TWI492751B - 柴胡皂苷製備之醫藥組合物、其用途及其製備方法 - Google Patents
柴胡皂苷製備之醫藥組合物、其用途及其製備方法 Download PDFInfo
- Publication number
- TWI492751B TWI492751B TW102119835A TW102119835A TWI492751B TW I492751 B TWI492751 B TW I492751B TW 102119835 A TW102119835 A TW 102119835A TW 102119835 A TW102119835 A TW 102119835A TW I492751 B TWI492751 B TW I492751B
- Authority
- TW
- Taiwan
- Prior art keywords
- virus
- saikosaponin
- ssb2
- pharmaceutical composition
- hepatitis
- Prior art date
Links
- 229930192014 saikosaponin Natural products 0.000 title claims description 74
- KYWSCMDFVARMPN-LCSVLAELSA-N Saikosaponin D Chemical compound O([C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@]([C@H]3[C@]([C@@H]4[C@@]([C@@]5(C[C@@H](O)[C@]67CO[C@]5([C@@H]6CC(C)(C)CC7)C=C4)C)(C)CC3)(C)CC2)(C)CO)O[C@@H]([C@@H]1O)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O KYWSCMDFVARMPN-LCSVLAELSA-N 0.000 title claims description 69
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 40
- 238000002360 preparation method Methods 0.000 title claims description 33
- 241000700605 Viruses Species 0.000 claims description 41
- 241000711549 Hepacivirus C Species 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 24
- 229940079593 drug Drugs 0.000 claims description 22
- 208000015181 infectious disease Diseases 0.000 claims description 22
- 241000725619 Dengue virus Species 0.000 claims description 12
- 241000712079 Measles morbillivirus Species 0.000 claims description 9
- 241000702263 Reovirus sp. Species 0.000 claims description 9
- 241000711975 Vesicular stomatitis virus Species 0.000 claims description 9
- 239000000645 desinfectant Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000006210 lotion Substances 0.000 claims description 7
- 241000709661 Enterovirus Species 0.000 claims description 6
- 241001263478 Norovirus Species 0.000 claims description 6
- 239000000077 insect repellent Substances 0.000 claims description 6
- 241000701161 unidentified adenovirus Species 0.000 claims description 6
- 241000407958 Bupleurum kaoi Species 0.000 claims description 3
- 230000004927 fusion Effects 0.000 claims description 3
- 230000000241 respiratory effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 description 26
- 239000000284 extract Substances 0.000 description 21
- 230000002401 inhibitory effect Effects 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 15
- 230000000840 anti-viral effect Effects 0.000 description 13
- 229920000642 polymer Polymers 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 11
- 239000003960 organic solvent Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 208000010710 hepatitis C virus infection Diseases 0.000 description 10
- 230000009385 viral infection Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 208000005176 Hepatitis C Diseases 0.000 description 8
