CN101195570B - Salt amino acid of ferulic acid - Google Patents
Salt amino acid of ferulic acid Download PDFInfo
- Publication number
- CN101195570B CN101195570B CN2007101970293A CN200710197029A CN101195570B CN 101195570 B CN101195570 B CN 101195570B CN 2007101970293 A CN2007101970293 A CN 2007101970293A CN 200710197029 A CN200710197029 A CN 200710197029A CN 101195570 B CN101195570 B CN 101195570B
- Authority
- CN
- China
- Prior art keywords
- salt
- acid
- injection
- ornithine
- amino acid
- 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.)
- Expired - Fee Related
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- -1 Salt amino acid Chemical class 0.000 title claims abstract description 39
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 title description 10
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 title 1
- 229940114124 ferulic acid Drugs 0.000 title 1
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 title 1
- 235000001785 ferulic acid Nutrition 0.000 title 1
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 title 1
- 239000002253 acid Substances 0.000 claims abstract description 86
- 238000002360 preparation method Methods 0.000 claims abstract description 44
- 239000003814 drug Substances 0.000 claims abstract description 23
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 8
- 208000026106 cerebrovascular disease Diseases 0.000 claims abstract description 8
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 8
- 238000002347 injection Methods 0.000 claims description 66
- 239000007924 injection Substances 0.000 claims description 66
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical class NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 41
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 6
- 229960003104 ornithine Drugs 0.000 claims description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 3
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- 229930195722 L-methionine Natural products 0.000 claims description 3
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- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 229930182817 methionine Natural products 0.000 claims description 2
- NCTHNHPAQAVBEB-WGCWOXMQSA-M sodium ferulate Chemical compound [Na+].COC1=CC(\C=C\C([O-])=O)=CC=C1O NCTHNHPAQAVBEB-WGCWOXMQSA-M 0.000 abstract description 18
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- ODKSFYDXXFIFQN-UHFFFAOYSA-M argininate Chemical compound [O-]C(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-M 0.000 abstract 1
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- 125000001176 L-lysyl group Chemical class [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C([H])([H])C([H])([H])C(N([H])[H])([H])[H] 0.000 description 30
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
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- QADGOPWTSNPYTK-UHFFFAOYSA-N 2-methoxyphenol;prop-2-enoic acid Chemical compound OC(=O)C=C.COC1=CC=CC=C1O QADGOPWTSNPYTK-UHFFFAOYSA-N 0.000 description 3
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- 235000014852 L-arginine Nutrition 0.000 description 3
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- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 2
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- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 2
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical class NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 description 2
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- ADYPXRFPBQGGAH-WVVAGBSPSA-N dihydroergotoxine Chemical compound CS(O)(=O)=O.C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C=3C=CC=C4NC=C(C=34)C2)C1)C)C1=CC=CC=C1 ADYPXRFPBQGGAH-WVVAGBSPSA-N 0.000 description 1
- 229940120500 dihydroergotoxine Drugs 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
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- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 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
- 229940095529 heparin calcium Drugs 0.000 description 1
- 150000004687 hexahydrates Chemical class 0.000 description 1
- 125000000487 histidyl group Chemical class [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 150000004686 pentahydrates Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000007965 phenolic acids Chemical class 0.000 description 1
- 229960004526 piracetam Drugs 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 150000004684 trihydrates Chemical class 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
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Abstract
The invention belongs to the medicinal technical field and relates to 4-hydroxy-3-methoxy phenylacrylic acid which is amino acid salt and hydrate of ferulaic acid and a method for preparation and application in the drug for treating cardiovascular and cerebrovascular disease. The experiment proves that the stability of amino acid salt of ferulaic acid and hydrate, especially for argininate, lysinate, ornithinate of ferulaic acid is improved obviously in contrast to sodium ferulate, which is more beneficial to store the drug and improves the security of clinical dosage.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to amino acid salts and hydrate thereof that 4-hydroxy 3-methoxybenzene vinylformic acid is forulic acid, and preparation method thereof and the purposes in the medicine of preparation treatment cardiovascular and cerebrovascular diseases.
