CN102670588A - 鞣花酸用于制备抗病毒药物的应用 - Google Patents
鞣花酸用于制备抗病毒药物的应用 Download PDFInfo
- Publication number
- CN102670588A CN102670588A CN2012101383793A CN201210138379A CN102670588A CN 102670588 A CN102670588 A CN 102670588A CN 2012101383793 A CN2012101383793 A CN 2012101383793A CN 201210138379 A CN201210138379 A CN 201210138379A CN 102670588 A CN102670588 A CN 102670588A
- Authority
- CN
- China
- Prior art keywords
- ellagic acid
- pharmaceutical composition
- application
- herpes simplex
- agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- AFSDNFLWKVMVRB-UHFFFAOYSA-N Ellagic acid Chemical compound OC1=C(O)C(OC2=O)=C3C4=C2C=C(O)C(O)=C4OC(=O)C3=C1 AFSDNFLWKVMVRB-UHFFFAOYSA-N 0.000 title claims abstract description 46
- ATJXMQHAMYVHRX-CPCISQLKSA-N Ellagic acid Natural products OC1=C(O)[C@H]2OC(=O)c3cc(O)c(O)c4OC(=O)C(=C1)[C@H]2c34 ATJXMQHAMYVHRX-CPCISQLKSA-N 0.000 title claims abstract description 46
- 229920002079 Ellagic acid Polymers 0.000 title claims abstract description 46
- 235000004132 ellagic acid Nutrition 0.000 title claims abstract description 46
- 229960002852 ellagic acid Drugs 0.000 title claims abstract description 46
- FAARLWTXUUQFSN-UHFFFAOYSA-N methylellagic acid Natural products O1C(=O)C2=CC(O)=C(O)C3=C2C2=C1C(OC)=C(O)C=C2C(=O)O3 FAARLWTXUUQFSN-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 230000000840 anti-viral effect Effects 0.000 title abstract description 3
- 239000003814 drug Substances 0.000 title abstract description 3
- 241000701806 Human papillomavirus Species 0.000 claims abstract description 16
- 241000700605 Viruses Species 0.000 claims abstract description 11
- 241000700584 Simplexvirus Species 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 241000701074 Human alphaherpesvirus 2 Species 0.000 claims description 11
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000003443 antiviral agent Substances 0.000 claims description 5
- -1 glycerol ester Chemical class 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 102000007327 Protamines Human genes 0.000 claims description 2
- 108010007568 Protamines Proteins 0.000 claims description 2
- 102000007562 Serum Albumin Human genes 0.000 claims description 2
- 108010071390 Serum Albumin Proteins 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000012928 buffer substance Substances 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 238000012377 drug delivery Methods 0.000 claims description 2
- 239000003792 electrolyte Substances 0.000 claims description 2
- 239000003623 enhancer Substances 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000000796 flavoring agent Substances 0.000 claims description 2
- 235000013355 food flavoring agent Nutrition 0.000 claims description 2
- 238000005342 ion exchange Methods 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 239000000391 magnesium silicate Substances 0.000 claims description 2
