify the thick product of gained to such an extent that pale yellow crystalline powder is standby.
1, the external test of killing smart effect of Niphesamide
(1) Niphesamide is made into 50mg/L solution with 5% aseptic glucose injection, and then with 5% Glucose Liquid be diluted to 20,10,5,2.5, the solution for standby of 1mg/L concentration;
(2) Freshman seminal fluid is provided by the man of health normal fertility, treat seminal fluid liquefaction after, press blood cell counting and count, sperm concentration is 7.2 * 10
7Individual/the ml vigor) 83%.Former seminal fluid is with 10 times of 5% aseptic D/W dilutions, and is standby.
(3) seminal fluid that has diluted and medicinal liquid be constant temperature in 37 ℃ of water temperature casees all, get 1ml and diluted seminal fluid, add in the small test tube that the 1ml medicinal liquid is housed, after test tube places and gently mixes in the thermostatic water tank, get mixed liquor 0.5ml, place on the slide immediately, microscopically is observed (* 100), writes down the sperm count of living in 20 seconds, 3 minutes respectively, repeats 3～5 times.Observed result, during Niphesamide liquor strength 2.5 〉=mg/L, the smart number of living in 20 seconds, 3 minutes is 0, and killing rate is 100%, and when liquor strength was 1mg/L, the smart number of living in 20 seconds, 3 minutes was 2～30, and killing rate is 98.33%～99.8%.The result shows that Niphesamide has extremely strong killing in vitro effect to human body sperm alive.
2, the acute toxicity test of Niphesamide
(1) the oral acute toxicity test of mice
Intragastrically is measured Niphesamide to white mice LD by two step trial test methods
50Be 1420mg/kg, judge that according to the fractionated standard of China's poisonous substance per os acute toxicity Niphesamide belongs to low toxicity to mammalian toxicity, high dose causes that the cardinal symptom that chmice acute is poisoned is central nervous system's toxic reaction.
(2) rabbit skin irritant test and eye conjunctiva irritant test
With three of test rabbits, select a 4 * 4cm every rabbit abdominal part both sides
2The zone evenly cuts off hair, tests in second day.It is Niphesamide ointment 1.25 grams that every rabbit is coated with dose, evenly be applied to a side cropping district, opposite side is the isotonic saline solution check plot, behind the coating 4h, with warm suds detergency test district skin, no any reaction behind the coating 24h, then every day coating 1 time, reaction appears in skin behind the coating three times, and examines and write down skin irritation reaction and recovery situation.With three of experimental rabbits, 20% Niphesamide suspension 0.1ml is splashed in the rabbit one branch hole conjunctival sac, make and close one's eyes and oppress nasolacrimal duct, with isotonic saline solution that medicine in the eye conjunctival sac is fully clean after 1 minute, opposite side compares with isotonic saline solution.Observe and write down 1,12,24,48,72 and the 96h medicine to the irritant reaction and the recovery situation thereof of eye conjunctiva.The result shows that Niphesamide has the minimal irritation reaction to rabbit skin, to eye conjunctiva vacuum response.
(3) three tests of genetic toxicity
Send Niphesamide sample to " Beijing Scientific and Technical Cooperation Centre branch of Nat'l Pharmaceutical ﹠ Biological Products Control Institute " to do three tests of genetic toxicity: the result is negative for (1) histidine auxotroph Salmonella typhimurium mutagenesis testing (Salmonella reversion test); (2) NIH mouse marrow cell micro nuclear test, microscopy bone marrow polychromatic erythrocyte micronucleus brings out rate, and the result shows relatively there was no significant difference of Niphesamide and negative control group (Oleum Sesami group); (3) CHL cells in vitro chromosomal aberration test, test shows under activation and disactivation condition, Niphesamide acts at 24 hours and 48 hours the CHL cell and does not all bring out obvious distortion, and promptly Niphesamide is negative to CHL cells in vitro chromosomal aberration test result.Therefore, the survey report of three tests of genetic toxicity shows that Niphesamide does not have mutagenicity, no teratogenecity, non-carcinogenesis.