2, background technology
Forulic acid (being 4-hydroxy 3-methoxybenzene vinylformic acid) is the ubiquitous a kind of phenolic acid of vegitabilia, seldom exists with free state in plant materials, and main and oligose, polyamines, lipid and polysaccharide form combined.Forulic acid is one of effective constituent of plurality of Chinese such as asafoetide, Ligusticum wallichii, Radix Angelicae Sinensis, rattletop, scouring rush.It has multiple pharmacological effect: 1) anti-oxidant and removing free radical effect; 2) anti thrombotic action; 3) reducing blood lipid; 4) prevent and treat coronary heart disease; 5) certain antibacterial and anti-inflammation functions is arranged; 6) anti-mutation and protective effect on cancer risk etc.Be widely used in the treatment of cardiovascular and cerebrovascular diseases clinically.
Forulic acid sodium salt commonly used clinically at present, but the stability of its sodium salt is very undesirable, and especially when making injection liquid, through placing, its content can descend rapidly, brings great inconvenience for production, storage, circulation and clinical application.
3, summary of the invention
The purpose of this invention is to provide a kind of amino acid salts, and its preparation method and the application in the medicine of preparation treatment cardiovascular and cerebrovascular diseases are provided with forulic acid of satisfactory stability.
In order to solve the problem of Sodium Ferulate poor stability, the inventor finds that through a large amount of screening operations the amino acid salts and the hydrate thereof of forulic acid can improve its stability greatly.
Technical scheme of the present invention is as follows:
Amino acid salts and hydrate thereof that to the invention provides a kind of 4-hydroxy 3-methoxybenzene vinylformic acid be forulic acid, amino acid salts wherein is an alkaline amino acid salt, is selected from arginic acid salt, lysine salt, Histidine salt or ornithine salt.
Be preferably: the arginic acid salt of forulic acid and hydrate thereof, arginine wherein is preferably the L-arginine, and structural formula is as follows:
Or: the lysine salt of forulic acid and hydrate thereof, Methionin wherein is preferably L-Methionin, and structural formula is as follows:
Or: the ornithine salt of forulic acid and hydrate thereof, ornithine wherein are preferably DL-ornithine or L-ornithine, and structural formula is as follows:
The amino acid salts of arbitrary forulic acid mentioned above and hydrate thereof, hydrate wherein are semihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate or hexahydrate.
The present invention also provides the preparation method of forulic acid amino acid salts, but is not limited only to following preparation method:
Forulic acid is dropped in the reaction flask, add 95% ethanol, sodium bisulfite, slowly heating up is stirred to dissolving, adds then and contains the amino acid whose aqueous solution, measure the pH of solution with precision test paper, stir the back and add activated carbon decolorizing, filter the freezing crystallization of filtrate, filter, the filter cake absolute ethanol washing, vacuum-drying, the crude product of forulic acid amino acid salts.
The crude product of above-mentioned forulic acid amino acid salts is dissolved in the deionized water, adds gac, stir decolouring, filter, after filtrate is freezing, stir down slowly adding acetone, separate out a large amount of white crystals, leave standstill, filter, filter cake vacuum-drying, the highly finished product of forulic acid amino acid salts.
The application in the medicine of preparation treatment cardiovascular and cerebrovascular diseases of the L-arginic acid salt of the amino acid salts of the further claimed forulic acid of the present invention and hydrate thereof, especially forulic acid, L-lysine salt, DL-ornithine salt or L-ornithine salt.
The further claimed amino acid salts of forulic acid and the hydrate thereof of comprising of the present invention treated the composition of the medicine of cardiovascular and cerebrovascular diseases with other.The medicine of these treatment cardiovascular and cerebrovascular diseases comprises acetylsalicylic acid, indomethacin, low molecular sodium heparin, low molecular heparin calcium, Ligustrazine, Win-35833, gemfibrozil, piracetam, aniracetam, Dihydroergotoxine, bilobalide etc.