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 2
- 235000019792 magnesium silicate Nutrition 0.000 claims description 2
- ZADYMNAVLSWLEQ-UHFFFAOYSA-N magnesium;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[Mg+2].[Si+4] ZADYMNAVLSWLEQ-UHFFFAOYSA-N 0.000 claims description 2
- 230000036961 partial effect Effects 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 150000003904 phospholipids Chemical class 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 229940048914 protamine Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 239000000080 wetting agent Substances 0.000 claims description 2
- 150000003751 zinc Chemical class 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 206010059313 Anogenital warts Diseases 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 201000010153 skin papilloma Diseases 0.000 description 5
- 208000000260 Warts Diseases 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000002147 killing effect Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 241000340969 Alphapapillomavirus 10 Species 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 241000700721 Hepatitis B virus Species 0.000 description 2
- 208000001688 Herpes Genitalis Diseases 0.000 description 2
- 241000701828 Human papillomavirus type 11 Species 0.000 description 2
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 208000019802 Sexually transmitted disease Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 201000004946 genital herpes Diseases 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 231100000915 pathological change Toxicity 0.000 description 2
- 230000036285 pathological change Effects 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000003501 vero cell Anatomy 0.000 description 2
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 238000009007 Diagnostic Kit Methods 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 208000005100 Herpetic Keratitis Diseases 0.000 description 1
- 241000341655 Human papillomavirus type 16 Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010051141 Myeloblastoma Diseases 0.000 description 1
- 206010073938 Ophthalmic herpes simplex Diseases 0.000 description 1
- 208000001300 Perinatal Death Diseases 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 244000294611 Punica granatum Species 0.000 description 1
- 235000014360 Punica granatum Nutrition 0.000 description 1
- 206010043966 Tongue neoplasm malignant stage unspecified Diseases 0.000 description 1
- 240000001717 Vaccinium macrocarpon Species 0.000 description 1
- 235000012545 Vaccinium macrocarpon Nutrition 0.000 description 1
- 244000078534 Vaccinium myrtillus Species 0.000 description 1
- 235000002118 Vaccinium oxycoccus Nutrition 0.000 description 1
