CN1634241A - Compound formulation of notoginseng for treating cardiovascular and cerebrovascular diseases and its preparing process - Google Patents
Compound formulation of notoginseng for treating cardiovascular and cerebrovascular diseases and its preparing process Download PDFInfo
- Publication number
- CN1634241A CN1634241A CN 200410040764 CN200410040764A CN1634241A CN 1634241 A CN1634241 A CN 1634241A CN 200410040764 CN200410040764 CN 200410040764 CN 200410040764 A CN200410040764 A CN 200410040764A CN 1634241 A CN1634241 A CN 1634241A
- Authority
- CN
- China
- Prior art keywords
- extract
- notoginseng
- radix
- radix notoginseng
- radix astragali
- 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.)
- Pending
Links
- 241000180649 Panax notoginseng Species 0.000 title claims abstract description 128
- 235000003143 Panax notoginseng Nutrition 0.000 title claims abstract description 128
- 230000002526 effect on cardiovascular system Effects 0.000 title claims abstract description 24
- 208000024172 Cardiovascular disease Diseases 0.000 title claims abstract description 23
- 208000026106 cerebrovascular disease Diseases 0.000 title claims abstract description 23
- 239000000203 mixture Substances 0.000 title claims abstract description 20
- 238000009472 formulation Methods 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title abstract description 18
- 230000008569 process Effects 0.000 title abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 41
- 239000000284 extract Substances 0.000 claims description 110
- 239000009636 Huang Qi Substances 0.000 claims description 76
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 239000011347 resin Substances 0.000 claims description 32
- 229920005989 resin Polymers 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 30
- 238000002347 injection Methods 0.000 claims description 27
- 239000007924 injection Substances 0.000 claims description 27
- 238000010792 warming Methods 0.000 claims description 24
- 244000131316 Panax pseudoginseng Species 0.000 claims description 23
- 239000003463 adsorbent Substances 0.000 claims description 23
- 238000011282 treatment Methods 0.000 claims description 23
- 239000000843 powder Substances 0.000 claims description 20
- 239000008215 water for injection Substances 0.000 claims description 18
- 239000000706 filtrate Substances 0.000 claims description 17
- 238000010828 elution Methods 0.000 claims description 16
- 239000003480 eluent Substances 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- 238000000605 extraction Methods 0.000 claims description 14
- 238000001291 vacuum drying Methods 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 239000012982 microporous membrane Substances 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 238000005303 weighing Methods 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- 239000006187 pill Substances 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 9
- 238000004321 preservation Methods 0.000 claims description 9
- 238000007670 refining Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 241000545442 Radix Species 0.000 claims description 6
- 230000008901 benefit Effects 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000004108 freeze drying Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 229920002307 Dextran Polymers 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 239000007919 dispersible tablet Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 5
- 239000008188 pellet Substances 0.000 claims description 5
- 239000007901 soft capsule Substances 0.000 claims description 5
- 239000006196 drop Substances 0.000 claims description 4
- 239000011664 nicotinic acid Substances 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 239000003826 tablet Substances 0.000 claims description 4
- 238000012856 packing Methods 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 238000001694 spray drying Methods 0.000 claims description 3
- 235000003181 Panax pseudoginseng Nutrition 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 239000003405 delayed action preparation Substances 0.000 claims description 2
- 239000012528 membrane Substances 0.000 claims description 2
- 239000003094 microcapsule Substances 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims 1
- 230000017531 blood circulation Effects 0.000 abstract description 8
- 230000004060 metabolic process Effects 0.000 abstract description 5
- 230000001737 promoting effect Effects 0.000 abstract description 3
- 229940107666 astragalus root Drugs 0.000 abstract description 2
- 239000008280 blood Substances 0.000 description 32
- 210000004369 blood Anatomy 0.000 description 32
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 21
- 235000003140 Panax quinquefolius Nutrition 0.000 description 21
- 235000008434 ginseng Nutrition 0.000 description 21
- 230000000694 effects Effects 0.000 description 20
- 239000003814 drug Substances 0.000 description 18
- 229930182490 saponin Natural products 0.000 description 15
- 235000017709 saponins Nutrition 0.000 description 15
- 150000007949 saponins Chemical class 0.000 description 15
- 241000700159 Rattus Species 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 10
- 208000029078 coronary artery disease Diseases 0.000 description 8
- 206010012601 diabetes mellitus Diseases 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 7
- 230000009471 action Effects 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 206010021143 Hypoxia Diseases 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 235000018553 tannin Nutrition 0.000 description 5
- 229920001864 tannin Polymers 0.000 description 5
- 239000001648 tannin Substances 0.000 description 5
- 208000024827 Alzheimer disease Diseases 0.000 description 4
- 206010002383 Angina Pectoris Diseases 0.000 description 4
- 241000976983 Anoxia Species 0.000 description 4
- 206010002660 Anoxia Diseases 0.000 description 4
- 206010008132 Cerebral thrombosis Diseases 0.000 description 4
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 230000007953 anoxia Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 208000019622 heart disease Diseases 0.000 description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 4
- 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 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- 230000036039 immunity Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000010298 pulverizing process Methods 0.000 description 3
- 230000009182 swimming Effects 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 2
- 208000019693 Lung disease Diseases 0.000 description 2
- 206010041956 Stasis syndrome Diseases 0.000 description 2
- 244000269722 Thea sinensis Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- 208000005634 blind loop syndrome Diseases 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 208000026758 coronary atherosclerosis Diseases 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 201000011200 hepatorenal syndrome Diseases 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000001465 metallisation Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- -1 phenol aldehyde Chemical class 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- WTPPRJKFRFIQKT-UHFFFAOYSA-N 1,6-dimethyl-8,9-dihydronaphtho[1,2-g][1]benzofuran-10,11-dione;1-methyl-6-methylidene-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-10,11-dione Chemical compound O=C1C(=O)C2=C3CCCC(=C)C3=CC=C2C2=C1C(C)=CO2.O=C1C(=O)C2=C3CCC=C(C)C3=CC=C2C2=C1C(C)=CO2 WTPPRJKFRFIQKT-UHFFFAOYSA-N 0.000 description 1
- FZIPCQLKPTZZIM-UHFFFAOYSA-N 2-oxidanylpropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O FZIPCQLKPTZZIM-UHFFFAOYSA-N 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N Calcium oxide Chemical compound [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- GVKKJJOMQCNPGB-JTQLQIEISA-N Cryptotanshinone Chemical compound O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1[C@@H](C)CO2 GVKKJJOMQCNPGB-JTQLQIEISA-N 0.000 description 1
- GVKKJJOMQCNPGB-UHFFFAOYSA-N Cryptotanshinone Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)CO2 GVKKJJOMQCNPGB-UHFFFAOYSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 241000899749 Dypsis lutescens Species 0.000 description 1
- 102000002045 Endothelin Human genes 0.000 description 1
- 108050009340 Endothelin Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021079 Hypopnoea Diseases 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
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- RXUWDKBZZLIASQ-UHFFFAOYSA-N Puerarin Natural products OCC1OC(Oc2c(O)cc(O)c3C(=O)C(=COc23)c4ccc(O)cc4)C(O)C(O)C1O RXUWDKBZZLIASQ-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010038669 Respiratory arrest Diseases 0.000 description 1
- 240000007164 Salvia officinalis Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 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
- 239000011149 active material Substances 0.000 description 1
- 238000001467 acupuncture Methods 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 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
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 230000001723 fibrinogenic effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 235000009048 phenolic acids Nutrition 0.000 description 1
- 150000007965 phenolic acids Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- HKEAFJYKMMKDOR-VPRICQMDSA-N puerarin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=CC(C2=O)=C1OC=C2C1=CC=C(O)C=C1 HKEAFJYKMMKDOR-VPRICQMDSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 244000132619 red sage Species 0.000 description 1
- 235000005412 red sage Nutrition 0.000 description 1
- 210000005245 right atrium Anatomy 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 238000004879 turbidimetry Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
Landscapes
- Medicines Containing Plant Substances (AREA)
Abstract
The invention relates to a compound formulation of notoginseng for treating cardiovascular and cerebrovascular diseases and its preparing process, wherein the preparation is mainly prepared from ontoginseng and astragalus root, the preparation has the functions of promoting blood circulation and improving metabolism.