The amino acid salts of forulic acid and hydrate thereof can be made pharmaceutically arbitrary or acceptable forms clinically with acceptable accessories, the unitary dose that wherein contains the amino acid salts of forulic acid is 10mg～500mg, for example: 10mg, 20mg, 25mg, 30mg, 40mg, 50mg, 60mg, 80mg, 100mg, 125mg, 150mg, 200mg, 250mg, 300mg, 400mg, 500mg, preferred dose is 50mg, 100mg.The patient who needs this treatment be can be applied in the mode of parenteral or oral administration, injection or oral preparations are preferably.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can add suitable additives according to the character of medicine, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
The amino acid salts of forulic acid of the present invention and hydrate thereof are compared with immediate prior art, have the following advantages:
(1) the present invention provides the amino acid salts of forulic acid first, especially its L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt are compared with commercially available Sodium Ferulate salt, and the stable utmost point of solution significantly improves, be more conducive to the storage of medicine, improved clinical application safety;
(2) preparation technology of the amino acid salts of forulic acid of the present invention and hydrate thereof is simple, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
Below example has been carried out stability study to forulic acid amino acid salt injection of the present invention (preparation method is with reference to experimental example 5) by experiment, and contrasts with injection of sodium ferulate, and the result is as follows:
The stability study of experimental example forulic acid amino acid salts of the present invention
Instrument: HP8453E ultraviolet spectrophotometer; PHS-3C type digital ph; The HP1100 high performance liquid chromatograph; The electric heating constant temperature water bath.
Test solution: injection of sodium ferulate (2ml:50mg, the bright medicine company in Shandong side limited-liability company);
Forulic acid L-arginic acid salt injection liquid, self-control is called for short compound 1;
Forulic acid L-lysine salt injection liquid, self-control is called for short compound 2;
Forulic acid L-ornithine salt injection liquid, self-control is called for short compound 3;
Methyl alcohol (chromatographically pure); Phosphoric acid (analytical pure); Triethylamine (analytical pure).
Experimental technique:
1, the influence of pH value experiment
Preparation pH is respectively the forulic acid amino acid salt injection and the injection of sodium ferulate sample of four kinds of pH values of 6.0,6.5,7.0,7.5,100 ℃ of constant temperature leave standstill, respectively 10,20, the 30min timing sampling measures the content of sample, relatively calculates degradation rate with heated sample content not.
2, strong illumination experiment
Forulic acid amino acid salt injection and injection of sodium ferulate were placed under the 4500lx high light irradiation 10 days, and 20 ℃ of experimental temperatures were respectively at 0,5,10 day every index of sampling and measuring regularly.
3, high temperature experiment
Forulic acid amino acid salt injection and injection of sodium ferulate are placed respectively under 40 ℃, the 60 ℃ hot conditionss, and constant temperature was placed 10 days, respectively at 0,5,10 day every index of timing sampling and measuring.
4, the mensuration of every index
1) outward appearance is observed appearance luster, proterties
2) the pH value detects with acidometer
3) the related substance inspection detects according to high performance liquid chromatograph
Chromatographic condition: with octadecyl silane is weighting agent, and chromatographic column is C
18Post; Moving phase is phosphoric acid buffer (get 8ml phosphoric acid, add water to 1000ml, regulate pH to 3.5 with triethylamine)-methyl alcohol (70: 30); Detect wavelength: 310nm; Flow velocity 1.0ml/min.
Assay method: it is an amount of that precision is measured sample, adds the solution that 0.25mg/ml is made in the moving phase dilution, as need testing solution; It is an amount of to measure need testing solution, adds solution that moving phase makes 5 μ g/ml solution in contrast.Get contrast solution 20 μ l and inject liquid chromatograph, regulate sensitivity, the peak height that makes main composition chromatographic peak is 20% of a full range; Get trial-product 20 μ l again, inject liquid chromatograph, the record color atlas is to 2 times of main composition peak retention time, in the need testing solution color atlas if any impurity peaks, each impurity peak area and must not be greater than contrast solution main peak area.