- 241000934136 Verruca Species 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 201000006083 Xeroderma Pigmentosum Diseases 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 201000004196 common wart Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000004634 cranberry Nutrition 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 201000010884 herpes simplex virus keratitis Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 208000015994 miscarriage Diseases 0.000 description 1
- 238000004264 monolayer culture Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000002530 phenolic antioxidant Substances 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 201000004303 plantar wart Diseases 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000005919 time-dependent effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000002477 vacuolizing effect Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种鞣花酸用于制备抗病毒药物的应用，所述病毒为单纯疱疹病毒和人乳头瘤病毒。本发明还公开了一种以鞣花酸为活性成分的药物组合物。本发明为鞣花酸的应用开辟了一条新的途径。
Description
技术领域
本发明属于生物医药领域，具体地说，是关于一种鞣花酸用于制备抗病毒药物的应用。
背景技术
鞣花酸（Ellagic acid）是存在于众多水果和蔬菜中的天然酚类抗氧化剂。黑莓、覆盆子、草莓、蔓越莓、五倍子、山核桃、石榴、枸杞等植物内鞣花酸含量较高。鞣花酸具有多种生物活性功能，如抗氧化功能、抗癌、抗突变、抗菌、降压、镇静等作用，对人体免疫缺陷病毒、乙肝病毒HBV、小鼠疱疹病毒、鸟的成髓细胞瘤的逆转录病毒有抑制作用。此外，研究发现，鞣花酸还能抑制HPV18的E7蛋白的表达以及诱导HPV16阳性细胞Caski的凋亡（J.Agr Food Chem,1987,35:808-812;Phytochemistry,1988,27:1315-1320;Antibiotixs,1989,42:107-115;BioorgMed Chem Lett,1993,3(2):225-230;Antiviral Research,2006,72(2):100-106;Journal of Virology,2009,83(11):5630-5639;Cancer Lett,1999,136(2):215-21）。
单纯疱疹病毒HSV（Herpes simplex virus）属于疱疹病毒科a病毒亚科，根据抗原性的差别分为1型和2型（HSV-1和HSV-2），可引起口唇性疱疹、疱疹性角膜炎、疱疹性皮肤炎、阴部疱疹、卡波西病等，有时也是脑膜炎、脑炎的病因，HSV-1常引起腰部以上感染，尤其眼及口腔部位的感染，HSV-1也能引起生殖器疱疹（10%），HSV-2是生殖器疱疹的主要病原体（90%），可通过胎盘及产道感染新生儿，导致流产及新生儿死亡，与宫颈癌的发生也有关，危害较大。
人乳头瘤病毒HPV（Human papillomavirus）是一种属于乳多空病毒科的乳头瘤空泡病毒A属，是球形DNA病毒，人是它唯一的宿主，HPV与多种疾病有关，分为许多亚型，按其对组织恶性转化程度不同，可分为高危型、中危型和低危型三类。HPV与其他病原体不同，它并不引起炎症性反应，而是促发宿主细胞的增殖，呈肿瘤性生长，可导致恶性肿瘤的发生，如皮肤癌、舌癌等，上个世纪末，国际上已确认宫颈上皮HPV的慢性感染是宫颈癌的病因，此外HPV常会引起人类的各种疣，如寻常疣、扁平疣、跖疣、甲缘疣及尖锐湿疣等。尖锐湿疣是我国最主要的性病之一，至少有10个类型与其有关，其中又以HPV6、11型最常见，目前的治疗方式很难直接从病毒入手，因此治标不治本。
至今为止，尚未发现鞣花酸具有抑制人的单纯疱疹病毒及直接破坏人乳头瘤病毒6和11型DNA作用的文献。
发明内容
本申请的发明人在长期的研究中发现，鞣花酸对2型单纯疱疹病毒（HSV-2）和人乳头瘤病毒（HPV6/11）均有较强的抑制作用。
因此，本发明的目的在于提供一种鞣花酸用于制备抗病毒药物的应用。
根据本发明，所述病毒为单纯疱疹病毒和人乳头瘤病毒。
根据本发明的优选实施例，所述单纯疱疹病毒为单纯疱疹病毒2型，所述人乳头瘤病毒为人乳头瘤病毒6型和11型。
本发明还提供了一种药物组合物，该药物组合物以鞣花酸为活性成分。
根据本发明，所述药物组合物包括治疗有效量的鞣花酸和一种或多种可药用载体。
本发明为鞣花酸的应用开辟了一条新的途径。
具体实施方式
本发明的问世部分是基于这样一个意外发现：鞣花酸在体外可显著抑制人乳头瘤病毒6和11（HPV6/11）和单纯疱疹病毒2型（HSV-2），因而可以用于制备抗病毒药物。
本发明的上下文中，术语“治疗有效量”是指能够达到治疗效果的提取物的量。本领域的专业人员能够理解“治疗有效量”可以随着给药的方式、载体的使用以及可能和其他治疗剂合用等而有所不同。
根据本发明，鞣花酸可以单独使用或以药物组合物的形式使用。药物组合物以本发明的鞣花酸为活性成分，包括治疗有效量的鞣花酸以及一种或多种可药用载体。“可药用载体”不会破坏本发明的鞣花酸的药学活性，同时其有效用量，即能发挥药物载体作用时的用量对人体无毒。
所述可药用载体包括但不限于：软磷脂、硬脂酸铝、氧化铝、离子交换材料、自乳化药物传递系统、吐温或其他表面活化剂、血清蛋白、缓冲物质如磷酸盐、氨基乙酸、山梨酸、水、盐、电解质如硫酸盐精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅酸镁、饱和脂肪酸部分甘油酯混合物等。