Description
Technical field: the present invention is a kind of compound formulation of notoginseng for the treatment of cardiovascular and cerebrovascular disease and preparation method thereof, belongs to technical field of Chinese medicine.
Technical background: cardiovascular and cerebrovascular disease such as coronary heart disease, cerebral thrombosis, alzheimer disease etc. all are one of the most common and diseases that harm is maximum in the world today, have become human mortality's one of the main reasons in many countries; According to investigations, sickness rate in recent years has and increases trend year by year, and in, young patient constantly increases, ischemic cardiovascular and cerebral vascular disease has become commonly encountered diseases, the frequently-occurring disease of harm China people ' s health; Prevent and treat purpose in order to reach, a large amount of research has been done by many inventors and medicine enterprise, and the product of some treatments also is provided; As: number of patent application is: 03141834, name is called " capsule preparations of a kind of blood lipid regulation and blood pressure ".Under study for action, the clear people in this Shen finds only to adopt the Radix Astragali, Radix Notoginseng prescription product good effect, and effective component in red sage is mainly adjacent benzene dihydroxy compounds such as water-soluble phenolic acids material original pair tea phenol aldehyde and liposoluble constituent cryptotanshinone etc., and the acid ingredient of original pair tea phenol aldehyde and some band phenolic hydroxyl groups is similar to the chemical constituent of tannin, physicochemical property is approaching, so in process for preparing injection liquid, desire to remove tannin, the water soluble ingredient that keeps Radix Salviae Miltiorrhizae is difficult, bring very big inconvenience for big production, tannin can produce extremely strong zest; And tannin is the active material of chemical property that polyhydroxy fragrant acid is formed, it enters and can be used as hapten behind the body and associate more macromolecular complex with the amino of plasma protein, cause allergy, cause anaphylactic shock, especially this situation danger close in injection; The inventor participated in once also having finished that a application number is 200410022503.5, name is called the patent application of " Chinese medicine preparation of a kind of antitumor and enhancing immunity and preparation method thereof ", this part patent application has used Radix Ginseng as one of raw material, the benefiting action of product is better, but treats the weak curative effect of cardiovascular and cerebrovascular disease.The applicant is further finding in the research: the people participates in the pharmacological action of Radix Notoginseng in tonification, there is similarity many aspects such as blood circulation promoting and blood stasis dispelling, but certain difference is arranged, experimental studies have found that Radix Notoginseng with the equal experiment condition of Radix Ginseng under, can play and the akin resisting fatigue of Radix Ginseng, anoxia enduring, the cold resistant effect, illustrate that Radix Notoginseng has the benefiting action similar to Radix Ginseng, and Radix Notoginseng has the ability of improving the anxious stasis of blood model of rat blood " dense; sticking; as to coagulate; poly-" state more by force, can make low whole blood viscosity and the plasma viscosity cut of blood stasis rat, packed cell volume significantly reduces, and red cell deformability is increased, the Radix Ginseng low dose then can only obviously reduce the low whole blood viscosity of cutting, and other blood index are not had obvious improvement effect, and the anxious toxicity of Radix Notoginseng total arasaponins is significantly less than Radix Ginseng total saponins; In order to reduce the drug administration amount, this product has adopted process for refining, but traditional impurity removal process is very limited for the accumulation ability of effective ingredient.In view of such circumstances, seek a kind of active drug for the treatment of cardiovascular and cerebrovascular disease, compatibility is simple, therapeutic effect is desirable, does not have toxic and side effects, the thing that preparation technology's rational and effective medicine preparation has become people to be badly in need of solving.
Summary of the invention: the objective of the invention is to: a kind of compound formulation of notoginseng for the treatment of cardiovascular and cerebrovascular disease and preparation method thereof is provided; At prior art, the present invention according to cardiovascular and cerebrovascular disease such as coronary heart disease, cerebral thrombosis, alzheimer disease etc. all contract because of blood vessel is narrow, reason such as blood flow minimizing causes the diseases induced principle of blood supply insufficiency, adopts the Radix Astragali and Radix Notoginseng compatibility to make preparation; The product that obtains has activating blood circulation to dissipate blood stasis, TONGMAI SHULUO, improves blood circulation and metabolism.For example coronary heart disease is that coronary atherosclerosis causes myocardial ischemia, anoxia and the heart disease that causes, and two medicines share, and can play to improve the myocardial metabolism effect, increase coronary flow, and the blood that improves cardiac muscle is provided with the effect of allevating angina pectoris.The present invention not only has curative effect preferably for treating cardiovascular and cerebrovascular disease such as coronary heart disease, angina pectoris, arrhythmia, cerebral thrombosis, alzheimer disease etc., can also be used for diseases such as enhance immunity antitumor, treatment hepatorenal syndrome, heart and lung diseases, diabetes and complication thereof.And the present invention is a pure Chinese medicinal preparation, but the little patients life-time service of its untoward reaction, at selecting for use the Radix Astragali and Radix Notoginseng compatibility to make preparation, the present invention also provides preparation method, guarantee that the product of producing satisfies the treatment needs, can solve the problem that prior art exists.