4) assay lucifuge operation
Sample thief, thin up become the solution of 10 μ g/ml, according to spectrophotometry, measure optical density at the wavelength place of 310nm, calculate content.
Experimental result:
1, different pH values are to the influence of ferulate injection liquid stability
By table 1-1 and table 1-2 experimental result as seen,
The stability of injection of sodium ferulate is subjected to the influence of pH, and under the same conditions, pH is high more, and the degradation rate of injection of sodium ferulate is big more, and pH is when higher, and along with the prolongation of heated time, the color and luster of soup is deepened.
The stability of forulic acid L-arginic acid salt injection liquid, forulic acid L-lysine salt injection liquid, forulic acid L-ornithine salt injection liquid is subjected to the influence of pH less, under the same conditions, pH raises, degradation rate changes little, and the solution color and luster does not have considerable change, compare with injection of sodium ferulate, degradation rate obviously reduces, and stability obviously improves.
The stability experiment research of the ferulate injection liquid of the different pH values of table 1-1
The stability experiment research of the ferulate injection liquid of the different pH values of table 1-2
2, strong illumination is to the influence of the stability of ferulate injection liquid
Table 2 strong illumination is to the stability experiment research of ferulate injection liquid
Annotate: A
AssortedBe the impurity peaks total area; A
RightBe the contrast solution peak total area.
By table 2 experimental result as seen,
Injection of sodium ferulate was placed 10 days under the 4500lx strong illumination, and pH changes little, and content obviously reduces, and related substance significantly increases.
Forulic acid L-arginic acid salt injection liquid, forulic acid L-lysine salt injection liquid, forulic acid L-ornithine salt injection liquid were placed 10 days under the 4500lx strong illumination, pH changes little, and content is little, and related substance does not have showed increased, compare with injection of sodium ferulate, stability obviously improves.
3, high temperature is to the influence of the stability of ferulate injection liquid
40 ℃ of stability experiment researchs of table 3 high temperature to the ferulate injection liquid
Annotate: A
AssortedBe the impurity peaks total area; A
RightBe the contrast solution peak total area.
By table 3 as seen, under 40 ℃ of hot conditionss, injection of sodium ferulate was placed 10 days, and the pH value raises, content obviously reduces, and related substance is not seen showed increased; Forulic acid L-arginic acid salt injection liquid, forulic acid L-lysine salt injection liquid, forulic acid L-ornithine salt injection liquid were placed 10 days under 40 ℃ of hot conditionss, and pH, content all change not quite, compared with injection of sodium ferulate, and stability obviously improves.
60 ℃ of stability experiment researchs of table 4 high temperature to the ferulate injection liquid
Annotate: A
AssortedBe the impurity peaks total area; A
RightBe the contrast solution peak total area.
By table 4 as seen, under 60 ℃ of hot conditionss, injection of sodium ferulate was placed 10 days, and the pH value enlarges markedly, and content reduces bigger, and related substance significantly increases, less stable; Forulic acid L-arginic acid salt injection liquid, forulic acid L-lysine salt injection liquid, forulic acid L-ornithine salt injection liquid were placed 10 days under 60 ℃ of hot conditionss, and pH changes little, and content decreases, but compared with injection of sodium ferulate, and stability obviously improves.
Conclusion: stability experiment is the result show, forulic acid amino acid salts of the present invention has stability preferably in solution, the injection liquid of forulic acid L-arginic acid salt, forulic acid L-lysine salt, the forulic acid L-ornithine salt stability of comparing with injection of sodium ferulate significantly improves, be beneficial to the storage of medicine, improved clinical application safety.