其他常用的药物辅料如粘合剂（如微晶纤维素）、填充剂（如淀粉、葡萄糖、无水乳糖和乳糖珠粒）、崩解剂（如交联PVP、交联羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素）、润滑剂（如硬脂酸镁）以及吸收促进剂、吸附载体、香味剂、甜味剂、赋形剂、稀释剂、润湿剂等。
以下结合具体实施例对本发明作进一步说明，但并不意味着本发明仅限于此。
以下实施例中所使用的鞣花酸为市售产品。
实施例1、鞣花酸对HSV-2病毒的抑制作用
实验材料：
细胞：非洲绿猴肾细胞（Vero），购自中科院细胞库。
病毒：单纯疱疹病毒HSV-2型Sm333标准毒株，由北京中国医学科学院医药生物技术研究所提供。
受试药物：鞣花酸，溶解于DMSO中，制备得60mg/mL母液。
阳性对照：阿昔洛韦（ACV，购自湖北科益药业股份有限公司）。
实验方法：
Vero细胞按常规方法培养于含10%FBS的DMEM培养基中，次日，以1×105/孔接种于96孔板，单层培养24小时后，吸弃上清液、洗涤，加入10TCID50的病毒液，吸附2小时后，吸去病毒，加入不同浓度的药液，培养72小时后观察CPE（病变），设细胞对照组、病毒对照组、阳性对照组、实验药物组，同时观察CPE，抑制病变超过50%的，计算IC50。
实验结果如以下表1所示：
表1、鞣花酸对HSV-2的抑制作用
以上表1的实验结果表明，在Vero细胞中，鞣花酸对HSV-2病毒具有明显抑制作用，且鞣花酸对HSV-2的抑制呈剂量依赖关系。
实施例2、鞣花酸对HPV6、11型病毒的抑制作用
实验材料：
HPV6/11型病毒来源：HPV6、11型病毒取自未经治疗的尖锐湿疣病人的疣体，经生理盐水清洗后在无菌条件下研磨成组织匀浆备用。
受试药物：鞣花酸，溶解于DMSO中，制备得60mg/mL母液。
主要仪器：ABI 7500荧光定量PCR仪。
HPV6/11型FQ-PCR诊断试剂盒：中山大学达安基因股份有限公司。
实验方法：
取尖锐湿疣组织匀浆液100uL，加入受试药物10uL，对照管则加入生理盐水10uL，每次实验同时设阴性及阳性对照管，37℃孵育24小时。
按试剂盒方法提取DNA，取2uL加入反应管中，放入ABI 7500荧光定量PCR仪进行反应，定量结果由电脑软件自动分析，计算其初始拷贝数。
实验结果如以下表2和表3所示：
表2、鞣花酸对HPV6/11抑制的剂量依赖效应
由表2的结果可见，尖锐湿疣组织匀浆液在加入50ug/mL的鞣花酸20小时后，HPV6/11已检测不出，而空白对照管具有很高浓度的HPV病毒量，说明鞣花酸具有快速有效地杀灭尖锐湿疣病毒的作用，且鞣花酸对HPV6/11的杀灭作用呈剂量依赖关系，而且鞣花酸对HPV病毒的杀灭作用可能是通过破坏HPV6/11的DNA而起效。
表3、鞣花酸对HPV6/11抑制的时间依赖效应
以上结果表明，鞣花酸在50ug/mL的浓度下，0.5小时即可完全杀灭HPV6/11，显示其破坏HPV6/11病毒DNA的速度相当快。
实施例3、片剂的制备
片剂组成：
将鞣花酸、HPMCLVIOO、乳糖混匀，以75%乙醇制软材，24目筛制粒，50℃干燥3小时，18目筛整粒，加入硬脂酸镁混匀压片，制成1000片，每片0.1g。
实施例4、胶囊剂的制备
胶囊组成：
将鞣花酸、淀粉、硬脂酸镁混匀，装胶囊，共1000粒，每粒0.1g。
实施例5、注射剂的制备
注射液组成：
鞣花酸，加入10%碳酸钠调PH值至7.0~7.5，冷藏过滤，加入吐温80和尼泊金乙酯，加注射用水至1000mL，滤过，分装，灌封，100℃流通蒸汽灭菌，30min即得。
本发明的鞣花酸可以单独使用或以药物组合物的形式使用。药物组合物以本发明的鞣花酸为活性成分，包括治疗有效量的鞣花酸以及一种或多种可药用载体。这对于本领域的技术人员来说是显而易见的。
本发明所涉及的多个方面已做如上阐述。然而，应理解的是，在不偏离本发明精神之前提下，本领域专业人员可对其进行等同改变和修饰，所述改变和修饰同样落入本申请所附权利要求的覆盖范围。
Claims (8)
1.鞣花酸用于制备抗病毒药物的应用，其特征在于，所述病毒为单纯疱疹病毒和人乳头瘤病毒。
2.如权利要求1所述的应用，其特征在于，所述单纯疱疹病毒为单纯疱疹病毒2型。
3.如权利要求1所述的应用，其特征在于，所述人乳头瘤病毒为人乳头瘤病毒6型和11型。
4.一种药物组合物，其特征在于，所述药物组合物以鞣花酸为活性成分。
5.如权利要求4所述的药物组合物，其特征在于，所述药物组合物包括治疗有效量的鞣花酸以及一种或多种可药用载体。
6.如权利要求5所述的药物组合物，其特征在于，所述可药用载体选自：软磷脂、硬脂酸铝、氧化铝、离子交换材料、自乳化药物传递系统、吐温或其他表面活化剂、血清蛋白、缓冲物质如磷酸盐、氨基乙酸、山梨酸、水、盐、电解质如硫酸盐精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅酸镁、饱和脂肪酸部分甘油酯混合物。
7.如权利要求4所述的药物组合物，其特征在于，还包括一种或多种药物辅料。
8.如权利要求7所述的药物组合物，其特征在于，所述药物辅料选自：粘合剂、填充剂、崩解剂、润滑剂、吸收促进剂、吸附载体、香味剂、甜味剂、赋形剂、稀释剂、以及润湿剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101383793A CN102670588B (zh) | 2012-05-04 | 2012-05-04 | 鞣花酸用于制备抗病毒药物的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101383793A CN102670588B (zh) | 2012-05-04 | 2012-05-04 | 鞣花酸用于制备抗病毒药物的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102670588A true CN102670588A (zh) | 2012-09-19 |
| CN102670588B CN102670588B (zh) | 2013-11-20 |
Family
ID=46803582
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012101383793A Active CN102670588B (zh) | 2012-05-04 | 2012-05-04 | 鞣花酸用于制备抗病毒药物的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102670588B (zh) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018521124A (ja) * | 2015-06-10 | 2018-08-02 | メータ、ラマン | 粘膜病変の治療のための配合物 |
| CN109674783A (zh) * | 2019-02-18 | 2019-04-26 | 新疆医科大学 | 鞣花酸在制备抑制变异链球菌致病力的药物中的应用 |
| CN110339156A (zh) * | 2019-08-26 | 2019-10-18 | 广州二天堂制药有限公司 | 一种外用抗菌抗病毒制剂、其制备方法及其应用 |
| CN111358781A (zh) * | 2020-04-20 | 2020-07-03 | 云南农业大学 | 鞣花酸在防治新型冠状病毒感染中的应用 |
| US10758587B2 (en) | 2015-06-10 | 2020-09-01 | Raman Mehta | Formulations for the treatment of disorders of the mouth, throat and respiratory tract |
| KR20210046634A (ko) * | 2018-04-19 | 2021-04-28 | 가천대학교 산학협력단 | 담팔수 추출물에서 분리한 화합물을 유효성분으로 함유하는 수두-대상포진 바이러스 억제용 약학적 조성물 |
| CN113384548A (zh) * | 2020-12-31 | 2021-09-14 | 江苏正阳药业有限公司 | 一种具有抗hpv病毒感染的阴道泡腾片及其制备方法 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20230233514A1 (en) * | 2020-06-23 | 2023-07-27 | Flagship Pioneering, Inc. | Antiviral compounds and methods of using the same |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101057953A (zh) * | 2006-04-21 | 2007-10-24 | 陈祖辉 | 对付病毒感染疾患的多靶协同防治制剂 |
| CN101375846A (zh) * | 2007-08-30 | 2009-03-04 | 沈阳皓天万嘉医药科技有限公司 | 一种鞣花酸超分子组合物及制备方法 |
-
2012
- 2012-05-04 CN CN2012101383793A patent/CN102670588B/zh active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101057953A (zh) * | 2006-04-21 | 2007-10-24 | 陈祖辉 | 对付病毒感染疾患的多靶协同防治制剂 |
| CN101375846A (zh) * | 2007-08-30 | 2009-03-04 | 沈阳皓天万嘉医药科技有限公司 | 一种鞣花酸超分子组合物及制备方法 |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018521124A (ja) * | 2015-06-10 | 2018-08-02 | メータ、ラマン | 粘膜病変の治療のための配合物 |
| US10758587B2 (en) | 2015-06-10 | 2020-09-01 | Raman Mehta | Formulations for the treatment of disorders of the mouth, throat and respiratory tract |
| US10786540B2 (en) | 2015-06-10 | 2020-09-29 | Raman Mehta | Formulations for the treatment of mucosal lesions |
| KR20210046634A (ko) * | 2018-04-19 | 2021-04-28 | 가천대학교 산학협력단 | 담팔수 추출물에서 분리한 화합물을 유효성분으로 함유하는 수두-대상포진 바이러스 억제용 약학적 조성물 |
| CN109674783A (zh) * | 2019-02-18 | 2019-04-26 | 新疆医科大学 | 鞣花酸在制备抑制变异链球菌致病力的药物中的应用 |
| CN110339156A (zh) * | 2019-08-26 | 2019-10-18 | 广州二天堂制药有限公司 | 一种外用抗菌抗病毒制剂、其制备方法及其应用 |
| CN111358781A (zh) * | 2020-04-20 | 2020-07-03 | 云南农业大学 | 鞣花酸在防治新型冠状病毒感染中的应用 |
| CN113384548A (zh) * | 2020-12-31 | 2021-09-14 | 江苏正阳药业有限公司 | 一种具有抗hpv病毒感染的阴道泡腾片及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102670588B (zh) | 2013-11-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102670588B (zh) | 鞣花酸用于制备抗病毒药物的应用 | |
| CN100427082C (zh) | 羟基苯甲酸酯及其类似物在制备预防和治疗病毒性感染药物中的应用 | |
| CN103393821B (zh) | 一种治疗慢性盆腔炎的中药组合物及其制备方法 | |
| CN102908559A (zh) | 一种治疗人乳头状瘤病毒感染的外用中药药剂 | |
| CN104127749A (zh) | 一种治疗有机磷农药中毒的中药及制备方法 | |
| CN104353058A (zh) | 商陆抗病毒蛋白冻干粉复合剂及其制备方法 | |
| CN102335223B (zh) | 一种治疗人乳头瘤病毒感染症的中药制剂及其制备方法和应用 | |
| CN102671135B (zh) | 一种治疗卵巢囊肿的中药组合物及其制备方法 | |
| JP2021516696A (ja) | 漢方薬組成物、漢方薬配合製剤及びその調製方法と応用 | |
| CN103100007A (zh) | 一种用于治疗人乳头瘤病毒感染的中药组合物及其制备方法和应用 | |
| CN101342194B (zh) | 一种治疗中晚期肿瘤、慢性乙肝的中药制剂及其制备方法 | |
| CN102872246B (zh) | 使人乳头状瘤病毒阳转阴治疗宫颈糜烂的药物 | |
| CN103877508A (zh) | 一种治疗子宫癌的中药组合物 | |
| CN114903944B (zh) | 一种改善宫颈hpv感染症状的组合物、制剂及制备方法 | |
| US11278583B2 (en) | Traditional Chinese medicine composition for treating diseases caused by human papillomavirus, preparation method and use thereof | |
| CN110302211A (zh) | 三氧化二砷联合抗坏血酸在治疗结肠癌中的应用 | |
| CN102302484A (zh) | 异黄酮类化合物的用途 | |
| CN102988422A (zh) | 美洲大蠊纳米提取物及其制备方法 | |
| CN102670684B (zh) | 白薇总皂苷的应用 | |
| CN101829188B (zh) | 一种治疗泌尿系感染和结石病的药物 | |
| CN1935145A (zh) | 鞣酸苦参碱在制备预防和治疗皮肤黏膜感染药物中的应用 | |
| CN103536851A (zh) | 一种治疗酒精性脂肪肝的中药组合物 | |
| CN103893280B (zh) | 拳参提取物在制备抗病毒药物中的应用及其提取方法 | |
| CN103800684A (zh) | 一种中西药同步外用治疗宫颈人乳头病毒(hpv)、上皮内瘤变(cin)及宫颈糜烂的根治术 | |
| CN104587017B (zh) | 一种清热通腑，行气活血的药物组合物及其制备方法和用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: ZHEJIANG ZHONGKE HONGSHOU PHARMACEUTICAL TECHNOLOG Free format text: FORMER OWNER: BEIJING COSCI MED-TECH CO., LTD. Effective date: 20150710 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20150710 Address after: 322000 No. 968 Xuefeng West Road, Beiyuan street, Zhejiang, Yiwu Patentee after: ZHEJIANG ZHONGKE HONGSHOU PHARMACEUTICAL TECHNOLOGY CO.,LTD. Address before: 313000 No. 1366 Hongfeng Road, Zhejiang, Huzhou Patentee before: HUZHOU R & D CENTER FOR NUTRITION AND HEALTH, SHANGHAI INSTITUTES FOR BIOLOGICAL SCIENCES, CHINESE ACADEMY OF SCIENCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20180806 Address after: 313000 Hongfeng Road, Huzhou, Zhejiang 1366 Patentee after: HUZHOU R & D CENTER FOR NUTRITION AND HEALTH, SHANGHAI INSTITUTES FOR BIOLOGICAL SCIENCES, CHINESE ACADEMY OF SCIENCE Address before: 322000 Xuefeng West Road, Beiyuan street, Yiwu, Zhejiang, 968 Patentee before: ZHEJIANG ZHONGKE HONGSHOU PHARMACEUTICAL TECHNOLOGY CO.,LTD. |
|
| TR01 | Transfer of patent right | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 313000 Hongfeng Road, Huzhou, Zhejiang 1366 Patentee after: Huzhou Zhongke nutrition and health innovation center Address before: 313000 Hongfeng Road, Huzhou, Zhejiang 1366 Patentee before: HUZHOU R & D CENTER FOR NUTRITION AND HEALTH, SHANGHAI INSTITUTES FOR BIOLOGICAL SCIENCES, CHINESE ACADEMY OF SCIENCE |
|
| CP01 | Change in the name or title of a patent holder | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20211228 Address after: 313000 Hongfeng Road, Huzhou, Zhejiang 1366 Patentee after: Huzhou Zhongke nutrition and health innovation center Patentee after: Shanghai Institute of nutrition and health, Chinese Academy of Sciences Address before: 313000 Hongfeng Road, Huzhou, Zhejiang 1366 Patentee before: Huzhou Zhongke nutrition and health innovation center |
|
| TR01 | Transfer of patent right |