- 241000725643 Respiratory syncytial virus Species 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 8
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 8
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 7
- 208000036142 Viral infection Diseases 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 229960000329 ribavirin Drugs 0.000 description 7
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000002441 X-ray diffraction Methods 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 6
- 238000000576 coating method Methods 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 241000202726 Bupleurum Species 0.000 description 5
- 241000723346 Cinnamomum camphora Species 0.000 description 5
- 102000006992 Interferon-alpha Human genes 0.000 description 5
- 108010047761 Interferon-alpha Proteins 0.000 description 5
- 229960000846 camphor Drugs 0.000 description 5
- 229930008380 camphor Natural products 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000004372 Polyvinyl alcohol Substances 0.000 description 4
- -1 camphor saponin Chemical class 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000009878 intermolecular interaction Effects 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002547 new drug Substances 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- 230000003449 preventive effect Effects 0.000 description 3
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 3
- 229930182490 saponin Natural products 0.000 description 3
- 229940126585 therapeutic drug Drugs 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 2
- 241000001488 Bothrioplana sinensis Species 0.000 description 2
- 241000510654 Bupleurum chinense Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 108090000288 Glycoproteins Proteins 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
- 230000001442 anti-mosquito Effects 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229960000517 boceprevir Drugs 0.000 description 2
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 229940121657 clinical drug Drugs 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 238000005108 dry cleaning Methods 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000006194 liquid suspension Substances 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000007709 nanocrystallization Methods 0.000 description 2
- 244000309711 non-enveloped viruses Species 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 229960002935 telaprevir Drugs 0.000 description 2
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 2
- 108010017101 telaprevir Proteins 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000001550 time effect Effects 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 108091032955 Bacterial small RNA Proteins 0.000 description 1