4, embodiment
Embodiment by the following examples is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
The preparation of embodiment 1 forulic acid L-arginic acid salt
Forulic acid 194g (1mol) is dropped in the reaction flask, add 95% ethanol 1000ml, sodium bisulfite 2g, slowly heat up and be stirred to dissolving, in about 70 ℃, add then and contain the arginic aqueous solution 500ml of 174g (1mol) L-, when measuring the pH 6.0-7.0 of solution with precision test paper, stop to add alkali lye, add the 10g activated carbon decolorizing behind the stirring 10min, filter, the freezing crystallization 2h of filtrate, filter filter cake absolute ethanol washing, 60 ℃ of vacuum-dryings, get the crude product 348.6g of forulic acid L-arginic acid salt, yield: 94.7%.
The crude product of above-mentioned forulic acid L-arginic acid salt is dissolved in the 500ml deionized water, add the 1g gac, stir decolouring 15min, filtration in 70 ℃, after filtrate is refrigerated to 5-10 ℃, stir and slowly to add 1500ml acetone down, separate out a large amount of white crystals, leave standstill 1h after, filter, 60 ℃ of vacuum-dryings of filter cake, the highly finished product of 322g forulic acid L-arginic acid salt, refining yield: 92.4%.
Ultimate analysis (molecular formula: C
16H
24N
4O
6)
Measured value: C:52.11%; H:6.59%; N:15.18%;
Theoretical value: C:52.17%; H:6.57%; N:15.21%.
The preparation of embodiment 2 forulic acid L-lysine salts
Concrete operations and charge ratio replace with L-Methionin with the L-arginine, total recovery: 78.3% with reference to embodiment 1.
Ultimate analysis (molecular formula: C
16H
24N
2O
6)
Measured value: C:54.37%; H:7.15%; N:8.19%;
Theoretical value: C:54.46%; H:7.11%; N:8.23%.
The preparation of embodiment 3 forulic acid DL-ornithine salts or forulic acid L-ornithine salt
Concrete operations and charge ratio replace with DL-ornithine or L-ornithine, total recovery: 74.2% with reference to embodiment 1 with the L-arginine.
Ultimate analysis (molecular formula: C
15H
22N
2O
6)
Measured value: C:55.13%; H:6.95%; N:8.49%;
Theoretical value: C:55.21%; H:6.79%; N:8.58%;
The preparation of embodiment 4 aseptic powder of the present invention
1, prescription
Prescription 1:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 50g
Prepare 1000 altogether
Prescription 2:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 100g
Prepare 1000 altogether
Prescription 3:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 200g
Prepare 1000 altogether
2, preparation technology:
In aseptic weighing room, take by weighing aseptic ferulate by prescription, packing is sealed, promptly.
The preparation of embodiment 5 aqueous injections of the present invention
1, prescription
Prescription 1:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 50g
Water for injection adds to 2000ml
Prepare 1000 altogether
Prescription 2:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 100g
Water for injection adds to 5000ml
Prepare 1000 altogether
Prescription 3:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 200g
Water for injection adds to 10000ml
Prepare 1000 altogether
Prescription 4:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 300g
Water for injection adds to 10000ml
Prepare 1000 altogether
2, preparation technology:
1) container of earlier dosing being used, ampoule, the plant-scale equipment, instrument etc. carry out pre-treatment.
2) take by weighing raw material by recipe quantity.
3) raw material is added stirring and dissolving in the water for injection of dosing amount 80%, add 0.1% needle-use activated carbon temperature control and stirred filtering decarbonization 10 minutes for 50 ℃.
4) the pH value of survey solution adds water and is settled to cumulative volume.
5) with the filtering with microporous membrane of 0.45 μ m.
6) clarity of inspection solution.
7) inspection of semifinished product.
8) the qualified back of inspection of semifinished product sealing by fusing is in ampoule.
9) 100 ℃ of flowing steam sterilizations are 30 minutes.
10) while hot sample being put into 0.05% methylene blue solution hunts leak.
11) warehouse-in is examined, packed to finished product entirely.