The above results shows: Niphesamide toxicity is little, and mucosa is had no stimulation, and does not have three and causes effect (teratogenesis, carcinogenic, mutagenesis), and (2.5mg/l) still has great killing action to the human body sperm during extremely low concentration, kills rapidly, and killing rate is 100%.Its effect is 20 times of the present spermicide Nonoxynol-9 that uses.(the Nonoxynol-9 minimal effective concentration of killing sperm is 50mg/l, and each component spermicide least concentration of alkane benzene polyalcohol ether is 150～250mg/l).Therefore Niphesamide is 2.5～5mg/L as the suitable concentration that spermicide uses, it is the new active component of external applied contraceptive, alternative nonoxynolum is prepared into contraceptive membrane or other exterior-applied formulation such as water preparation, tablet, suppository etc., and it is 0.02～0.08 gram that everyone each dosage of insurance contraception consumption is converted former powder.
From above result, can draw and the invention has the advantages that:
1, product is easy to synthesize that (synthetic route is short, and technology is simple, the yield height; 2, production cost low (about 5～100,000 yuan of Niphesamide per ton); 3, kill smart effective (external kill smart least concentration be 2.5mg/L); 4, toxicity is low, and is safe; 5, having concurrently extremely, gonococcus, infusorian, mycete etc. prevent and treat the effect of part gynaecopathia.
From the performance of Niphesamide and spermicide nonoxynolum commonly used more as can be seen: Niphesamide is a kind of safer, efficient, inexpensive contraceptive active component, can be used as the renewal product of nonoxynolum, replace nonoxynolum and be prepared into multi-pharmaceutics external applied contraceptives such as contraceptive membrane.
The relevant performance with spermicide nonoxynolum commonly used of table 1 Niphesamide relatively
| Compare content | Nonylbenzene ferment ether | Niphesamide |
| 1, external minimum spermaticide substrate concentration (mg/L) 2, white mice LD 50(mg/kg) 3, the external osteocyte micronucleus test 4 of NIH white mice, Ame ' s test 5, CHL cells in vitro chromosomal aberration test 6, to mucocutaneous stimulation 7, whether medicine absorbs 8 on mucosa, influence to liver | 150～250 (domestic) 50 (U.S.'s product), 124.2 ± 9.8 (Americanas) cloudy cloudy light (doe vagina mucosa) absorb the human liver are had infringement (domestic technical magazine has report) | 2.5 the cloudy cloudy nothing (lagophthalmos mucous membrane) of～5.0 1420.21 (food additives amounts) does not absorb nothing (small white mouse, rabbit) |
Embodiment 1: adopt the synthetic former medicine of Niphesamide of the method for fractional steps, (pale yellow crystalline powder), be made into the solution for standby of 2.5mg/L concentration with 5% aseptic glucose injection, get the Freshman seminal fluid and dilute 10 times with 5% aseptic D/W, diluted in the seminal fluid at 1mL, add 1mL Niphesamide medicinal liquid, watching the smart number of living at microscopically is 0, and killing rate is 100%.
Embodiment 2: get the former medicine 100g of Niphesamide, replace nonoxynolum by the method that well known to a person skilled in the art with Niphesamide and prepare the Niphesamide contraceptive membrane, every of this contraceptive membrane contains former powder 0.02 gram.Using method is identical with the nonoxynolum contraceptive membrane.
Embodiment 3: get the former medicine 100g of Niphesamide, prepare the Niphesamide contraceptive membrane with the method among the embodiment 2, every of wherein said contraceptive membrane contains former powder 0.08 gram, and using method is with embodiment 2.
Claims (2)
1, Niphesamide is as the application of spermicide.
2, application according to claim 1 is characterized in that: Niphesamide is in the application of preparation in the external applied contraceptive, and the application of double as antifungal, gonococcus, infusorian agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011069694A CN1143677C (en) | 2001-03-24 | 2001-03-24 | Application of nifedipine as spermicide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011069694A CN1143677C (en) | 2001-03-24 | 2001-03-24 | Application of nifedipine as spermicide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1314152A true CN1314152A (en) | 2001-09-26 |
| CN1143677C CN1143677C (en) | 2004-03-31 |
Family
ID=4655924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB011069694A Expired - Fee Related CN1143677C (en) | 2001-03-24 | 2001-03-24 | Application of nifedipine as spermicide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1143677C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113453673A (en) * | 2019-02-22 | 2021-09-28 | 加利福尼亚大学董事会 | Non-hormone contraceptive for both men and women |
-
2001
- 2001-03-24 CN CNB011069694A patent/CN1143677C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113453673A (en) * | 2019-02-22 | 2021-09-28 | 加利福尼亚大学董事会 | Non-hormone contraceptive for both men and women |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1143677C (en) | 2004-03-31 |
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