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- 208000001490 Dengue Diseases 0.000 description 1
- 206010012310 Dengue fever Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000002832 anti-viral assay Methods 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000005138 cryopreservation Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 208000025729 dengue disease Diseases 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- SPSXSWRZQFPVTJ-ZQQKUFEYSA-N hepatitis b vaccine Chemical compound C([C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCSC)C(=O)N[C@@H](CC1N=CN=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)OC(=O)CNC(=O)CNC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@@H](N)CCCNC(N)=N)C1=CC=CC=C1 SPSXSWRZQFPVTJ-ZQQKUFEYSA-N 0.000 description 1
- 229940124736 hepatitis-B vaccine Drugs 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000001595 mastoid Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/48—Medical, disinfecting agents, disinfecting, antibacterial, germicidal or antimicrobial compositions
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
- A01N43/08—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with oxygen as the ring hetero atom
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N65/00—Biocides, pest repellants or attractants, or plant growth regulators containing material from algae, lichens, bryophyta, multi-cellular fungi or plants, or extracts thereof
- A01N65/08—Magnoliopsida [dicotyledons]
- A01N65/10—Apiaceae or Umbelliferae [Carrot family], e.g. parsley, caraway, dill, lovage, fennel or snakebed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
- A61K36/233—Bupleurum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/60—Sugars; Derivatives thereof
- A61K8/602—Glycosides, e.g. rutin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/63—Steroids; Derivatives thereof
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/005—Antimicrobial preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/10—Washing or bathing preparations
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D17/00—Detergent materials or soaps characterised by their shape or physical properties
- C11D17/08—Liquid soap, e.g. for dispensers; capsuled
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Virology (AREA)
- Zoology (AREA)
- Agronomy & Crop Science (AREA)
- Communicable Diseases (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Plant Pathology (AREA)
- Dentistry (AREA)
- Dermatology (AREA)
- Environmental Sciences (AREA)
- Birds (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Alternative & Traditional Medicine (AREA)
- Medical Informatics (AREA)
- Botany (AREA)
- Physics & Mathematics (AREA)
- Pest Control & Pesticides (AREA)
- Biomedical Technology (AREA)
- Nanotechnology (AREA)
Description
本發明涉及柴胡皂苷對治療及預防病毒感染的用途、包含柴胡皂苷的藥物組合物以及製備該藥物組合物之方法。
全球目前有1億七千萬人左右(佔全球人口2%)感染C型肝炎病毒(hepatitis C virus,HCV),而它所帶來的肝疾病(肝炎、肝硬化及肝癌)是全球嚴重的健康與醫療負擔。目前C型肝炎無預防疫苗,而現有的臨床治療藥物干擾素-α(interferon-alpha,IFN-α)+雷巴威林(ribavirin)對於最普遍的基因型第一型的治療效果並不理想(約50%治癒率)且副作用大,更需要龐大的醫療資金,造成許多患者身體無法承受療程及經濟負擔。雖然2011年5月美國食品藥物管理局(FDA)核准了波普瑞韋(boceprevir)及替拉瑞韋(telaprevir)這兩個新藥,用於治療基因型第一型病毒感染的病人,但其只能與IFN-α及ribavirin合併使用,不適合單一治療。因此開發C型肝炎病毒及其引起的肝病之治療藥物乃是優先考慮的課題。
台灣約有五十萬到七十萬人為C型肝炎帶原者,雖然在台灣感染C型肝炎病毒所引發的肝癌佔30%,遠遠不如感染B型肝炎病毒所造成的肝癌比例(70%),然而B型肝炎疫苗全面實施後已經達到相當高的預防效果。相對的,C型肝炎病毒的高度變異性在疫苗研發上遭遇到非常大的困難,因此推測未來在台灣C型肝炎所引發的肝癌會漸漸取代B型肝炎,成為頭號殺手。過去十多年,病毒學家致力於開發更有效的C型肝炎非結構蛋白抑制劑以影響病毒複製,以此方法希望能取代或與現有的臨床藥物IFN-α+ribavirin合併治療。這樣的抗病毒策略雖使許多C型肝炎病人受
惠,然而許多問題隨之出現,如藥物副作用、價格昂貴兩大主要問題。
為了研發經濟、有效且副作用少的C型肝炎治療藥物,本發明採用本土特有種藥用植物高氏柴胡,利用其中萃取獲得的柴胡皂苷發展一種用於治療或預防病毒感染的方法,並進一步改善柴胡皂苷溶解度不佳的問題,製備一種具有上述用途的藥物組合物,不僅對C型肝炎提供另一種藥物治療的選擇,同時也開發台灣本土生藥資源。
本案申請人鑑於習知技術中的不足,經過悉心試驗與研究,並一本鍥而不捨之精神,終構思出本案,能夠克服先前技術的不足,以下為本案之簡要說明。
本發明提供一種利用柴胡皂苷製備醫藥組合物的用途,該醫藥組合物用於預防或治療C型肝炎病毒、麻疹病毒、呼吸道融合病毒、水泡性口炎病毒、登革熱病毒及無套膜病毒其中之一的感染。本發明期望開發新藥取代或輔助現有臨床藥物(IFN-α/ribavirin),以達到減少副作用及經濟負擔的效益。同時,本發明提供的醫藥組合物,不僅能作為C型肝炎病毒抑制劑,也是廣效性的抗病毒藥物,能應用於多種病毒的預防及治療。
此外,本發明進一步提供一種藥物組合物,包括主要成分柴胡皂苷,以及與該主要成分混合的高分子聚合物。本發明之藥物組合物藉由將藥物奈米化以改善藥物水溶性不佳之問題,提升生物利用率及抗病毒之功效。
本發明進一步提供一種製造一藥物組合物的方法,包括下列步驟:將一柴胡皂苷溶解於一有機溶劑中;將含有該柴胡皂苷的該有機溶劑加入一溶液中,該溶液中含有一高分子聚合物;使該柴胡皂苷分散於該高分子聚合物中;以及去除該有機溶劑,以獲得該藥物組合物。
本發明證實柴胡皂苷可運用在治療及預防C型肝炎病毒感染,亦能防止麻疹病毒、呼吸道融合病毒、水泡性口炎病毒、登革熱病毒及無套膜病毒侵入細胞,具有廣效性病毒抑制劑的效果。本發明也成功地製作柴胡皂苷之奈米劑型,可將其配製於水中,提高生物利用率。除了運
用柴胡皂苷及其奈米製劑作為病毒預防與治療藥物之外,未來亦可將其應用在口罩、手套、防蚊液、洗手乳、乾洗手(消毒劑)與各種清潔用品中,達到抗病毒感染之效果,讓防疫工作變得更容易。
第一圖(A)為柴胡醇萃取物之高效液相層析(High Performance Liquid Chromatography,HPLC)分析結果。
第一圖(B)為柴胡皂苷SSa之HPLC分析結果。
第一圖(C)為柴胡皂苷SSb2之HPLC分析結果。
第一圖(D)為柴胡皂苷SSc之HPLC分析結果。
第一圖(E)為柴胡皂苷SSd之HPLC分析結果。
第二圖(A)為柴胡醇萃取物抑制C型肝炎病毒(HCV)感染之效果。
第二圖(B)為柴胡皂苷SSa抑制C型肝炎病毒感染之效果。
第二圖(C)為柴胡皂苷SSb2抑制C型肝炎病毒感染之效果。
第二圖(D)為柴胡皂苷SSc抑制C型肝炎病毒感染之效果。
第二圖(E)為柴胡皂苷SSd抑制C型肝炎病毒感染之效果。
第三圖為柴胡醇萃取物及柴胡皂苷SSa、SSb2、SSc及SSd對C型肝炎病毒感染時間點效應。
第四圖為柴胡醇萃取物及柴胡皂苷SSa、SSb2、SSc及SSd之病毒侵入實驗(entry assays)結果。
第五圖為柴胡皂苷SSb2抑制病毒與細胞結合之結果。
第六圖為柴胡皂苷SSb2抑制多種不同基因型C型肝炎病毒感染之結果。
第七圖為柴胡皂苷SSb2抑制臨床病人血清中病毒與細胞結合之結果。
第八圖(A)為SSb2抑制麻疹病毒(measles virus,MV)感染之效果。
第八圖(B)為SSb2抑制呼吸道融合病毒(respiratory syncytial virus,RSV)感染之效果。
第八圖(C)為SSb2抑制水泡性口炎病毒(vesicular stomatitis virus,VSV)感染之效果。
第八圖(D)為SSb2抑制登革熱病毒(dengue virus,DENV)感染之效果。
第八圖(E)為SSb2抑制呼腸孤病毒(reovirus,RV)感染之效果。
第九圖(A)為本發明藥物組合物利用X光繞射分析儀(XRD)鑑定結晶性質之結果。
第九圖(B)為本發明藥物組合物利用紅外線光譜儀(FTIR)鑑定兩材料之分子間交互作用之結果。
第九圖(C)為本發明藥物組合物之溶解度鑑定結果。
第十圖(A)為本發明奈米製劑抑制HCV感染之效果。
第十圖(B)為本發明奈米製劑抑制DENV感染之效果。
本發明可由以下的實施例說明而得到,然而本發明之實施並非可由下列實施例而被限制其實施型態,熟習本技藝之人士仍可依據已揭露之實施例的精神推演出其他實施例,該等實施例皆當屬於本發明之範圍。
本發明提供一種利用柴胡皂苷製備醫藥組合物的用途,該醫藥組合物用於預防或治療C型肝炎病毒、麻疹病毒、呼吸道融合病毒、水泡性口炎病毒、登革熱病毒及無套膜病毒(包括呼腸孤病毒、腸病毒、諾羅病毒、腺病毒)其中之一的感染。