The preparation of embodiment 6 powder pins of the present invention
1, prescription:
Prescription 1:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 50g
N.F,USP MANNITOL 100g
Water for injection adds to 3000ml
Prepare 1000 altogether
Prescription 2:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 100g
N.F,USP MANNITOL 200g
Water for injection adds to 5000ml
Prepare 1000 altogether
2, preparation technology:
1) will produce used cillin bottle, plug and dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation;
2) take by weighing raw material and auxiliary material by prescription;
3) N.F,USP MANNITOL is added dosing amount 80% water for injection, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% then stirs 15min, filters, and takes off charcoal;
4) in solution, add raw material, stirring and dissolving;
5) the pH value of survey solution;
6) benefit adds to the full amount of water for injection constant volume;
7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m;
8) inspection of semifinished product;
9) soup packing 2ml is in cillin bottle, half tamponade;
10) sample is put in the Freeze Drying Equipment, adopted following freeze-dry process freeze-drying :-40 ℃ of pre-freezes 4 hours ,-30～0 ℃ of low-temperature vacuum drying 18 hours, 0～30 ℃ heated up dry 2 hours, 30 ℃ of freeze-day with constant temperature 2 hours.
11) freeze-drying finishes tamponade, Zha Gai;
12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 7 sodium chloride injections of the present invention
1, prescription
Prescription 1:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 100g
Sodium-chlor 900g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 2:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 200g
Sodium-chlor 900g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 3:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 300g
Sodium-chlor 2250g
Water for injection 250000ml
Prepare 1000 bottles altogether
2, preparation technology:
1) with dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation.
2) take by weighing raw material and auxiliary material by prescription.
3) get the water for injection that sodium-chlor adds dosing amount 80%, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal.
4) in solution, add raw material, stirring and dissolving.
5) the pH value of survey solution is used adjust pH in case of necessity.
6) benefit adds to the full amount of water for injection constant volume.
7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m.
8) inspection of semifinished product.
9) soup is loaded in the infusion bottle 250ml/ bottle.
10) 115 ℃ of pressure sterilizing 30min;
11) leak detection, the lamp inspection.
12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8 glucose injections of the present invention
1, prescription
Prescription 1:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 100g
Glucose 5000g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 2:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 100g
Glucose 10000g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 3:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 300g
Glucose 5000g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 4:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 300g
Glucose 12500g
Water for injection 250000ml
Prepare 1000 bottles altogether
2, preparation technology:
1) with dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation.
2) take by weighing raw material and auxiliary material by prescription.
3) get the water for injection that glucose adds dosing amount 80%, stirring and dissolving, heated and boiled; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal.
4) in solution, add raw material, stirring and dissolving.
5) the pH value of survey solution is used adjust pH in case of necessity.
6) benefit adds to the full amount of water for injection constant volume.
7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m.
8) inspection of semifinished product.
9) soup is loaded in the infusion bottle 250ml/ bottle.
10) 115 ℃ of pressure sterilizing 30min;
11) leak detection, the lamp inspection;
12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 9 tablets of the present invention
1, prescription
Prescription 1:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 10g
Pregelatinized Starch 50.0g
Microcrystalline Cellulose 60.0g
10%PVP (50% ethanol) solution 50ml
Magnesium Stearate 1.5g
Silicon-dioxide 2.5g
Prepare 1000 altogether
Prescription 2:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 50g
Pregelatinized Starch 100.0g
Microcrystalline Cellulose 120.0g
10%PVP (50% alcohol) solution 50ml
Magnesium Stearate 3g
Silicon-dioxide 5g
Prepare 1000 altogether
Prescription 3:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 100g
Pregelatinized Starch 100.0g
Microcrystalline Cellulose 120.0g
10%PVP (50% ethanol) solution 100ml
Magnesium Stearate 3g
Silicon-dioxide 5g
Prepare 1000 altogether
2, preparation technology:
1) raw material pulverizing is crossed 100 mesh sieves, and all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
2) PVPk30 is soaked dissolving and make 10% 50% ethanolic soln, standby.
3) take by weighing raw material and auxiliary material according to recipe quantity.
4) raw material and Microcrystalline Cellulose, pregelatinized Starch are mixed, add the tackiness agent of getting ready, stir, make suitable softwood, cross 20 mesh sieve system particles.
5) dry under 50 ℃ the condition.
6) particle is crossed the whole grain of 18 mesh sieves, adds Magnesium Stearate and silicon-dioxide and mixes.
7) sampling, work in-process chemical examination, the content of The compounds of this invention in the mensuration particle.
8) compressing tablet.
9) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 10 capsules of the present invention
1, prescription
Prescription 1:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 50g
Starch 30.0g
Microcrystalline Cellulose 50.0g
2%HPMC (50% ethanol) solution 50ml
Magnesium Stearate 1.0g
Prepare 1000 altogether
Prescription 2:
Forulic acid L-arginic acid salt, L-lysine salt, DL-ornithine salt or L-ornithine salt 100g
Starch 60.0g
Microcrystalline Cellulose 100.0g
2%HPMC (50% ethanol) solution 70ml
Magnesium Stearate 2.0g
Prepare 1000 altogether
2, preparation technology:
1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
2) take by weighing raw material and auxiliary material according to recipe quantity.
3) hypromellose is dissolved in to make 2% the aqueous solution in the 50% ethanol water standby.
4) raw material, starch, Microcrystalline Cellulose are mixed, the adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable softwood.
5) cross 20 mesh sieve system particles.
6) particle is dried under 60 ℃ condition.
7) dry good particle adds Magnesium Stearate, crosses the whole grain of 18 mesh sieves, mixes.
8) sampling, the work in-process chemical examination.
9) loading amount of determining according to chemical examination incapsulates.
10) finished product is examined entirely, the packing warehouse-in.
Claims (6)
1.4-hydroxy 3-methoxybenzene vinylformic acid is the amino acid salts of forulic acid, amino acid salts wherein is lysine salt or ornithine salt.
2. the amino acid salts of forulic acid as claimed in claim 1, Methionin wherein is L-Methionin.
3. the amino acid salts of forulic acid as claimed in claim 1, ornithine wherein is DL-ornithine or L-ornithine.
4. as the application in the medicine of preparation treatment cardiovascular and cerebrovascular diseases of the amino acid salts of the described forulic acid of the arbitrary claim of claim 1-3.
5. as the amino acid salts of the described forulic acid of the arbitrary claim of claim 1-3, it is characterized in that, make pharmaceutically arbitrary or acceptable forms clinically with acceptable accessories.
6. formulation as claimed in claim 5 is oral preparations or injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101970293A CN101195570B (en) | 2006-12-01 | 2007-12-01 | Salt amino acid of ferulic acid |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610070614 | 2006-12-01 | ||
| CN200610070614.2 | 2006-12-01 | ||
| CN2007101970293A CN101195570B (en) | 2006-12-01 | 2007-12-01 | Salt amino acid of ferulic acid |
Publications (2)
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| CN101195570A CN101195570A (en) | 2008-06-11 |
| CN101195570B true CN101195570B (en) | 2011-02-02 |
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| CN2007101970293A Expired - Fee Related CN101195570B (en) | 2006-12-01 | 2007-12-01 | Salt amino acid of ferulic acid |
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| CN102657638A (en) * | 2012-05-29 | 2012-09-12 | 海南卫康制药(潜山)有限公司 | Sodium ferulate lyophilized powder composition for injection and preparation method thereof |
| CN104856944A (en) * | 2015-05-13 | 2015-08-26 | 苏州沪云肿瘤研究中心股份有限公司 | Bornyl ferulate injection |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101410089A (en) * | 2006-03-27 | 2009-04-15 | 碧欧特莫林简易股份公司 | Cosmetic active ingredient composed of arginine ferrulate and a microalgae extract and its uses |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101410089A (en) * | 2006-03-27 | 2009-04-15 | 碧欧特莫林简易股份公司 | Cosmetic active ingredient composed of arginine ferrulate and a microalgae extract and its uses |
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