The present invention constitutes like this: calculate according to components by weight percent, it is mainly by 1～99 part of Radix Notoginseng, or corresponding the weight fraction Radix Notoginseng extract and 99～1 parts of the Radixs Astragali that obtain after extracting, or the Radix Astragali extract that corresponding weight fraction obtains after extraction is made.Say accurately: calculate according to components by weight percent, it is mainly by 20～80 parts of Radix Notoginseng, or corresponding the weight fraction Radix Notoginseng extract and 80～20 parts of the Radixs Astragali that obtain after extracting, or the Radix Astragali extract that corresponding weight fraction obtains after extraction is made.Best prescription is: calculate according to components by weight percent, it is by 50 parts of the Radixs Astragali, or corresponding the weight fraction Radix Astragali extract and 50 parts of Radix Notoginseng that obtain after extracting, or the Radix Notoginseng extract that corresponding weight fraction obtains after extraction is made.Preparation of the present invention is: injection, comprising: injection, powder pin, freeze-dried powder, tablet, dispersible tablet, capsule, soft capsule, microcapsule, granule, pill, pellet, powder, drop pill, slow releasing preparation, controlled release preparation, oral liquid, soft extract, extractum and membrane.Say accurately: preparation of the present invention is: injection, comprising: injection, powder pin, freeze thousand powder pins, tablet, capsule, granule, drop pill, pellet, soft capsule, dispersible tablet.
Extract of the present invention is: Radix Notoginseng extract can be the highly finished product of Radix Notoginseng alcohol extract, pseudo-ginseng water extract, Radix Notoginseng water extract-alcohol precipitation extract, Radix Notoginseng semi-bionic extraction thing, Radix Notoginseng supercritical extract or above extract; Radix Astragali extract can be the highly finished product of (+)-Astragenol extract, Radix Astragali water extract, Radix Astragali water extract-alcohol precipitation extract, Radix Astragali semi-bionic extraction thing, Radix Astragali supercritical extract or above extract.The preparation method of the compound formulation of notoginseng of treatment cardiovascular and cerebrovascular disease of the present invention is: takes by weighing Radix Notoginseng, pulverizes, and alcohol reflux, the collection extracting solution filters, and reclaims ethanol, gets the Radix Notoginseng extracting solution, and macroporous adsorbent resin is refining, and drying gets Radix Notoginseng extract; Get the Radix Astragali, water boiling and extraction is filtered, and macroporous adsorbent resin is refining, and drying gets Radix Astragali extract; Make different preparations then respectively.Say that exactly the preparation method of the compound formulation of notoginseng of treatment cardiovascular and cerebrovascular disease of the present invention is got and taken by weighing Radix Notoginseng, pulverize, measure 80% alcohol reflux 3 times, each 1 hour for 8 times, collect extracting solution, filter, reclaim ethanol, get the Radix Notoginseng extracting solution, last D101 type macroporous adsorbent resin, 70% ethanol elution, eluent concentrating under reduced pressure, vacuum drying gets Radix Notoginseng extract; Get the Radix Astragali, 8 times of water gagings decoct and extract 3 times, and each 1 hour, filter, AB-8 type macroporous adsorbent resin on the filtrate, 95% ethanol elution, the eluent water-bath volatilizes, concentrating under reduced pressure, vacuum drying gets Radix Astragali extract; Make different preparations then respectively.Concrete:
Get Radix Notoginseng extract, Radix Astragali extract, add water for injection, and add 0.9% sodium chloride, stir evenly, cold preservation filters, filtrate adds 0.2% active carbon, boils 30 minutes, puts cold, be filtered to clear and brightly, with 10%NaOH adjust pH 5.5～7.5, benefit adds to the full amount of water for injection, filtering with microporous membrane through 0.25～0.45 μ m, fill was sterilized 30 minutes, and was promptly got great transfusion preparation for 115 ℃.
Get Radix Notoginseng extract, Radix Astragali extract, add water for injection, stir evenly cold preservation, filter, filtrate adds 0.2% active carbon, boils 30 minutes, put cold, be filtered to clear and bright, with 10%NaOH adjust pH 5.5～7.5, in medicinal liquid: it is caffolding agent that the ratio of caffolding agent=2: 3 adds dextran, and mixing is through the filtering with microporous membrane of 0.25～0.45 μ m, fill, lyophilization, lyophilisation condition :-10 ℃ of pre-freezes 3 hours,-45 ℃ of pre-freezes began evacuation after 6 hours, and were warming up to-35 ℃, kept 3 hours; Be warming up to-30 ℃, kept 6 hours; Be warming up to-20 ℃, kept 6 hours; Be warming up to-10 ℃, kept 10 hours; Be warming up to 0 ℃, kept 2 hours; Be warming up to 10 ℃, kept 2 hours; Be warming up to 20 ℃, kept 2 hours; Be warming up to 30 ℃, kept 2 hours, promptly get lyophilized injectable powder.
Get Radix Notoginseng extract, Radix Astragali extract, add water for injection, stir evenly, cold preservation filters, filtrate adds 0.2% active carbon, boils 30 minutes, put cold, be filtered to clear and bright, with 10%NaOH adjust pH 5.5～7.5, through the filtering with microporous membrane of 0.25～0.45 μ m, spray drying, packing promptly gets injectable powder.
Get Radix Notoginseng extract, Radix Astragali extract, add water for injection, add 0.2% active carbon, boiled 30 minutes, put cold, be filtered to clear and brightly, with 10%NaOH adjust pH 5.5～7.5, benefit adds to the full amount of water for injection, filtering with microporous membrane through 0.25～0.45 μ m, fill was sterilized 30 minutes, and was promptly got injection for 115 ℃.
Compared with prior art, product provided by the invention has activating blood circulation to dissipate blood stasis, TONGMAI SHULUO, improves blood circulation and metabolism.For example coronary heart disease is that coronary atherosclerosis causes myocardial ischemia, anoxia and the heart disease that causes, and two medicines share, and can play to improve the myocardial metabolism effect, increase coronary flow, and the blood that improves cardiac muscle is provided with the effect of allevating angina pectoris.The present invention not only has curative effect preferably for treating cardiovascular and cerebrovascular disease such as coronary heart disease, angina pectoris, arrhythmia, cerebral thrombosis, alzheimer disease etc., can also be used for diseases such as enhance immunity antitumor, treatment hepatorenal syndrome, heart and lung diseases, diabetes and complication thereof.And the present invention is pure Chinese medicinal preparation, but the little patients life-time service of its untoward reaction; The present invention selects the Radix Notoginseng that similarity is arranged aspect many at tonification, blood circulation promoting and blood stasis dispelling etc. with Radix Ginseng for use, and discover by experiment Radix Notoginseng with the equal experiment condition of Radix Ginseng under, can play and the akin resisting fatigue of Radix Ginseng, anoxia enduring, cold resistant effect, illustrate that Radix Notoginseng has the benefiting action similar to Radix Ginseng; And Radix Notoginseng has the ability of improving the anxious stasis of blood model of rat blood " dense, sticking, coagulate, gather " state more by force, can make that the blood stasis rat is low to cut whole blood viscosity and plasma viscosity, packed cell volume significantly reduce, and red cell deformability is increased, the improvement effect obviously is better than Radix Ginseng, and the anxious toxicity of Radix Notoginseng total arasaponins is significantly less than Radix Ginseng total saponins.
The applicant screens by experiment, has adopted the macroporous resin enrichment effective ingredient, and finds that the effect of the resin of different model differs greatly, and the applicant is determined by experiment best process for refining; The applicant also is determined by experiment the suitable pH value of injection, guaranteed the stable of Radix Notoginseng, Radix Astragali effective ingredient.The applicant does not adopt Radix Salviae Miltiorrhizae, and be to use Radix Notoginseng, Radix Astragali prescription preparing product, curative effect ideal not only, and do not have a large amount of tannins that Danshen root injection is difficult to remove in the preparation process, safety and stability more, solved the problem that prior art exists, the present invention also provides the detailed processing technology of several formulations, can be directly used in and instruct actual production; Reached the purpose of invention.
The applicant has carried out a series of experiments, can prove that medicine provided by the invention has effective effect; Experimental example 1: the people participates in the pharmacodynamics comparative study of Radix Notoginseng
(1) comparative study of benefiting action
1. to the influence of mice swimming time: 30 of mices, body weight 22.0 ± 1.4g, male and female half and half are divided into 3 groups at random.Ig gives medicine or equal-volume normal saline respectively, and 1h after the administration is stained with the clay that is equivalent to from heavy sensation of the whole body 10% at each mouse tail, puts into basin, makes its free swimming, picks up counting, and a submerged 10s can not emerge to mice, stops timing.The record respectively organize the mice swimming time (x ± s, min), matched group is 5.38 ± 3.02 as a result, Radix Ginseng 6g/kg is 8.71 ± 2.86, Radix Notoginseng 6g/kg is 8.65 ± 2.55.The result shows that the people participates in the trip ice time that Radix Notoginseng all can obviously prolong mice.
2. to the influence of mice normal pressure hypoxia-bearing capability: get 30 of mices, body weight 22.3 ± 1.6g, male and female half and half, grouping is the same with medication.1h after the administration puts into the 250ml wide mouthed bottle that fills the 10g sodica calx respectively with mice, and the bottleneck of obturaging picks up counting simultaneously.With the respiratory arrest is index, and the record mouse diing time (x ± s, min), matched group is 31.04 ± 3.12 as a result, and Radix Ginseng 6g/kg is 35.27 ± 2.04, and Radix Notoginseng 6g/kg is 34.98 ± 2.57.The result shows that the people participates in Radix Notoginseng all can obviously prolong the time-to-live of mice under the normobaric hypoxia condition.
The result shows, Radix Ginseng, Radix Notoginseng benefiting action are similar.
(2) acute toxicity testing: Kunming mouse, 10 every group, male and female half and half, the administration of intraperitoneal single injection is observed reaction of animals and is write down the animal dead situation behind the medicine, obtain LD
50
Radix Notoginseng total arasaponins and Radix Ginseng total saponins get LD
50Be respectively 826.8 (730.5-928.9) and 624.8 (559.7-677.3) mg/kg, behind the heavy dose of Radix Notoginseng total arasaponins and Radix Ginseng total saponins lumbar injection, mice is movable significantly to be reduced, hypopnea, death is mainly in behind the medicine 2-3 days, and the postmortem naked eyes are not seen obvious organ disease, with the LD of two medicines
50Value is carried out the t check, and the two has significant difference.Experimental result shows that the acute toxicity of Radix Notoginseng total arasaponins is less than Radix Ginseng total saponins.
(3) to the influence of stasis syndrome rat blood rheological characteristic: 60 of rats, male and female half and half, body weight 270 ± 20g successive administration 12 days, 1h after the last administration, all the other respectively organize equal sc injection epinephrine 0.8mg/kg, totally twice, two minor tick 4h except that the normal control group.(front and back each 2 hours at interval) immerse 5min in the frozen water, fasting with rat between twice.Femoral artery blood sampling in morning next day, each index of hemorheology is measured in the heparin sodium anticoagulant.
Group plasma viscosity packed cell volume reduced viscosity
Normal control 1.54 ± 0.25 0.43 ± 0.02 7.69 ± 0.86
Model contrast 2.13 ± 0.15 0.52 ± 0.04 8.54 ± 2.51
Radix Ginseng 2g/kg 1.97 ± 0.21 0.49 ± 0.04 8.40 ± 1.33
Radix Notoginseng 2g/kg 1.80 ± 0.16 0.44 ± 0.05 8.10 ± 2.72
RENSHEN HUANGQI ZHUSHEYE 1.79 ± 0.22 0.44 ± 0.01 8.04 ± 1.26
Radix Notoginseng Radix Astragali injection 1.75 ± 0.14 0.43 ± 0.05 7.95 ± 1.75
The result shows, Radix Notoginseng has the ability of improving the anxious stasis of blood model of rat blood status more by force, blood stasis rat plasma viscosity, packed cell volume are significantly reduced, the Radix Ginseng low dose does not have obvious improvement effect to other blood index, and preparation of the present invention is better than the Radix Ginseng formulation of astragalus root to the effect of stasis syndrome rat blood rheological characteristic.
Experimental example 2: refining pure metallization processes research: the applicant has carried out different process for purification and different model macroporous adsorbent resin to the Radix Astragali, Radix Notoginseng total arasaponins enrichment and than the result of study of adsorbance.Weight than adsorbance (absorption saponin amount with dried resin weight ratio)=(for the amount of the amount of saponin in the upper prop liquid-be saponin in the post effluent-be the amount of saponin in the water elution liquid)/dried resin.
(1) Radix Astragali saponin purifying process research:
1. the comparison of process for purification:
Saponin content % in the process for purification yield % total extract
Extraction 0.89 70.50
Macroporous adsorbent resin method 1.31 82.23
2. the selection of resin model
The resin model compares adsorbance
D101 68.5
D605 45.9
AB-8 80.2
(2) arasaponin purifying process research:
1. the comparison of process for purification: n-butanol extraction: precision is measured Radix Astragali extract, extracts 3 times with water saturated n-butyl alcohol jolting, merges n-butyl alcohol liquid, and evaporate to dryness, residue add methanol makes dissolving; Macroporous adsorbent resin method precision is measured Radix Astragali extractive solution, be added on the AB-8 resin column of pre-treatment, reuse 95% ethanol elution, collect eluent to effluent colourless till.
Saponin content % in the process for purification yield % total extract
N-butanol extraction 0.90 79.52
Macroporous adsorbent resin method 1.21 80.46
2. the selection of resin model
The resin model compares adsorbance
D101 81.5
D605 55.1
AB-8 40.8
The result shows that refining pure metallization processes of the present invention is rationally feasible.
Experimental example 3: Study on Forming
(1) pH value is to the influence of injection: the applicant finds in development, product arasaponin of the present invention, Radix Astragali saponin are one of main onset composition, because of facile hydrolysis causes the medicine instability, its drug effect reduces, suitable acid-base value is the stable key factor of medicine, in order to improve the quality of this injection, the applicant placed 3 months for 40 ℃ the injection of 6 kinds of different pH value, investigated its stability respectively.
0 month March
PH value clarity total saponins (mg/ml) clarity total saponins (mg/ml)
Differ from 1.02 5.0 differ from 1.52
5.5 clear and bright 1.50 clear and bright 1.47
6.0 clear and bright 1.50 clear and bright 1.46
6.5 clear and bright 1.48 clear and bright 1.46
7.0 clear and bright 1.49 clear and bright 1.41
7.5 clear and bright 1.49 clear and bright 1.47
Differ from 1.21 8.0 differ from 1.57
(2) pH value is to the influence of freeze-dried powder
Number 123456789
PH value of solution 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 before the lyophilizing
The good job difference is poor carefully for insufficient formability
The yellowish yellowish yellowish-brown deep yellow palm fibre of color and luster
PH value of solution 4.8 5.3 5.7 6.3 6.5 7.2 7.5 8.1 8.8 after the lyophilizing
The result shows that technology of the present invention is rationally feasible, and product quality is good.
Experimental example 4: preparation pharmacodynamic study
(1) to the influence of blood stasis model rabbit blood rheological characteristic
Test 1 group: Radix Notoginseng injection; Test 2 groups: Radix Astragali injection; Test 3 groups: injection of the present invention
48 of rabbit are divided into 6 groups at random, and 8 every group, ♀ ♂ half and half is respectively blank group, model control group, positive drug control group and tests 1,2,3 group.Each treated animal elder generation auricular vein is injected (iv) administration.Blank and model control group injecting normal saline (NS) 1ml/kg, positive drug group iv puerarin injection 30mg/kg (being made into 30mg/ml) with NS, experimental group is injected the medicinal liquid (being made into NF) of 0.25mg/ml respectively, dosage is 1ml/kg, two weeks of successive administration (14d), in administration the 2nd, 13d, except that the blank group, each rabbit is annotated 10% high molecular dextran 5ml/kg through auricular vein respectively, every day twice, causes blood stasis model.Behind the last administration h, inject 10% high molecular dextran 5ml/kg once more, behind the 15min, heart is taked fasting blood 6ml, carrying out hemorheology index detects, wherein platelet aggregation rate adopts turbidimetry for Determination: the rotary cone-plate viscosity apparatus mensuration of other employing LBY-N6A+ with LBY-NJ2 type platelet aggregation instrument.
To rabbit platelet aggregation and fibrinogenic influence (x ± s, n=6)
Group dosage (mg/kg) body weight (kg) platelet aggregation (%) Fibrinogen (g/L)
Blank group-2.31 ± 0.15 15.54 ± 2.46 2.53 ± 1.16
Model group-2.45 ± 0.08 38.27 ± 15.05 2.73 ± 1.41
Positive drug group 30 2.37 ± 0.11 12.74 ± 3.47 3.12 ± 1.83
Test 1 group 0.25 2.32 ± 0.24 14.80 ± 1.36 2.69 ± 2.32
Test 2 group 0.25 2.38 ± 0.18 14.58 ± 4.08 2.58 ± 1.29
Test 3 group 0.25 2.35 ± 0.35 13.03 ± 3.71 2.53 ± 2.35
The result shows: preparation good effect of the present invention, be better than single medicinal material, and prescription has the effect of Synergistic.
(2) experimentation of treatment rat diabetes nephropathy
Select 30 of the healthy male Wistar rats of 150～190g for use, be divided into normal control group, diabetic groups and powder acupuncture treatment group of the present invention at random, every group 10, divide cage to feed, arbitrarily drink water, with diabetes rats, fasting 10h, be dissolved in 0.1mol/L citric acid sodium citrate buffer solution (pH4.5) with streptozotocin, be made into 1% solution, press the 50mg/kg single intraperitoneal injection, get tail vein behind the 5d, measure blood glucose with blood glucose meter, blood glucose 〉=16.7mmol/L is diabetes rat (becoming mould rate 100%).The citric acid citrate buffer solution of normal control group injection respective volume.Injectable powder of the present invention is become 0.5g/L solution with physiological saline solution, the treatment group is pressed 70mgkg-1d-1 dosage filling stomach morning every day, and the diabetic groups stomach is raised the normal saline of equivalent, continues to feed to 12 all backs collect specimens, metabolic cage is collected 24h urine, surveys 24h excretion quantity of urinary protein (UPE).Claim to anaesthetize after the quality, right atrium is got blood and is surveyed Endothelin, puts the method for exempting from and measures insulin, surveys blood urea nitrogen (BUN) with the CX7 automatic biochemistry analyzer, and calculates endogenous creatinine clearance rate (Ccr), and the result proofreaies and correct with the body constitution amount.Get two kidneys, right kidney part is fixed with 4% paraformaldehyde, conventional film-making, and light microscopy checking is measured MGPA and MGV with image analyzer, and left kidney is used to organize the ET assay.
Normal control group diabetic groups injectable powder group of the present invention
MGPA 51.14±3.56 65.26±4.25 53.13±0.15
MGV 430.4±36.5 648.2±23.2 446.2±13.7
BUN 7.26±0.65 11.30±1.43 8.14±1.04
Ccr 5.10±0.75 2.62±0.12 4.35±0.15
UPE 9.24±1.20 42.78±10.10 19.17±1.38
The result shows that preparation of the present invention all significantly improves than the diabetic nephropathy rat for MGPA, MGV, BUN, Ccr and 24h excretion quantity of urinary protein.
Concrete embodiment:
Embodiments of the invention 1: Radix Notoginseng 10g, Radix Astragali 990g
Get and take by weighing Radix Notoginseng, pulverize, measure 80% alcohol reflux 3 times for 8 times, each 1 hour, collect extracting solution, filter, reclaim ethanol, get the Radix Notoginseng extracting solution, last D101 type macroporous adsorbent resin, 70% ethanol elution, the eluent concentrating under reduced pressure, vacuum drying gets Radix Notoginseng extract; Get the Radix Astragali, 8 times of water gagings decoct and extract each 1 hour 3 times, filter AB-8 type macroporous adsorbent resin on the filtrate, 95% ethanol elution, the eluent water-bath volatilizes, concentrating under reduced pressure, vacuum drying, get Radix Astragali extract, get Radix Notoginseng extract, Radix Astragali extract adds water for injection, and add 0.9% sodium chloride, stir evenly cold preservation, filter, filtrate adds 0.2% active carbon, boils 30 minutes, put cold, be filtered to clear and brightly, with 10%NaOH adjust pH 5.5～7.5, benefit adds to the full amount of water for injection, filtering with microporous membrane through 0.25～0.45 μ m, fill was sterilized 30 minutes, and was promptly got great transfusion preparation for 115 ℃.
Embodiments of the invention 2: Radix Notoginseng 990g, Radix Astragali 10g
Get and take by weighing Radix Notoginseng, pulverize, measure 80% alcohol reflux 3 times for 8 times, each 1 hour, collect extracting solution, filter, reclaim ethanol, get the Radix Notoginseng extracting solution, last D101 type macroporous adsorbent resin, 70% ethanol elution, the eluent concentrating under reduced pressure, vacuum drying gets Radix Notoginseng extract; Get the Radix Astragali, 8 times of water gagings decoct and extract each 1 hour 3 times, filter AB-8 type macroporous adsorbent resin on the filtrate, 95% ethanol elution, the eluent water-bath volatilizes, concentrating under reduced pressure, vacuum drying, get Radix Astragali extract, get Radix Notoginseng extract, Radix Astragali extract adds water for injection, stir evenly, cold preservation filters, filtrate adds 0.2% active carbon, boiled 30 minutes, and put coldly, be filtered to clear and bright, with 10%NaOH adjust pH 5.5～7.5, in medicinal liquid: it is caffolding agent that the ratio of caffolding agent=2: 3 adds dextran, and mixing is through the filtering with microporous membrane of 0.25～0.45 μ m, fill, lyophilization, lyophilisation condition :-10 ℃ of pre-freezes 3 hours ,-45 ℃ of pre-freezes began evacuation after 6 hours, and be warming up to-35 ℃, kept 3 hours; Be warming up to-30 ℃, kept 6 hours; Be warming up to-20 ℃, kept 6 hours; Be warming up to-10 ℃, kept 10 hours; Be warming up to 0 ℃, kept 2 hours; Be warming up to 10 ℃, kept 2 hours; Be warming up to 20 ℃, kept 2 hours; Be warming up to 30 ℃, kept 2 hours, promptly get lyophilized injectable powder.
Embodiments of the invention 3: Radix Notoginseng 800g, Radix Astragali 200g
Get and take by weighing Radix Notoginseng, pulverize, measure 80% alcohol reflux 3 times for 8 times, each 1 hour, collect extracting solution, filter, reclaim ethanol, get the Radix Notoginseng extracting solution, last D101 type macroporous adsorbent resin, 70% ethanol elution, the eluent concentrating under reduced pressure, vacuum drying gets Radix Notoginseng extract; Get the Radix Astragali, 8 times of water gagings decoct and extract each 1 hour 3 times, filter AB-8 type macroporous adsorbent resin on the filtrate, 95% ethanol elution, the eluent water-bath volatilizes, concentrating under reduced pressure, vacuum drying, get Radix Astragali extract, get Radix Notoginseng extract, Radix Astragali extract, add water for injection, stir evenly, cold preservation filters, and filtrate adds 0.2% active carbon, boiled 30 minutes, put cold, be filtered to clear and bright, with 10%NaOH adjust pH 5.5～7.5, filtering with microporous membrane through 0.25～0.45 μ m, spray drying, packing promptly gets injectable powder.
Embodiments of the invention 4: Radix Notoginseng 200g, Radix Astragali 800g
Get and take by weighing Radix Notoginseng, pulverize, measure 80% alcohol reflux 3 times for 8 times, each 1 hour, collect extracting solution, filter, reclaim ethanol, get the Radix Notoginseng extracting solution, last D101 type macroporous adsorbent resin, 70% ethanol elution, the eluent concentrating under reduced pressure, vacuum drying gets Radix Notoginseng extract; Get the Radix Astragali, 8 times of water gagings decoct and extract each 1 hour 3 times, filter AB-8 type macroporous adsorbent resin on the filtrate, 95% ethanol elution, the eluent water-bath volatilizes, concentrating under reduced pressure, vacuum drying gets Radix Astragali extract, get Radix Notoginseng extract, Radix Astragali extract, add water for injection, add 0.2% active carbon, boiled 30 minutes, put cold, be filtered to clear and brightly, with 10%NaOH adjust pH 5.5～7.5, benefit adds to the full amount of water for injection, filtering with microporous membrane through 0.25～0.45 μ m, fill was sterilized 30 minutes, and was promptly got injection for 115 ℃.
Embodiments of the invention 5: Radix Notoginseng 500g, Radix Astragali 500g
Get and take by weighing Radix Notoginseng, pulverizing is measured 20% alcohol reflux 1 time for 3 times, and each 2 hours, collect extracting solution, filter, reclaim ethanol, get the Radix Notoginseng extracting solution, centrifugal remove impurity gets Radix Notoginseng extract; Get the Radix Astragali, 3 times of water gagings decoct and extract 2 times, each 2 hours, filter, the centrifugal remove impurity of filtrate gets Radix Astragali extract, gets Radix Notoginseng extract, Radix Astragali extract, adds the soybean oil mixing, the pressing pill promptly gets soft capsule, this product oral, three times on the one, each 2.
Embodiments of the invention 6: Radix Notoginseng 500g, Radix Astragali 500g
Get and take by weighing Radix Notoginseng, pulverizing is measured 95% alcohol reflux 5 times for 15 times, and each 3 hours, the collection extracting solution filtered, and reclaims ethanol, gets the Radix Notoginseng extracting solution, and extraction is made with extra care, and gets Radix Notoginseng extract; Get the Radix Astragali, 15 times of water gagings decoct and extract 5 times, and each 3 hours, filter, organic solvent extraction gets Radix Astragali extract, gets Radix Notoginseng extract, Radix Astragali extract, adds the PEG4000 mixing, and the dropping preparation method pill promptly gets drop pill.
Embodiments of the invention 7: Radix Notoginseng 500g, Radix Astragali 500g
Get and take by weighing Radix Notoginseng, pulverizing is measured 50% alcohol reflux 2 times for 10 times, and each 2 hours, the collection extracting solution filtered, and reclaims ethanol, gets the Radix Notoginseng extracting solution, and chromatography is made with extra care, and gets Radix Notoginseng extract; Get the Radix Astragali, 10 times of water gagings decoct and extract 2 times, and each 2 hours, filter, macroporous adsorbent resin is refining, gets Radix Astragali extract, gets Radix Notoginseng extract, Radix Astragali extract, adds 4% sodium carboxymethyl cellulose, extrudes-the spheronization pill, promptly gets pellet.
Embodiments of the invention 8: Radix Notoginseng 500g, Radix Astragali 500g
Get and take by weighing Radix Notoginseng, pulverize, measure 80% alcohol reflux 3 times for 8 times, each 1 hour, collect extracting solution, filter, reclaim ethanol, get the Radix Notoginseng extracting solution, last D101 type macroporous adsorbent resin, 70% ethanol elution, the eluent concentrating under reduced pressure, vacuum drying gets Radix Notoginseng extract; Get the Radix Astragali, 8 times of water gagings decoct and extract 3 times, each 1 hour, filter, AB-8 type macroporous adsorbent resin on the filtrate, 95% ethanol elution, the eluent water-bath volatilizes, concentrating under reduced pressure, vacuum drying gets Radix Astragali extract, get Radix Notoginseng extract, Radix Astragali extract, mixing adds 3% methylcellulose, it is moistening to add water, makes granule, drying, add 2% carboxymethyl starch sodium, tabletting promptly gets dispersible tablet.
Claims (10)
1, a kind of compound formulation of notoginseng for the treatment of cardiovascular and cerebrovascular disease, it is characterized in that: calculate according to components by weight percent, it is mainly by 1～99 part of Radix Notoginseng, or 99～1 parts of the Radix Notoginseng extract that after extracting, obtains of corresponding weight fraction and the Radixs Astragali, or the Radix Astragali extract that corresponding weight fraction obtains after extracting is made into injection, comprise: injection, the powder pin, freeze-dried powder, tablet, dispersible tablet, capsule, soft capsule, microcapsule, granule, pill, pellet, powder, drop pill, slow releasing preparation, controlled release preparation, oral liquid, gel, soft extract, extractum and membrane.
2, according to the compound formulation of notoginseng of the described treatment cardiovascular and cerebrovascular disease of claim 1, it is characterized in that: calculate according to components by weight percent, it is mainly by 20～80 parts of Radix Notoginseng, or corresponding the weight fraction Radix Notoginseng extract and 80～20 parts of the Radixs Astragali that obtain after extracting, or the Radix Astragali extract that corresponding weight fraction obtains after extraction is made.
3, according to the compound formulation of notoginseng of claim 1 or 2 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: calculate according to components by weight percent, it is by 50 parts of the Radixs Astragali, or 50 parts of the Radix Astragali extract that after extracting, obtains of corresponding weight fraction and Radix Notoginseng, or the Radix Notoginseng extract that corresponding weight fraction obtains after extracting is made described extract: Radix Notoginseng extract can be the highly finished product of Radix Notoginseng alcohol extract, pseudo-ginseng water extract, Radix Notoginseng water extract-alcohol precipitation extract, Radix Notoginseng semi-bionic extraction thing, Radix Notoginseng supercritical extract or above extract; Radix Astragali extract can be the highly finished product of (+)-Astragenol extract, Radix Astragali water extract, Radix Astragali water extract-alcohol precipitation extract, Radix Astragali semi-bionic extraction thing, Radix Astragali supercritical extract or above extract.
4, according to the compound formulation of notoginseng of claim 1,2 or 3 described this treatment cardiovascular and cerebrovascular diseases, it is characterized in that: described preparation is: injection, comprising: injection, powder pin, freeze-dried powder, tablet, capsule, granule, drop pill, pellet, gel, soft capsule, dispersible tablet.
5, as the preparation method of the compound formulation of notoginseng of any described treatment cardiovascular and cerebrovascular disease in the claim 1～4, it is characterized in that: take by weighing Radix Notoginseng, pulverize, alcohol reflux is collected extracting solution, filter, reclaim ethanol, get the Radix Notoginseng extracting solution, macroporous adsorbent resin is refining, drying gets Radix Notoginseng extract; Get the Radix Astragali, water boiling and extraction is filtered, and macroporous adsorbent resin is refining, and drying gets Radix Astragali extract; Make different preparations then respectively.
6, according to the preparation method of the compound formulation of notoginseng of the described treatment cardiovascular and cerebrovascular disease of claim 5, it is characterized in that: get and take by weighing Radix Notoginseng, pulverize, measure 80% alcohol reflux 3 times for 8 times, each 1 hour, collect extracting solution, filter, reclaim ethanol, get the Radix Notoginseng extracting solution, last D101 type macroporous adsorbent resin, 70% ethanol elution, the eluent concentrating under reduced pressure, vacuum drying gets Radix Notoginseng extract; Get the Radix Astragali, 8 times of water gagings decoct and extract 3 times, and each 1 hour, filter, AB-8 type macroporous adsorbent resin on the filtrate, 95% ethanol elution, the eluent water-bath volatilizes, concentrating under reduced pressure, vacuum drying gets Radix Astragali extract; Make different preparations then respectively.
7, according to the preparation method of the compound formulation of notoginseng of claim 5 or 6 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: get Radix Notoginseng extract, Radix Astragali extract, add water for injection, and add 0.9% sodium chloride, stir evenly, cold preservation filters, filtrate adds 0.2% active carbon, boiled 30 minutes, and put coldly, be filtered to clear and bright, with 10%NaOH adjust pH 5.5～7.5, benefit adds to the full amount of water for injection, through the filtering with microporous membrane of 0.25～0.45 μ m, fill, sterilized 30 minutes, and promptly got great transfusion preparation for 115 ℃.
8, preparation method according to the compound formulation of notoginseng of claim 5 or 6 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: get Radix Notoginseng extract, Radix Astragali extract adds water for injection, stirs evenly, cold preservation, filter, filtrate adds 0.2% active carbon, boils 30 minutes, put cold, be filtered to clear and brightly, with 10%NaOH adjust pH 5.5～7.5, by medicinal liquid: the ratio adding dextran of caffolding agent=2: 3 is a caffolding agent, mixing, through the filtering with microporous membrane of 0.25～0.45 μ m, fill, lyophilization, lyophilisation condition :-10 ℃ of pre-freezes 3 hours,-45 ℃ of pre-freezes began evacuation after 6 hours, and were warming up to-35 ℃, kept 3 hours; Be warming up to-30 ℃, kept 6 hours; Be warming up to-20 ℃, kept 6 hours; Be warming up to-10 ℃, kept 10 hours; Be warming up to 0 ℃, kept 2 hours; Be warming up to 10 ℃, kept 2 hours; Be warming up to 20 ℃, kept 2 hours; Be warming up to 30 ℃, kept 2 hours, promptly get lyophilized injectable powder.
9, according to the preparation method of the compound formulation of notoginseng of claim 5 or 6 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: get Radix Notoginseng extract, Radix Astragali extract, add water for injection, stir evenly, cold preservation filters, filtrate adds 0.2% active carbon, boils 30 minutes, puts cold, be filtered to clear and bright, with 10%NaOH adjust pH 5.5～7.5, through the filtering with microporous membrane of 0.25～0.45 μ m, spray drying, packing promptly gets injectable powder.
10, according to the preparation method of the compound formulation of notoginseng of claim 5 or 6 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: get Radix Notoginseng extract, Radix Astragali extract, add water for injection, add 0.2% active carbon, boiled 30 minutes, and put coldly, be filtered to clear and bright, with 10%NaOH adjust pH 5.5～7.5, benefit adds to the full amount of water for injection, through the filtering with microporous membrane of 0.25～0.45 μ m, fill, sterilized 30 minutes, and promptly got injection for 115 ℃.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410040764 CN1634241A (en) | 2004-09-24 | 2004-09-24 | Compound formulation of notoginseng for treating cardiovascular and cerebrovascular diseases and its preparing process |
| CN 200510200552 CN1762401A (en) | 2004-09-24 | 2005-09-22 | Compound formulation of notoginseng for treating cardiovascular and cerebrovascular diseases, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410040764 CN1634241A (en) | 2004-09-24 | 2004-09-24 | Compound formulation of notoginseng for treating cardiovascular and cerebrovascular diseases and its preparing process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1634241A true CN1634241A (en) | 2005-07-06 |
Family
ID=34845857
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410040764 Pending CN1634241A (en) | 2004-09-24 | 2004-09-24 | Compound formulation of notoginseng for treating cardiovascular and cerebrovascular diseases and its preparing process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1634241A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100457129C (en) * | 2005-08-15 | 2009-02-04 | 黑龙江省珍宝岛制药有限公司 | Preparation of Shuxiening injection, technique and adaptive disease |
| CN104147127A (en) * | 2014-07-25 | 2014-11-19 | 黑龙江中医药大学 | Traditional Chinese medicinal composition for treating malignant tumors, as well as preparation method and application thereof |
| CN108236677A (en) * | 2016-12-23 | 2018-07-03 | 北京济全生物科技有限公司 | A kind of Chinese medicine preparation and preparation method for treating cerebrovascular disease |
| CN114732848A (en) * | 2022-04-29 | 2022-07-12 | 浙江维康药业股份有限公司 | Application of traditional Chinese medicine composition in preparation of medicine for preventing and treating Alzheimer disease |
-
2004
- 2004-09-24 CN CN 200410040764 patent/CN1634241A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100457129C (en) * | 2005-08-15 | 2009-02-04 | 黑龙江省珍宝岛制药有限公司 | Preparation of Shuxiening injection, technique and adaptive disease |
| CN104147127A (en) * | 2014-07-25 | 2014-11-19 | 黑龙江中医药大学 | Traditional Chinese medicinal composition for treating malignant tumors, as well as preparation method and application thereof |
| CN104147127B (en) * | 2014-07-25 | 2019-09-27 | 黑龙江中医药大学 | A traditional Chinese medicine composition for treating malignant tumors and its preparation method and application |
| CN108236677A (en) * | 2016-12-23 | 2018-07-03 | 北京济全生物科技有限公司 | A kind of Chinese medicine preparation and preparation method for treating cerebrovascular disease |
| CN114732848A (en) * | 2022-04-29 | 2022-07-12 | 浙江维康药业股份有限公司 | Application of traditional Chinese medicine composition in preparation of medicine for preventing and treating Alzheimer disease |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1839996A (en) | Chinese traditional medicine compound preparation for treating chronic hepatiosis and preparation method thereof | |
| CN1229324C (en) | Extraction process of tanshin general phenolic acid and its prepn and use | |
| CN100345558C (en) | Extract product of general flavone of kudzuvine root, preparation method and application | |
| CN1762401A (en) | Compound formulation of notoginseng for treating cardiovascular and cerebrovascular diseases, preparation method and application thereof | |
| CN1634241A (en) | Compound formulation of notoginseng for treating cardiovascular and cerebrovascular diseases and its preparing process | |
| CN1631902A (en) | A kind of angelica polysaccharide and its preparation method and application | |
| CN1272026C (en) | Medicinal composition for treating cardiocerebral vasculr disease and its preparing method | |
| CN101036707A (en) | Pill for easing heart and the method for preparing the same | |
| CN1150918C (en) | Medicine containing active components of Panax japonicum root and preparing process thereof | |
| CN1634246A (en) | Compound formulation of breviscapine and asarum herb for treating cardiovascular and cerebrovascular diseases and its preparing process | |
| CN1291727C (en) | Chinese medicinal composition for treating cardiovascular disease, preparation and use thereof | |
| CN1278698C (en) | Freeze dried injection of seeding of autumnal sowthistle-leaf ixeris and preparation method thereof | |
| CN1557403A (en) | Medicine for treating angiocardiopathy and cerebrovascular disease and its preparing method | |
| CN1291733C (en) | Chinese medicine composition for treating cardiac and cerebral vascular diseases and its prepn process | |
| CN1799602A (en) | Qi-invigorating, yin-nourishing medicinal pills and preparation method thereof | |
| CN1602949A (en) | Compound capsule for treating meridian wind-phlegm stasis in stroke and preparation method thereof | |
| CN1795901A (en) | Medication for removing toxic heat, eliminating wetness and treating jaundice | |
| CN1660284A (en) | A compound preparation of notoginseng and safflower for treating cardiovascular and cerebrovascular diseases | |
| CN108743654B (en) | A kind of traditional Chinese medicine composition for treating ischemic heart disease and its preparation method and application | |
| CN1899385A (en) | Process for preparing Chinese medicine compound injection for treating chronic renal failure and use | |
| CN1634254A (en) | Compound formulation of astragalus root for treating cardiovascular and cerebrovascular diseases and its preparing process | |
| CN101073598A (en) | Medicinal composition for treating cardiovascular and cerebrovascular disease and its preparation | |
| CN101077364A (en) | Traditional Chinese medicine composition for treating cardio cerebrovasculer disease and its preparations and preparation method | |
| CN1596954A (en) | Red ginseng and ophiopogon root preparation and its making method | |
| CN1544021A (en) | Chinese traditional medicine preparation Qishenmai for treating coronary heart disease and angina pectoris and its preparing process |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |