CN106854190A - A kind of new Andrographolide compound and its pharmaceutical composition - Google Patents
A kind of new Andrographolide compound and its pharmaceutical composition Download PDFInfo
- Publication number
- CN106854190A CN106854190A CN201611014703.5A CN201611014703A CN106854190A CN 106854190 A CN106854190 A CN 106854190A CN 201611014703 A CN201611014703 A CN 201611014703A CN 106854190 A CN106854190 A CN 106854190A
- Authority
- CN
- China
- Prior art keywords
- andrographolide
- compound
- pharmaceutical composition
- speed
- preparation
- 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
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 title claims abstract description 73
- -1 Andrographolide compound Chemical class 0.000 title claims abstract description 53
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 34
- 239000007924 injection Substances 0.000 claims abstract description 39
- 238000002347 injection Methods 0.000 claims abstract description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000000843 powder Substances 0.000 claims abstract description 15
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 12
- 229940069338 potassium sorbate Drugs 0.000 claims abstract description 12
- 235000010241 potassium sorbate Nutrition 0.000 claims abstract description 12
- 239000004302 potassium sorbate Substances 0.000 claims abstract description 12
- 238000009472 formulation Methods 0.000 claims abstract description 11
- 238000004108 freeze drying Methods 0.000 claims abstract description 10
- 238000005259 measurement Methods 0.000 claims abstract description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 7
- 239000008215 water for injection Substances 0.000 claims abstract description 7
- 230000005260 alpha ray Effects 0.000 claims abstract description 6
- 239000013078 crystal Substances 0.000 claims abstract description 3
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 claims description 27
- 238000002360 preparation method Methods 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- 238000005086 pumping Methods 0.000 claims description 18
- 238000010792 warming Methods 0.000 claims description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 9
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 238000000967 suction filtration Methods 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 229910017488 Cu K Inorganic materials 0.000 claims description 5
- 229910017541 Cu-K Inorganic materials 0.000 claims description 5
- 238000010521 absorption reaction Methods 0.000 claims description 5
- 238000005261 decarburization Methods 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000012467 final product Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- YTHKMAIVPFVDNU-GPTWTFMPSA-N 4-[[(1r,2r,4ar,5r,8as)-2-(3-carboxypropanoyloxy)-1,4a-dimethyl-6-methylidene-5-[(e)-2-(5-oxo-2h-furan-4-yl)ethenyl]-3,4,5,7,8,8a-hexahydro-2h-naphthalen-1-yl]methoxy]-4-oxobutanoic acid Chemical compound C(/[C@@H]1C(=C)CC[C@H]2[C@@]1(C)CC[C@H]([C@]2(COC(=O)CCC(O)=O)C)OC(=O)CCC(O)=O)=C\C1=CCOC1=O YTHKMAIVPFVDNU-GPTWTFMPSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012982 microporous membrane Substances 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims description 2
- 230000000857 drug effect Effects 0.000 abstract description 8
- 238000005516 engineering process Methods 0.000 abstract description 5
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 abstract description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 23
- 230000000052 comparative effect Effects 0.000 description 17
- 230000036760 body temperature Effects 0.000 description 13
- 239000003814 drug Substances 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 11
- 239000002158 endotoxin Substances 0.000 description 10
- 229920006008 lipopolysaccharide Polymers 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 8
- 230000008859 change Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 3
- XMJAJFVLHDIEHF-UHFFFAOYSA-N 14-deoxy-11, 12-didehydroandrographolide Natural products OCC1(C)C(O)CCC2(C)C1CCC(=C)C2C=CC1=CCOC1=O XMJAJFVLHDIEHF-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 102000003777 Interleukin-1 beta Human genes 0.000 description 3
- 108090000193 Interleukin-1 beta Proteins 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- XMJAJFVLHDIEHF-YSDSKTICSA-N dehydroandrographolide Natural products C([C@@H]1C(=C)CC[C@H]2[C@@]1(C)CC[C@@H](O)[C@]2(CO)C)=CC1=CCOC1=O XMJAJFVLHDIEHF-YSDSKTICSA-N 0.000 description 3
- 125000005909 ethyl alcohol group Chemical group 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 210000003016 hypothalamus Anatomy 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 210000004404 adrenal cortex Anatomy 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 2
- 229960000258 corticotropin Drugs 0.000 description 2
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 2
- 229960002986 dinoprostone Drugs 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 102100037355 Chromosome alignment-maintaining phosphoprotein 1 Human genes 0.000 description 1
- 101000741320 Homo sapiens Cathelicidin antimicrobial peptide Proteins 0.000 description 1
- 101000880066 Homo sapiens Chromosome alignment-maintaining phosphoprotein 1 Proteins 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241001113283 Respirovirus Species 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002390 adhesive tape Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 210000003552 inferior colliculi Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000029219 regulation of pH Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology field, specifically, it is related to a kind of new Andrographolide compound and its pharmaceutical composition.Wherein, the new Andrographolide compound is crystal, and being 7.3 °, 9.6 °, 12.0 °, 13.4 °, 15.9 °, 17.5 °, 18.0 °, 19.8 °, 23.4 °, 23.8 °, 24.6 °, 27.1 ° in 2 θ using characteristic peak in the X ray powder diffraction patterns that Cu K alpha ray measurements are obtained shows.Described pharmaceutical composition includes new Andrographolide compound, glutamine, potassium sorbate and water for injection, and the formulation of pharmaceutical composition is freeze drying powder injection, and more preferably, drug effect is more superior for the 'Yanhuning ' frozen-dried powder injection stability obtained by the present invention.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically, it is related to a kind of new Andrographolide compound and its drug regimen
Thing.
Background technology
Scorching coloured glaze is peaceful, and chemical name is:14- deshydroxy -11, dehydrogenation andrographolide -3 of 12- bis-, 19- disuccinic acid half ester potassium
Sodium salt-hydrate, molecular formula is：C28H34KNaO10·H2O.Andrographolide is that the diterpene compound extracted from Chinese medicine Herba Andrographitis is worn
Heart lotus lactone through esterification, dehydration, the PSDS that is made into salt, with anti-inflammation,
It is clearing heat and detoxicating, promote adrenal cortex function and sedation, be one of common drug in current tcm emergency.
Andrographolide can suppress early stage capillary permeability and increase to ooze out oedema with inflammatory, can specifically excited hypophysis-
Adrenal cortex function, promotes ACTH releases, increases the biosynthesis of ACTH in anterior pituitary；In vitro have inactivated adenovirus,
The effect of various viruses such as influenza virus, Respirovirus.In practice, andrographolide not only has directly to some viruses and bacterium
Killing action, and defence and resistivity of the human body to disease can be improved, the various bacteriums of complete treatment and virus are to human body
The damage for causing.
Due to there is bridge shape conjugated structure, and α, β unsaturated lactone key in andrographolide molecular structure, therefore, its stabilization
Property is poor.When pharmaceutical preparation is prepared into, in preparing, storing and use each stage, andrographolide is oxidizable, so as to lead
Cause medicine to go bad, and then influence curative effect of medication, but also the generation of some adverse reactions can be caused during Clinical practice, from
And had a strong impact on the security of medication.
Prior art is more by adding auxiliary material to improve preparation stability in preparation, such as adding excipient, stabilization
Agent etc..But found in actual application, although the stability of obtained freeze-drying preparation is improved to a certain extent, but by
The consumption of auxiliary material is excessive in its prescription, causes the medicinal effects of powder-injection general, and holding time rear stability long still can
It is remarkably decreased.In addition the addition of auxiliary material increases the probability of adverse reaction appearance, and the species and consumption of auxiliary material equally can also influence
The quality of preparation, so as to limit its application.
In view of this, it is special to propose the present invention.
The content of the invention
It is an object of the invention to provide a kind of new Andrographolide compound.
To achieve the above object, the present invention comprises the following steps：
A kind of new Andrographolide compound as shown in formula (I)
The Andrographolide compound is crystal, uses feature in the X-ray powder diffraction figure that Cu-K alpha ray measurements are obtained
Peak is 7.3 °, 9.6 °, 12.0 °, 13.4 °, 15.9 °, 17.5 °, 18.0 °, 19.8 °, 23.4 °, 23.8 °, 24.6 °, 27.1 ° in 2 θ
Display.
The bioavilability of the Andrographolide compound obtained by the present invention is high, based on the Andrographolide compound obtained by the present invention
Pharmaceutical composition drug effect is more superior obtained in medicine.
The fusing point of the Andrographolide compound is 200~205 DEG C.
The preparation method of the Andrographolide compound comprises the following steps：
(1) it is 7 potassium dehydroandrographolide succinate to be dissolved in into volume ratio:In 1 water and the mixed solution of absolute ethyl alcohol, potassium dehydroandrographolide succinate and water and anhydrous
The amount ratio of the mixed solution of ethanol is 1g:4ml, obtains solution 1；
Add the sodium bicarbonate of 0.5mol/L water-soluble to the speed stirring in solution 1 with 20~30mL/min at (2) 20 DEG C
Liquid, adjusts pH to 6.5~7.0, is then warmed up to after 25~30 DEG C with the speed of 0.2~0.3 DEG C/min and adds activated carbon, continues
Stirring reaction 1~2 hour, suction filtration collects filtrate, obtains solution 2；
(3) 3~5 DEG C will be down at a temperature of solution 2 with the speed of 0.2~0.3 DEG C/min, stop stirring, stand growing the grain 5
~6 hours, suction filtration, filter cake absolute ethanol washing was dried 4 hours at 70~80 DEG C, obtains Andrographolide compound.
Another object of the present invention is to provide a kind of andrographolide pharmaceutical composition including above-mentioned Andrographolide compound, institute
The formulation of andrographolide pharmaceutical composition is stated for 'Yanhuning ' frozen-dried powder injection, including：
Glutamine has the effectiveness of enhance immunity, contributes to the recovery of patient, meanwhile, the paddy that glutamine is changed into
The sweet peptide of Guang has oxidation resistant effect, and it passes through to eliminate the effect that free radical reaches anti-inflammatory, so that the drug effect of pharmaceutical composition
It is more superior.
Potassium sorbate has oxidation resistant effect, is conducive to improving the stability of medicine, under control active constituent content
The increase of drop and other impurity substances contents, so as to improve the utilization rate of active ingredient, and then strengthens the drug effect of pharmaceutical composition.
The present inventor has found that the synergy of glutamine and potassium sorbate drastically increases pharmaceutical composition through experiment
Stability and drug effect.
Present invention also offers the preparation method of above-mentioned andrographolide pharmaceutical composition, the preparation method includes following step
Suddenly：
(1) injection bottle and plug cleaned respectively, sterilized；
(2) to the injection of the Andrographolide compound, potassium sorbate and recipe quantity 60% that recipe quantity is added in material-compound tank
Water, pH is adjusted to 6.5~7.0；
(3) glutamine of recipe quantity is added, after stirring and dissolving, the water for injection of addition adjusts pH to recipe quantity full dose
Save to 6.5~7.5；
(4) needle-use activated carbon is added, decarburization is filtered after absorption, it is degerming with filtering with microporous membrane after intermediate passed examination；
(5) it is filling in injection bottle and to press plug, andrographolide pharmaceutical composition is obtained final product after freeze-drying.
Before glutamine is added, the present invention has first carried out pH regulations to mixed solution, so that the pH of mixed solution is adding
Enter after glutamine still in preferred range, finally give the good andrographolide pharmaceutical composition of quality.
PH adjusting agent used is sodium bicarbonate.
The middle physical examination criterion of acceptability is pH=7.0~7.5.
Described freeze-drying specifically includes following steps：
(1) temperature that will be equipped with the injection bottle of liquid is down to -40 DEG C and keeps 2~3h；
(2) vacuum pumping is carried out, temperature -10 DEG C is warming up to the speed less than 19 DEG C/h, then with 1~27
DEG C/h speed be warming up to 40 DEG C, stop vacuum pumping after being kept for 2~11 hours.
Preferably, described freeze-drying specifically includes following steps：
(1) temperature that will be equipped with the injection bottle of liquid is down to -40 DEG C and keeps 3h；
(2) vacuum pumping is carried out, temperature -10 DEG C is warming up to 10~19 DEG C/h of speed, then with 18~27
DEG C/h speed be warming up to 40 DEG C, stop vacuum pumping after being kept for 5~10 hours.
It is furthermore preferred that described freeze-drying specifically includes following steps：
(1) temperature that will be equipped with the injection bottle of liquid is down to -40 DEG C and keeps 3h；
(2) vacuum pumping is carried out, temperature is warming up to -10 DEG C with 15 DEG C/h of speed, then with 22 DEG C/h
Speed be warming up to 40 DEG C, stop vacuum pumping after being kept for 8 hours.
Compared with prior art, the present invention has the advantages that：
1st, the present invention uses the Andrographolide compound of gained as bulk drug, and by glutamine and the association of potassium sorbate
Same-action, makes final obtained 'Yanhuning ' frozen-dried powder injection have more preferable stability and more superior drug effect.
2nd, there is preferable stability using 'Yanhuning ' frozen-dried powder injection obtained in process of the present invention, so that
Conscientiously the drug safety of patient is ensure that, while also having more superior drug effect.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction pattern of Andrographolide compound of the invention.
Specific embodiment
To make the purpose, technical scheme and advantage of the embodiment of the present invention clearer, below to the technical side in embodiment
Case is clearly and completely described, and following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.
The preparation of the new Andrographolide compound of embodiment 1
(1) 5g potassium dehydroandrographolide succinates are dissolved in the mixed solution of 17.5ml water and 2.5ml absolute ethyl alcohols, obtain solution 1；
The aqueous sodium bicarbonate of 0.5mol/L is added to the speed stirring in solution 1 with 20mL/min at (2) 20 DEG C, is adjusted
Section pH to 6.5, is then warmed up to the speed of 0.2 DEG C/min and activated carbon is added after 25 DEG C, continues stirring reaction 1 hour, suction filtration,
Filtrate is collected, solution 2 is obtained；
(3) 3 DEG C will be down at a temperature of solution 2 with the speed of 0.2 DEG C/min, stop stirring, stand growing the grain 5 hours, taken out
Filter, filter cake absolute ethanol washing is dried 4 hours at 70 DEG C, obtains Andrographolide compound.
Characteristic peak is in 2 θ in the X-ray powder diffraction figure that the Andrographolide compound is obtained using Cu-K alpha ray measurements
7.3 °, 9.6 °, 12.0 °, 13.4 °, 15.9 °, 17.5 °, 18.0 °, 19.8 °, 23.4 °, 23.8 °, 24.6 °, 27.1 ° of displays, melt
Point is 200 DEG C.
The preparation of the new Andrographolide compound of embodiment 2
(1) 5g potassium dehydroandrographolide succinates are dissolved in the mixed solution of 17.5ml water and 2.5ml absolute ethyl alcohols, obtain solution 1；
The aqueous sodium bicarbonate of 0.5mol/L is added to the speed stirring in solution 1 with 30mL/min at (2) 20 DEG C, is adjusted
Section pH to 7.0, is then warmed up to the speed of 0.3 DEG C/min and activated carbon is added after 30 DEG C, continues stirring reaction 2 hours, suction filtration,
Filtrate is collected, solution 2 is obtained；
(3) 5 DEG C will be down at a temperature of solution 2 with the speed of 0.3 DEG C/min, stop stirring, stand growing the grain 6 hours, taken out
Filter, filter cake absolute ethanol washing is dried 4 hours at 80 DEG C, obtains Andrographolide compound.
The Andrographolide compound is consistent with embodiment 1 using the X-ray powder diffraction figure that Cu-K alpha ray measurements are obtained,
Fusing point is 202 DEG C.
The preparation of the new Andrographolide compound of embodiment 3
(1) 5g potassium dehydroandrographolide succinates are dissolved in the mixed solution of 17.5ml water and 2.5ml absolute ethyl alcohols, obtain solution 1；
The aqueous sodium bicarbonate of 0.5mol/L is added to the speed stirring in solution 1 with 20mL/min at (2) 20 DEG C, is adjusted
Section pH to 7.0, is then warmed up to the speed of 0.3 DEG C/min and activated carbon is added after 25 DEG C, continues stirring reaction 2 hours, suction filtration,
Filtrate is collected, solution 2 is obtained；
(3) 5 DEG C will be down at a temperature of solution 2 with the speed of 0.2 DEG C/min, stop stirring, stand growing the grain 5 hours, taken out
Filter, filter cake absolute ethanol washing is dried 4 hours at 80 DEG C, obtains Andrographolide compound.
The Andrographolide compound is consistent with embodiment 1 using the X-ray powder diffraction figure that Cu-K alpha ray measurements are obtained,
Fusing point is 202 DEG C.
The preparation of the 'Yanhuning ' frozen-dried powder injection of example of formulations 1
Prescription：Specification：40mg
Preparation method：
(1) injection bottle and plug cleaned respectively, sterilized；
(2) to the injection of the Andrographolide compound, potassium sorbate and recipe quantity 60% that recipe quantity is added in material-compound tank
Water, is adjusted to 7.0 pH with sodium acid carbonate；
(3) glutamine of recipe quantity is added, after stirring and dissolving, the water for injection of addition uses carbonic acid to recipe quantity full dose
Hydrogen sodium adjusts to 6.8 pH；
(4) needle-use activated carbon is added, decarburization is filtered after absorption, the pH=7.0 of intermediate passed examination uses miillpore filter mistake
Filter bacterium；
(5) filling in injection bottle and to press plug, the temperature that will be equipped with the injection bottle of liquid is down to -40 DEG C and is protected
Hold 3h；
(6) vacuum pumping is carried out, temperature is warming up to -10 DEG C with 15 DEG C/h of speed, then with 22 DEG C/h
Speed be warming up to 40 DEG C, stop vacuum pumping after being kept for 8 hours, obtain final product andrographolide pharmaceutical composition.
The preparation of the 'Yanhuning ' frozen-dried powder injection of example of formulations 2
Prescription：Specification：80mg
Preparation method：
(1) injection bottle and plug cleaned respectively, sterilized；
(2) to the injection of the Andrographolide compound, potassium sorbate and recipe quantity 60% that recipe quantity is added in material-compound tank
Water, is adjusted to 6.5 pH with sodium acid carbonate；
(3) glutamine of recipe quantity is added, after stirring and dissolving, the water for injection of addition uses carbonic acid to recipe quantity full dose
Hydrogen sodium adjusts to 7.0 pH；
(4) needle-use activated carbon is added, decarburization is filtered after absorption, the pH=7.2 of intermediate passed examination uses miillpore filter mistake
Filter bacterium；
(5) filling in injection bottle and to press plug, the temperature that will be equipped with the injection bottle of liquid is down to -40 DEG C and is protected
Hold 2h；
(6) vacuum pumping is carried out, temperature is warming up to -10 DEG C with 19 DEG C/h of speed, then with 27 DEG C/h
Speed be warming up to 40 DEG C, stop vacuum pumping after being kept for 10 hours, obtain final product andrographolide pharmaceutical composition.
The preparation of the 'Yanhuning ' frozen-dried powder injection of example of formulations 3
Prescription：Specification：0.2g
Preparation method：
(1) injection bottle and plug cleaned respectively, sterilized；
(2) to the injection of the Andrographolide compound, potassium sorbate and recipe quantity 60% that recipe quantity is added in material-compound tank
Water, is adjusted to 6.5 pH with sodium acid carbonate；
(3) glutamine of recipe quantity is added, after stirring and dissolving, the water for injection of addition uses carbonic acid to recipe quantity full dose
Hydrogen sodium adjusts to 6.5 pH；
(4) needle-use activated carbon is added, decarburization is filtered after absorption, the pH=7.0 of intermediate passed examination uses miillpore filter mistake
Filter bacterium；
(5) filling in injection bottle and to press plug, the temperature that will be equipped with the injection bottle of liquid is down to -40 DEG C and is protected
Hold 3h；
(6) vacuum pumping is carried out, temperature is warming up to -10 DEG C with 10 DEG C/h of speed, then with 18 DEG C/h
Speed be warming up to 40 DEG C, stop vacuum pumping after being kept for 5 hours, obtain final product andrographolide pharmaceutical composition.
Comparative example 1
Other conditions are identical with example of formulations 1, differ only in Andrographolide compound and change commercially available andrographolide bulk pharmaceutical into.
Comparative example 2
Other conditions are identical with example of formulations 1, to differ only in and be added without potassium sorbate in step (2).
Comparative example 3
Other conditions are identical with example of formulations 1, to differ only in and be added without glutamine in step (3).
Comparative example 4
It is prepared by the process that embodiment 1 is provided in the Chinese patent according to number of patent application by 201110264481.3
Andrographolide compound and andrographolide pharmaceutical composition.
Comparative example 5
It is prepared by the process that embodiment 1 is provided in the Chinese patent according to number of patent application by 201410057789.4
Andrographolide compound and andrographolide pharmaceutical composition.
The stability test of test example 1
1st, compound stability experiment
This test example has investigated embodiment 1,2,3, the scorching amber of commercially available andrographolide bulk pharmaceutical and the gained of comparative example 4,5
The stability of Ninghua compound, the results are shown in Table 1.
Table 1
As shown in Table 1, with commercially available andrographolide bulk pharmaceutical and compound phase ratio obtained in comparative example 4,5, obtained by the present invention
The stability of Andrographolide compound is more preferable.
2nd, pharmaceutical composition stability test
This test example has investigated the andrographolide pharmaceutical composition of example of formulations 1,2,3 and the gained of comparative example 1,2,3,4,5
Stability, the results are shown in Table 2.
Table 2
As shown in Table 2, the stability of the andrographolide compound obtained by the present invention is better than pharmaceutical composition obtained in comparative example 1,
Understand, the Andrographolide compound obtained by the present invention plays a significant role in terms of the stability of pharmaceutical composition；Gained of the invention
Andrographolide compound stability be better than pharmaceutical composition obtained in comparative example 2,3, it is known that, glutamine and potassium sorbate are in medicine
The stability aspect of compositions plays a significant role；Meanwhile, the stability of the andrographolide pharmaceutical composition obtained by the present invention is excellent
In pharmaceutical composition obtained in comparative example 4,5.
The animal experiment of test example 2
1st, experiment material
Rabbit, 2.5~3.5kg of weight feeds in temperature (22 ± 2) DEG C, the experimental situation of relative humidity 50%~75%
Support.The operation of adaptability thermometric, 1 time/d are implemented to rabbit.Water is can't help in 10h fasting before experiment.Vaseline is applied on thermometric instrument probe, is inserted
Enter a rabbit rectum 6cm (can be in 6cm immobilizations with adhesive tape, it is ensured that each insertion depth is consistent), body temperature value is recorded after stabilization 1h.
2nd, experimental procedure
2.1 pairs of influences of lipopolysaccharides fever model rabbit body temperature
The experiment same day 9:00, survey rabbit body temperature 3 times per minor tick 30min before modeling administration, its average value is taken as base
Plinth body temperature, if wherein thering is body temperature to be eliminated beyond 38.0 DEG C or animal of the adjacent difference of body temperature twice more than 0.4 DEG C.It is qualified to filter out
Rabbit 48, is randomly divided into 8 groups, every group 6, respectively：
Control group (0.9% sodium chloride injection 10mL/kg)；
Model group (lipopolysaccharides 10EU/kg)；
Test I group of ('Yanhuning ' frozen-dried powder injection 80mg/ obtained in lipopolysaccharides 10EU/kg+ invention formulations embodiment 1
kg)；
Test II group ('Yanhuning ' frozen-dried powder injection 80mg/kg obtained in lipopolysaccharides 10EU/kg+ comparative examples 1 of the present invention)；
Test III group ('Yanhuning ' frozen-dried powder injection 80mg/kg obtained in lipopolysaccharides 10EU/kg+ comparative examples 2 of the present invention)；
Test IV group ('Yanhuning ' frozen-dried powder injection 80mg/kg obtained in lipopolysaccharides 10EU/kg+ comparative examples 3 of the present invention)；
Test V group ('Yanhuning ' frozen-dried powder injection 80mg/kg obtained in lipopolysaccharides 10EU/kg+ comparative examples 4 of the present invention)；
Test VI group ('Yanhuning ' frozen-dried powder injection 80mg/kg obtained in lipopolysaccharides 10EU/kg+ comparative examples 5 of the present invention)；
In 1 after administration, 2,3,4h monitoring record each group rabbit body temperatures, calculate each group rabbit each monitoring point liter temperature value
(actual measurement body temperature-basal body temperature), draws average heating curve.
The influence of 2.2 pairs of lipopolysaccharides heating rabbit anteserum cell factors and maincenter intensification mediator
After administration 4h detection rabbit body temperatures, Culling heart blood immediately, 3000r/min centrifugation 10min, isolate serum be placed in-
20 DEG C of Refrigerator stores are to be measured.Full brain is taken out rapidly, and precooling PBS solution is rinsed 2~3 times and washes away bloodstain, is operated on ice bath regarding friendship
Thalamus is removed between fork and tuberculum cinereum, inferior colliculus cerebral tissue adds physiological saline to be prepared into 10% brain homogenate, 3000r/min centrifugations
10min, taking supernatant, to be placed in -20 DEG C of Refrigerator stores to be measured.Illustrated by kit, determine serum in IL-1 β, TNF-α, IL-6,
CAMP, PGE2 in cAMP, PGE2 and hypothalamus.
3rd, statistical method
Counted using the softwares of SPSS 17.0, data withRepresent, one-way analysis of variance is carried out between each group.
4th, experimental result
Each group rabbit body temperature variation tendency after 4.1 administrations
Each group rabbit body temperature variation tendency is shown in Table 3.
Table 3
Compare with control group：aP ＜ 0.01；Compare with model group：bP ＜ 0.05,cP ＜ 0.01
Model group rabbit body temperature is significantly raised compared with control group, and (3h) rises temperature value and reach 1.0 DEG C during highest, hints model into
Work(.1h is have cooling effect to each administration group upon administration.Compare with model group, I~VI group of experiment can significantly press down in 2~4h of administration
Lipopolysaccharides fever model rabbit body temperature processed is raised.
4.2 administration after generate heat rabbit anteserum in cell factor change
The change of cell factor is shown in Table 4 in each group rabbit anteserum.
Table 4
Compare with control group：aP ＜ 0.01；Compare with model group：bP ＜ 0.05,cP ＜ 0.01
After modeling administration 4h, cell factor (TNF-α, IL-1 β, IL-6, cAMP, PGE in model group rabbit anteserum2) level
Significantly raised compared with control group.Compare with model group, I~VI group of experiment is to cell factor in rabbit anteserum (TNF-α, IL-1 β) water
It is flat to have no significant effect；I~VI group of experiment can substantially reduce cell factor (IL-6, cAMP, PGE in rabbit anteserum2) level.
4.3 administration after generate heat rabbit hypothalamus in intensification mediator change
The change of intensification mediator is shown in Table 5 in each group rabbit hypothalamus.
Table 5
Compare with control group：aP ＜ 0.01；Compare with model group：cP ＜ 0.01
After modeling administration 4h, intensification mediator (cAMP, PGE in model group rabbit hypothalamus2) level significantly rises compared with control group
It is high.Compare with model group, I~VI group of experiment can substantially reduce cAMP and PGE in heating rabbit hypothalamus2Level.
Contrasted by the data in table 3~5, it is known that, the present invention obtained by Andrographolide compound, glutamine and
Potassium sorbate plays a significant role in terms of the drug effect of pharmaceutical composition；Meanwhile, the medicine of andrographolide pharmaceutical composition of the invention
Pharmaceutical composition of the effect better than the gained of comparative example 4,5.
The above is only presently preferred embodiments of the present invention, and any formal limitation is not made to the present invention, though
So the present invention is disclosed above with preferred embodiment, but is not limited to the present invention, any to be familiar with technology people of the invention
Member without departing from the scope of the present invention, when using the technology contents of above-mentioned prompting make it is a little change or be modified to
The Equivalent embodiments of equivalent variations, as long as being the content without departing from technical solution of the present invention, according to technical spirit pair of the invention
Any simple modification, equivalent variations and modification that above example is made, still fall within the range of the present invention program.
Claims (10)
1. new Andrographolide compound of the one kind as shown in formula (I)
Characterized in that, the Andrographolide compound is crystal, the X-ray powder diffraction figure obtained using Cu-K alpha ray measurements
Middle characteristic peak 2 θ be 7.3 °, 9.6 °, 12.0 °, 13.4 °, 15.9 °, 17.5 °, 18.0 °, 19.8 °, 23.4 °, 23.8 °,
24.6 °, 27.1 ° of displays.
2. a kind of new Andrographolide compound according to claim 1, it is characterised in that the Andrographolide compound it is molten
Point is 200~205 DEG C.
3. the preparation method of a kind of new Andrographolide compound described in a kind of claim 1 or 2, it is characterised in that described
Preparation method comprises the following steps：
(1) it is 7 potassium dehydroandrographolide succinate to be dissolved in into volume ratio:In 1 water and the mixed solution of absolute ethyl alcohol, potassium dehydroandrographolide succinate and water and absolute ethyl alcohol
Mixed solution amount ratio be 1g:4ml, obtains solution 1；
The aqueous sodium bicarbonate of 0.5mol/L is added to the speed stirring in solution 1 with 20~30mL/min at (2) 20 DEG C, is adjusted
Section pH to 6.5~7.0, adds activated carbon after being then warmed up to 25-30 DEG C with the speed of 0.2~0.3 DEG C/min, continue to stir anti-
Answer 1~2 hour, suction filtration, collect filtrate, obtain solution 2；
(3) 3~5 DEG C will be down at a temperature of solution 2 with the speed of 0.2~0.3 DEG C/min, stop stirring, stand growing the grain 5~6
Hour, suction filtration, filter cake absolute ethanol washing is dried 4 hours at 70~80 DEG C, obtains Andrographolide compound.
4. a kind of andrographolide pharmaceutical composition, it is characterised in that the andrographolide pharmaceutical composition is included described in claim 1 or 2
New Andrographolide compound, the formulation of the andrographolide pharmaceutical composition is 'Yanhuning ' frozen-dried powder injection, including：
5. a kind of preparation method of the andrographolide pharmaceutical composition described in claim 4, it is characterised in that the preparation method bag
Include following steps：
(1) injection bottle and plug cleaned respectively, sterilized；
(2) to the water for injection of the Andrographolide compound, potassium sorbate and recipe quantity 60% that recipe quantity is added in material-compound tank, will
PH is adjusted to 6.5~7.0；
(3) add the glutamine of recipe quantity, after stirring and dissolving, the water for injection of addition to recipe quantity full dose, by pH adjust to
6.5~7.5；
(4) needle-use activated carbon is added, decarburization is filtered after absorption, it is degerming with filtering with microporous membrane after intermediate passed examination；
(5) it is filling in injection bottle and to press plug, andrographolide pharmaceutical composition is obtained final product after freeze-drying.
6. preparation method according to claim 5, it is characterised in that pH adjusting agent used is sodium acid carbonate.
7. preparation method according to claim 5, it is characterised in that the middle physical examination criterion of acceptability be pH=7.0~
7.5。
8. preparation method according to claim 5, it is characterised in that described freeze-drying specifically includes following steps：
(1) temperature that will be equipped with the injection bottle of liquid is down to -40 DEG C and keeps 2~3h；
(2) carry out vacuum pumping, temperature be warming up to -10 DEG C with the speed less than 19 DEG C/h, then with 1~27 DEG C/it is small
When speed be warming up to 40 DEG C, stop vacuum pumping after being kept for 2~11 hours.
9. preparation method according to claim 5, it is characterised in that described freeze-drying specifically includes following steps：
(1) temperature that will be equipped with the injection bottle of liquid is down to -40 DEG C and keeps 3h；
(2) carry out vacuum pumping, temperature be warming up to -10 DEG C with 10~19 DEG C/h of speed, then with 18~27 DEG C/
The speed of hour is warming up to 40 DEG C, and vacuum pumping is stopped after being kept for 5~10 hours.
10. preparation method according to claim 5, it is characterised in that described freeze-drying specifically includes following steps：
(1) temperature that will be equipped with the injection bottle of liquid is down to -40 DEG C and keeps 3h；
(2) vacuum pumping is carried out, temperature is warming up to -10 DEG C with 15 DEG C/h of speed, then with 22 DEG C/h of speed
Degree is warming up to 40 DEG C, and vacuum pumping is stopped after being kept for 8 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611014703.5A CN106854190A (en) | 2016-11-18 | 2016-11-18 | A kind of new Andrographolide compound and its pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611014703.5A CN106854190A (en) | 2016-11-18 | 2016-11-18 | A kind of new Andrographolide compound and its pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106854190A true CN106854190A (en) | 2017-06-16 |
Family
ID=59126198
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611014703.5A Pending CN106854190A (en) | 2016-11-18 | 2016-11-18 | A kind of new Andrographolide compound and its pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106854190A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108658905A (en) * | 2018-04-25 | 2018-10-16 | 四川子仁制药有限公司 | A method of for reducing related substance in andrographolide bulk pharmaceutical finished product |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101260097A (en) * | 2008-04-18 | 2008-09-10 | 长春迈灵生物工程有限公司 | Technique for preparing potassium sodium dehydroandroandrographolide succinic by using potassium dehydroandrographolide succinate |
| CN102382082A (en) * | 2011-09-07 | 2012-03-21 | 周晓东 | Novel potassium sodium dehydroandroan drographolide succinate compound and drug combination thereof |
| CN102603684A (en) * | 2012-01-19 | 2012-07-25 | 黑龙江珍宝岛药业股份有限公司 | Sterile andrographolide and preparation method thereof |
| CN102643255A (en) * | 2012-03-27 | 2012-08-22 | 黄金秀 | Andrographolide compound |
| CN102885775A (en) * | 2011-07-19 | 2013-01-23 | 重庆莱美药业股份有限公司 | Andrographolide sterile powder and its preparation method |
-
2016
- 2016-11-18 CN CN201611014703.5A patent/CN106854190A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101260097A (en) * | 2008-04-18 | 2008-09-10 | 长春迈灵生物工程有限公司 | Technique for preparing potassium sodium dehydroandroandrographolide succinic by using potassium dehydroandrographolide succinate |
| CN102885775A (en) * | 2011-07-19 | 2013-01-23 | 重庆莱美药业股份有限公司 | Andrographolide sterile powder and its preparation method |
| CN102382082A (en) * | 2011-09-07 | 2012-03-21 | 周晓东 | Novel potassium sodium dehydroandroan drographolide succinate compound and drug combination thereof |
| CN102603684A (en) * | 2012-01-19 | 2012-07-25 | 黑龙江珍宝岛药业股份有限公司 | Sterile andrographolide and preparation method thereof |
| CN102643255A (en) * | 2012-03-27 | 2012-08-22 | 黄金秀 | Andrographolide compound |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108658905A (en) * | 2018-04-25 | 2018-10-16 | 四川子仁制药有限公司 | A method of for reducing related substance in andrographolide bulk pharmaceutical finished product |
| CN108658905B (en) * | 2018-04-25 | 2023-02-14 | 四川子仁制药有限公司 | Method for reducing related substances in potassium sodium dehydroandroan drographolide succinate raw material medicine finished product |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2925021T3 (en) | Acetylcholinesterase inhibitors for the treatment of dermatological conditions | |
| CN106659711A (en) | Durable preparation of an injectable of melatonin exhibiting long-term stability | |
| CN109111501A (en) | The indoles alcohol derivative of fatty acid/amino acid modification, synthesis, activity and application | |
| CN104784157A (en) | Stable Montelukast oral film preparation | |
| CN102716076B (en) | Ambroxol hydrochloride medicine combination for injection | |
| CN106854190A (en) | A kind of new Andrographolide compound and its pharmaceutical composition | |
| CN102600119A (en) | Pediatric acetaminophen composition | |
| CN110054606A (en) | A kind of dihydromyricetin-Halomine pharmaceutical co-crystals and preparation method | |
| CN110123920A (en) | A kind of oral quick-dissolving film preparation and preparation method thereof for treatment of insomnia patients | |
| CN109820839A (en) | It is a kind of medical defervescence plaster used and preparation method thereof | |
| EP3708153A1 (en) | Solution preparation for aerosol inhalation of carbocisteine, and preparation method therefor | |
| CN105030716B (en) | Caffeinum pharmaceutical combination and preparation method thereof | |
| CN101559046A (en) | Therapeutic action of micromolecule sugar alcohol composite on nasal disease | |
| CN107753439A (en) | A kind of hydrochloride for injection amiodarone and preparation method thereof | |
| CN100522167C (en) | Palonosetron injection and its powder injection preparation of salt receptable on medicine and its preparing method | |
| CN108324688B (en) | Rizatriptan benzoate in-situ gel nasal spray | |
| CN106632031A (en) | Dequalinium chloride crystal and buccal tablet thereof, and preparation method of buccal tablet | |
| CN106176691A (en) | A kind of molten membrane of escitalopram oxalate mouth and preparation method thereof | |
| CN105496954A (en) | Method for preparing injection of muscle relaxant rocuronium bromide | |
| CN102008461B (en) | A kind of ibuprofen drug composite for injection | |
| CN100358562C (en) | Tendril-leaved fritillary bulb loquat drop pills and preparation method thereof | |
| CN100358496C (en) | 'Xingnaojing' dripping pills for treating cephalitis and hepatic coma and preparation process thereof | |
| CN103393593B (en) | Pharmaceutical composition containing ambroxol hydrochloride and fructose | |
| CN103446211B (en) | A kind of Cynanchum Komarovii total alkaloids and its preparation method and application | |
| CN103585101B (en) | A kind of Norcantharidin sodium injection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170616 |
|
| RJ01 | Rejection of invention patent application after publication |