本發明中使用的柴胡皂苷萃取自台灣特有種高氏柴胡(Bupleurum kaoi
),為高氏柴胡的醇萃取物,其中包括柴胡皂苷SSa、SSb2、SSc及SSd。應理解的是,本發明所指的柴胡皂苷不僅限於高氏柴胡的醇萃取物,也可以是來自其他品種的柴胡、以任何溶劑或任何方式所得之產物(包括合成產物)。另一方面,雖然本發明中分別顯示了柴胡醇萃取物、SSa、SSb2、SSc及SSd的抗病毒活性,但本發明中柴胡皂苷可以由柴胡醇萃取物、SSa、SSb2、SSc及SSd或其任意組合組成,例如僅包含SSb2、包含
SSa與SSb2、或者包含SSa、SSb2、SSc及SSd。
為了將柴胡皂苷製備為醫藥組合物,可將本發明柴胡皂苷與藥學可接受載體混合,獲得更具生物利用性的製劑。上述藥學上可接受載體或稱為『賦形劑』、『生物可利用之載體或賦形劑』,係包括溶媒、分散劑、包衣、抗菌或抗真菌劑、保存或延緩吸收劑等任何習知用於製備成劑型之適當化合物。通常此類載體或賦形劑,本身不具備治療疾病之活性,因此將本發明所揭示之柴胡皂苷,搭配藥學上可接受之載體或賦形劑製備為各種劑型時,投予動物或人類不致於造成不良反應、過敏或其它不適當反應。因而本發明所揭示之柴胡皂苷,搭配藥學上可接受之載體或賦形劑,適用於臨床而可達到治療或預防效果。
該載體隨各劑型而不同,用於口服投藥之組合物係採用任何一種口服可接受之劑型,其型式包括膠囊、錠劑、片劑、乳化劑、液狀懸浮液、分散劑、溶劑。口服劑型一般所使用之載體,以錠劑為例可為乳糖、玉米澱粉、潤滑劑、硬脂酸鎂等基本添加物。而膠囊使用之稀釋液包括乳糖與乾燥玉米澱粉。製成液狀懸浮液或乳化劑劑型,則將活性物質懸浮或溶解於結合乳化劑或懸浮劑之油狀介面,視需要添加適度之甜味劑、風味劑或色素。
依據用途的不同,本發明醫藥組合物可被製造為藥物、消毒液、手套、口罩、乾洗手、洗手乳及防蚊液其中之一。以下將詳細說明本發明醫藥組合物的製備實施例。
請參閱第1圖(A)至(E),分別為柴胡醇萃取物、柴胡皂苷SSa、SSb2、SSc及SSd之HPLC分析結果。本發明中使用HPLC確認柴胡皂苷SSa、SSb2、SSc、SSd皆確實存在於高氏柴胡醇抽萃取物(BK)中,並定量其含量。第1圖(A)至(E)中的量化結果如下表一所示。
第二圖(A)至(E)為柴胡醇萃取物、柴胡皂苷SSa、SSb2、SSc及SSd抑制C型肝炎病毒(HCV)感染之效果。將柴胡醇萃取物(BK)、柴胡皂苷SSa、SSb2、SSc及SSd溶解於二甲基亞颯(dimethyl sulfoxide,DMSO)並配製為多種濃度進行抗病毒活性之篩選,發現BK、SSa、SSb2、SSc、SSd皆具有抑制細胞培養衍生之C型肝炎病毒(HCVcc)基因型2a感染的效果,並呈現劑量依賴性。根據以上篩選結果,選擇不對細胞產生毒性且具有抗病毒活性之濃度,繼續進行抗病毒機轉之實驗,例如BK:50 μg/ml、SSa:8 μM、SSb2:50μM、SSc:200μM、SSd:2μM,以上劑量對病毒蛋白質的抑制率大約為2 log(100倍)。下表二為第二圖(A)至(E)之量化結果。
第三圖為柴胡醇萃取物及柴胡皂苷SSa、SSb2、SSc及SSd對C型肝炎病毒感染時間點效應。首先為探討完整的病毒感染週期,初步依三種不同方式加入病毒與藥物,分別為1)藥物作用在細胞24小時後移除,再加入病毒,三天後以冷光偵測病毒表現量(pre-treatment);2)病毒和藥物同時加入,3小時後一起移除,三天後以冷光偵測病毒表現量(co-addition);以及3)病毒感染3小時後再加入藥物,三天後以冷光偵測病毒表現量(post-infection)。在co-addition的實驗中,可觀察到柴胡醇萃取物及SSa、SSb2、SSd皆具有良好的抑制作用,證實藥物可干擾病毒感染;而在pre-treatment的實驗中,所有的藥物皆無效,因此初步推測藥物的作用並非在保護細胞防止病毒感染;在post-infection的結果中,發現所有的藥物皆無效,證實藥物可能並非作用於病毒的複製或轉譯作用階段,而SSc只有在藥物持續存在整個病毒感染過程(throughout)的實驗中才具有抑制效果(未顯示)。由以上結果可知,柴胡醇萃取物及SSa、SSb2及SSd的抗病毒機制為抑制C型肝炎病毒早期進入細胞的階段。
第四圖為柴胡醇萃取物及柴胡皂苷SSa、SSb2、SSc及SSd之病毒侵入實驗(entry assays)結果。在去活化(inactivation)及附著(attachment)的實驗中觀察到僅有SSb2可中和病毒顆粒及抑制病毒附著細胞,而融合(fusion)的實驗中發現柴胡醇萃取物及SSa與SSb2皆可防止病毒融合,以上的結果可證實柴胡醇萃取物及其活性成分SSa與SSb2抗病毒的主要機制為侵入抑制(entry inhibition),可作為病毒侵入抑制劑(entry inhibitor)。
第五圖為柴胡皂苷SSb2抑制病毒與細胞結合之結果。在4℃下於Huh-7.5細胞中加入細胞培養衍生C型肝炎病毒或可溶性醣蛋白E2(soluble glycoprotein E2,sE2),並同時以SSb2處理,作用3小時後,以磷酸鹽緩衝溶液(PBS)洗去SSb2及病毒,接著使用抗-E2抗體與細胞膜上的病毒或醣蛋白作用,最後以酵素免疫分析法(ELISA)偵測病毒量。結果顯示SSb2可藉由干擾HCVcc及sE2與細胞膜的結合而防止病毒侵入。藉由以上的實驗可知,高氏柴胡及其成分作用(SSa,SSb2,SSc,SSd)可做為慢性C型肝炎的治療藥物,另外高氏柴胡與SSa,SSb2,及SSd之作用機制為抑制病
毒早期侵入,因此也具有預防功能,可作為換肝手術時預防病毒入侵新肝臟組織之藥物(消毒用藥),此特殊用途改善過去IFN-α
+ribavirin只能用於治療而無法預防的缺點。
第六圖為柴胡皂苷SSb2抑制多種不同基因型C型肝炎病毒感染之結果。如圖所示,以基因型2b、3a、7aHCVcc感染Huh-7.5細胞並同時加入SSb2,結果顯示SSb2可抑制多種基因型C型肝炎病毒的感染。
第七圖為柴胡皂苷SSb2抑制臨床病人血清中病毒與細胞結合之結果。在4℃下於Huh-7.5細胞中加入臨床病人血清中的病毒,並同時加入SSb2,作用3小時後,以PBS洗去SSb2及病毒,接著萃取細胞中的總RNA,最後以即時聚合酶連鎖反應(qPCR)定量病毒。結果顯示SSb2可抑制臨床病人血清中基因型1a、1b、2a、6的C型肝炎病毒與細胞之結合。量化結果如下表三所示。
合併第六圖與第七圖的實驗結果,本發明證實柴胡皂苷SSb2除了可抑制基因型2a HCVcc以外,還能夠抑制其他基因型2b、3a、7aHCVcc的感染及臨床病人血清的基因型1a、1b、2a、6的C型肝炎病毒與細胞之結合,可對抗C型肝炎病毒高度變異性的特性。由SSb2可抑制多種基因型C型肝炎病毒之特點,說明柴胡皂苷可改善過去IFN-α
+ribavirin對於基因型第1型C型肝炎病毒治療效果不佳的問題,也能改善boceprevir及telaprevir這兩個新藥除了基因型第1型C型肝炎病毒以外的其他基因型治療效果皆不好且也不適合單獨治療(只能與IFN-α
+ribavirin併用)等問
題。
第八圖(A)至(E)分別為SSb2抑制麻疹病毒(MV)、呼吸道融合病毒(RSV)、水泡性口炎病毒(VSV)、登革熱病毒(DENV)及呼腸孤病毒(RV)感染之效果。量化結果如下表四所示。
由表四可知,這幾種病毒分別屬於不同的類型,結果顯示SSb2無論對於DNA或RNA病毒、單股或雙股基因、有套膜或無套膜(enveloped or non-enveloped)的病毒皆具抑制效果,證實SSb2為廣效性抗病毒藥物。根據SSb2對於無套膜病毒的抑制效果,可推知其對於腸病毒、諾羅病毒或腺病毒等無套膜病毒也具有抑制作用。本發明中所指的無套膜病毒,除了上述的呼腸孤病毒(RV)、腸病毒、諾羅病毒及腺病毒以外,更可包括本領域熟知的其他無套膜病毒,例如人類乳突病毒及小RNA病毒等等。
根據SSb2抑制多種病毒感染之特性,未來亦可將柴胡皂苷應用在口罩、手套、防蚊液、洗手乳、乾洗手(消毒劑)與各種清潔用品中,讓防疫工作變得更容易。例如將柴胡皂苷添加於防蚊液就可應用於每年夏季在台灣及東南亞等國固定爆發的登革熱疫情;或是根據SSb2對於無套膜病毒(如腸病毒、諾羅病毒或腺病毒)也具有抑制作用的特性,可將柴胡皂苷添加於乾洗手液中,解決酒精性乾洗手對於無套膜病毒無消毒效果的問題,使這些全世界流行性病毒爆發的危機獲得良好的改善。
由於柴胡皂苷水溶性差,若做為藥物則會發生生物利用率低的問題。柴胡皂苷除了可與前述藥學上可接受載體結合之外,為提高柴胡皂苷的溶解度,本發明利用奈米技術製備一種藥物組合物,以柴胡皂苷為主要成分,將柴胡皂苷與高分子聚合物混合,得到<50 nm的奈米粒子。由於本發明的藥物組合物可以液體形式冷藏保存,或以乾粉形式置於冷凍保存,因此可被製造為藥物、消毒液、手套、口罩、乾洗手、洗手乳及防蚊液等多種醫療防護用具及民生用品。
另一方面,本發明也提供一種製造一藥物組合物的方法,包括將一柴胡皂苷溶解於一有機溶劑中,將含有該柴胡皂苷的該有機溶劑加入一溶液中,該溶液中含有一高分子聚合物,使該柴胡皂苷分散於該高分子聚合物中,以及去除該有機溶劑,以獲得該藥物組合物。本發明以下實施例以SSb2為例,製備SSb2之奈米製劑(SSb2-NP)。應了解的是,本發明實施例中提供的製備方法也同樣適用於製備其它柴胡皂苷SSa、SSc、SSd或者柴胡醇萃取物的奈米製劑。
以乳化溶劑擴散法(emulsion solvent diffusion method)進行SSb2之分散、摻和反應,可製得SSb2奈米化製劑。本製程可以多種高分子聚合物執行,諸如三團聯聚合物(Pluronic® polymer)、聚乙烯醇(polyvinyl alcohol,PVA)、聚乙烯吡咯烷酮(polyvinylpyrrolidone,PVP)等。依據SSb2之溶解特性,並以聚乙烯吡咯烷酮為例,本製程先以適量乙醇溶解SSb2使成1 mg/ml溶液,以適量純淨水溶解聚乙烯吡咯烷酮配製成35%水溶液,隨後將SSb2溶液注入聚乙烯吡咯烷酮水溶液中,利用超音波促成SSb2與聚乙烯吡咯烷酮之分散、摻和反應,再以真空減壓濃縮機除去有機溶媒(本例為乙醇)與部分水分,即可得到初步SSb2奈米化製劑。以定性濾紙進行過濾,除去過大顆粒沈澱後,即可得到本例之完整SSb2奈米製劑。本製劑可以液體形式置於冷藏,或以乾粉形式置冷凍保藏,後者待使用時以純淨水回復即可。
根據本發明實施例中的製備方法,SSb2是溶解並配置於乙
醇溶液中,然而本領域具通常知識者應可將乙醇溶液置換成其他合適的有機溶劑。
以動態光散射技術(PCS)分析製劑粒子大小為16.57±3.88 nm,另以電子顯微鏡(TEM)驗證此製劑粒子的大小約10 nm左右,與PCS顯示一致結果;本製程產率可達81.45±6.14%。第九圖(A)為本發明藥物組合物利用X光繞射分析儀(XRD)鑑定結晶性質之結果。以X光繞射分析儀(XRD)鑑定結晶性質,並與不同比例簡單混合製成之各組(physical mixture,PM)相比,可見本例奈米製劑(SSb2-NP)喪失SSb2位於3.7°之結晶格訊號,由此可知奈米製劑之SSb2結晶格消失。第九圖(B)為本發明藥物組合物利用紅外線光譜儀(FTIR)鑑定兩材料之分子間交互作用之結果。以紅外線光譜儀(FTIR)鑑定兩材料之分子間交互作用,由奈米製劑(SSb2-NP)所得圖譜可見羥基位移(3,420 cm-1
),位移程度並不同於簡單混合者(SSb2-PM),顯示分子間交互作用確實發生於本例奈米製劑。兩材料分子間交互作用可解釋奈米製劑之SSb2結晶格特性消失的原因,而且有利於增加SSb2溶解度。第九圖(C)為本發明藥物組合物之溶解度鑑定結果。本製劑之溶解度性質以溶離試驗鑑定,以一般未經製劑處理之SSb2與本例SSb2奈米製劑比較,溶離試驗顯示本例奈米製劑對SSb2溶解度具顯著增強效果,經由奈米製劑改良,SSb2於20分鐘之內已達約50%溶解釋出,並在後續試驗期間可維持釋出趨勢。
第十圖(A)及(B)分別為本發明奈米製劑抑制HCV及DENV感染之效果。SSb2-NP的特色為僅以水調製即可進行活性應用,而無需併用其他助溶劑(如DMSO)。本實驗將SSb2-NP與以助溶劑(DMSO)配製的原料藥(SSb2-DMSO)、以水配製的原料藥SSb2-DW進行比較,分析其抗病毒效果。結果顯示SSb2-DW無論對於HCV(圖10A)或DENV(圖10B)均完全無法發揮抗病毒效果,而SSb2-NP的抗病毒效果幾乎可達到與使用助溶劑(SSb2-DMSO)相近。反映出本發明成功製造出只需配置於水中即能發揮其抗病毒藥效的柴胡皂苷奈米製劑SSb2-NP,提高柴胡皂苷的生物利用率及
抗病毒用途。
1.一種利用一柴胡皂苷製備一醫藥組合物的用途,該醫藥組合物用於預防或治療C型肝炎病毒、麻疹病毒、呼吸道融合病毒、水泡性口炎病毒、登革熱病毒及無套膜病毒其中之一的感染。
2.如實施例1所述的用途,其中該柴胡皂苷包括柴胡醇萃取物、SSa、SSb2、SSc及SSd至少其中之一。
3.如前述實施例所述的用途,其中該柴胡皂苷是衍生自高氏柴胡(Bupleurum kaoi
)。
4.如前述實施例所述的用途,其中該醫藥組合物更包括一藥學可接受載體。
5.如前述實施例所述的用途,其中該醫藥組合物被製造為藥物、消毒液、手套、口罩、乾洗手、洗手乳及防蚊液其中之一。
6.如前述實施例所述的用途,其中該無套膜病毒包括呼腸孤病毒、腸病毒、諾羅病毒及腺病毒。
7.一種藥物組合物,包括:一主要成分,包括一柴胡皂苷;以及一高分子聚合物,與該主要成分混合。
8.如前述實施例所述的藥物組合物,其中該藥物組合物的大小小於50 nm。
9.如前述實施例所述的藥物組合物,其中該藥物組合物被製造為藥物、消毒液、手套、口罩、乾洗手、洗手乳及防蚊液其中之一。
10.如前述實施例所述的藥物組合物,其中該高分子聚合物提高該柴胡皂苷之溶解度。
11.如前述實施例所述的藥物組合物,其中該高分子聚合物選自三團聯聚合物(Pluronic® polymer)、聚乙烯醇(polyvinyl alcohol,PVA)、聚乙烯吡咯烷酮(polyvinylpyrrolidone,PVP)所組成群組其中之一。
12.一種製造一藥物組合物的方法,包括:將一柴胡皂苷溶解於一有機溶劑中;將含有該柴胡皂苷的該有機溶劑加入一溶液中,該溶液中含有一高分子聚合物;使該柴胡皂苷分散於該高分子聚合物中;以及去除該有機溶劑,以獲得該藥物組合物。
本發明實屬難能的創新發明,深具產業價值,援依法提出申請。此外,本發明可以由本領域技術人員做任何修改,但不脫離如所附權利要求所要保護的範圍。
Claims (6)
- 一種利用一柴胡皂苷SSb2製備一醫藥組合物的用途,該醫藥組合物用於預防或治療一C型肝炎病毒、一麻疹病毒、一呼吸道融合病毒、一水泡性口炎病毒、一登革熱病毒及一無套膜病毒其中之一的感染。
- 如申請專利範圍第1項所述的用途,其中該醫藥組合物更包括柴胡皂苷SSa、柴胡皂苷SSc及柴胡皂苷SSd至少其中之一。
- 如申請專利範圍第1項所述的用途,其中該柴胡皂苷SSb2是衍生自高氏柴胡(Bupleurum kaoi )。
- 如申請專利範圍第1項所述的用途,其中該醫藥組合物更包括一藥學可接受載體。
- 如申請專利範圍第1項所述的用途,其中該醫藥組合物被製造為藥物、消毒液、手套、口罩、乾洗手、洗手乳及防蚊液其中之一。
- 如申請專利範圍第1項所述的用途,其中該無套膜病毒包括呼腸孤病毒、腸病毒、諾羅病毒及腺病毒。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
TW102119835A TWI492751B (zh) | 2013-06-04 | 2013-06-04 | 柴胡皂苷製備之醫藥組合物、其用途及其製備方法 |
PCT/US2014/040755 WO2014197510A1 (en) | 2013-06-04 | 2014-06-03 | Composition prepared from saikosaponin, the use and the preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
TW102119835A TWI492751B (zh) | 2013-06-04 | 2013-06-04 | 柴胡皂苷製備之醫藥組合物、其用途及其製備方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201446250A TW201446250A (zh) | 2014-12-16 |
TWI492751B true TWI492751B (zh) | 2015-07-21 |
Family
ID=52008540
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW102119835A TWI492751B (zh) | 2013-06-04 | 2013-06-04 | 柴胡皂苷製備之醫藥組合物、其用途及其製備方法 |
Country Status (2)
Country | Link |
---|---|
TW (1) | TWI492751B (zh) |
WO (1) | WO2014197510A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113633050A (zh) * | 2021-09-14 | 2021-11-12 | 刘中庆 | 一种半湿式消杀口罩 |
CN114306354A (zh) * | 2021-11-18 | 2022-04-12 | 广东中诚生物科技有限公司 | 一种具有抗2型登革病毒作用的植物单体及其应用 |
CN114767661B (zh) * | 2022-03-15 | 2023-08-08 | 浙江中医药大学 | 柴胡皂苷b1纳米制剂、制备方法及其在制备预防和治疗肝纤维化药物中的应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101062071A (zh) * | 2007-06-18 | 2007-10-31 | 石任兵 | 柴胡总皂苷提取物及其制备方法 |
CN102188372A (zh) * | 2010-03-12 | 2011-09-21 | 北京化工大学 | 一种药物透明纳米分散体及其制备方法 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1307473A (zh) * | 1998-05-19 | 2001-08-08 | 研究发展基金会 | 三萜组合物和它们的使用方法 |
US20070059358A1 (en) * | 2003-07-02 | 2007-03-15 | Tianjin Tasly Pharmaceutical Co., Ltd., China | Matrix adjuvants and the drop pills prepared with them |
EP1648519B1 (en) * | 2003-07-16 | 2014-10-08 | Protiva Biotherapeutics Inc. | Lipid encapsulated interfering rna |
US20070185216A1 (en) * | 2006-02-09 | 2007-08-09 | Marcia Snyder | Antiviral method |
TWI387648B (zh) * | 2009-03-26 | 2013-03-01 | Nat Univ Tsing Hua | 高氏柴胡之乙烯反應因子基因的應用 |
US20110268722A1 (en) * | 2010-04-22 | 2011-11-03 | Siegelin Markus D | Combination therapies with mitochondrial-targeted anti-tumor agents |
TWI410431B (zh) * | 2010-12-22 | 2013-10-01 | Ind Tech Res Inst | 齊敦果酸衍生物在製備預防或治療c型肝炎之藥物的用途 |
-
2013
- 2013-06-04 TW TW102119835A patent/TWI492751B/zh not_active IP Right Cessation
-
2014
- 2014-06-03 WO PCT/US2014/040755 patent/WO2014197510A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101062071A (zh) * | 2007-06-18 | 2007-10-31 | 石任兵 | 柴胡总皂苷提取物及其制备方法 |
CN102188372A (zh) * | 2010-03-12 | 2011-09-21 | 北京化工大学 | 一种药物透明纳米分散体及其制备方法 |
Non-Patent Citations (1)
Title |
---|
祖宁 等, 柴胡皂苷的生理作用及临床意义, Chinese Journal of Information on TCM Apr.2005 Vol.12 No.4. 陳唐麒 等, 台灣肝病醫藥產業累積基礎 廠商投入成果可期, 生技時代 No. 35, 2004/11/23. 林俊清, 勇抗肝炎的高氏柴胡, 頁38-41, 科學發展2003年4月,364期. * |
Also Published As
Publication number | Publication date |
---|---|
WO2014197510A1 (en) | 2014-12-11 |
TW201446250A (zh) | 2014-12-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Rani et al. | Potential molecular mechanisms of zinc-and copper-mediated antiviral activity on COVID-19 | |
Chen et al. | Activity of andrographolide and its derivatives against influenza virus in vivo and in vitro | |
US8765138B2 (en) | Antiviral and antibacterial activity from medicinal mushrooms | |
US20140105928A1 (en) | Antiviral and antibacterial activity from medicinal mushrooms | |
JP2011516613A5 (zh) | ||
WO2005074947A2 (en) | Anti-viral pharmaceutical compositions | |
TWI492751B (zh) | 柴胡皂苷製備之醫藥組合物、其用途及其製備方法 | |
KR20170056702A (ko) | 지효성 약제학적 조성물 | |
Alshaeri et al. | A contemporary look at COVID-19 medications: available and potentially effective drugs | |
TWI520739B (zh) | 柴胡皂苷製備之醫藥組合物及其製備方法 | |
CN101946771B (zh) | 柴胡皂苷a在制备抗烟草花叶病毒药物中的应用 | |
CN105358220A (zh) | 柴胡皂苷制备的药物组合物、其用途及其制备方法 | |
CN102772398A (zh) | 二氢杨梅素在制备防治流感药物中的应用 | |
CA2622508C (en) | Medicament for the prevention and treatment of influenza | |
CN101946784B (zh) | 银杏内酯b在制备抗烟草花叶病毒药物中的应用 | |
US7815945B2 (en) | Medicament for the prevention and treatment of influenza | |
RU2444363C2 (ru) | Противовирусное средство для профилактики и лечения клещевого энцефалита | |
WO2018042291A1 (en) | Composition for treating and preventing viral infections | |
CN110536690B (zh) | 用于预防或治疗丙型肝炎病毒感染疾病的药学组合物 | |
JPH11193242A (ja) | 抗インフルエンザウイルス剤 | |
CN107648249B (zh) | 去半乳糖替告皂甙在制备防治流感病毒感染的药物中的应用 | |
TWI624264B (zh) | 南洋山蘇水萃物的用途 | |
KR20220037979A (ko) | 수가용화된 담즙산을 포함하는 패혈증, 급성 폐손상 질환, 또는 급성 호흡곤란증후군의 예방 또는 치료용 약학 조성물 | |
WO2021257007A1 (en) | An antiviral pharmaceutical composition with therapeutic agent originated from astraeus asiaticus | |
JP2017514834A5 (zh) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |