CN101121696B - Metal salt of pyritinol and hydrate of the same - Google Patents
Metal salt of pyritinol and hydrate of the same Download PDFInfo
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- CN101121696B CN101121696B CN2006100696954A CN200610069695A CN101121696B CN 101121696 B CN101121696 B CN 101121696B CN 2006100696954 A CN2006100696954 A CN 2006100696954A CN 200610069695 A CN200610069695 A CN 200610069695A CN 101121696 B CN101121696 B CN 101121696B
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- Prior art keywords
- pyritinol
- salt
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- metal
- prescription
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- 229960004986 pyritinol Drugs 0.000 title claims abstract description 57
- SIXLXDIJGIWWFU-UHFFFAOYSA-N pyritinol Chemical compound OCC1=C(O)C(C)=NC=C1CSSCC1=CN=C(C)C(O)=C1CO SIXLXDIJGIWWFU-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 150000003839 salts Chemical class 0.000 title abstract description 4
- 239000002184 metal Substances 0.000 title abstract 3
- 238000002360 preparation method Methods 0.000 claims abstract description 35
- 230000002265 prevention Effects 0.000 claims abstract description 3
- 238000002347 injection Methods 0.000 claims description 44
- 239000007924 injection Substances 0.000 claims description 44
- 239000003814 drug Substances 0.000 claims description 16
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 11
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 11
- 159000000000 sodium salts Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000001103 potassium chloride Substances 0.000 claims description 6
- 235000011164 potassium chloride Nutrition 0.000 claims description 6
- 210000004556 brain Anatomy 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 208000019553 vascular disease Diseases 0.000 claims description 2
- 238000005516 engineering process Methods 0.000 abstract description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 4
- 208000026106 cerebrovascular disease Diseases 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- 239000000890 drug combination Substances 0.000 abstract 1
- 230000007794 irritation Effects 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 41
- 239000007787 solid Substances 0.000 description 40
- 239000000243 solution Substances 0.000 description 26
- 239000007788 liquid Substances 0.000 description 25
- 238000003756 stirring Methods 0.000 description 19
- 239000000843 powder Substances 0.000 description 18
- 210000001519 tissue Anatomy 0.000 description 17
- 239000011734 sodium Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 206010028851 Necrosis Diseases 0.000 description 15
- 239000002775 capsule Substances 0.000 description 15
- 238000002425 crystallisation Methods 0.000 description 15
- 230000008025 crystallization Effects 0.000 description 15
- 230000017074 necrotic cell death Effects 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 241000283973 Oryctolagus cuniculus Species 0.000 description 14
- 239000000463 material Substances 0.000 description 14
- 239000002994 raw material Substances 0.000 description 14
- 210000003462 vein Anatomy 0.000 description 14
- 238000005303 weighing Methods 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 239000002245 particle Substances 0.000 description 13
- 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 11
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 11
- 229910052700 potassium Inorganic materials 0.000 description 11
- 239000011591 potassium Substances 0.000 description 11
- 229910052708 sodium Inorganic materials 0.000 description 11
- 206010020565 Hyperaemia Diseases 0.000 description 10
- 206010030113 Oedema Diseases 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 230000008859 change Effects 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- VFEKMAOUJHONFD-UHFFFAOYSA-N 5-[[[5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl]methyldisulfanyl]methyl]-4-(hydroxymethyl)-2-methylpyridin-3-ol;hydrate;dihydrochloride Chemical compound O.Cl.Cl.OCC1=C(O)C(C)=NC=C1CSSCC1=CN=C(C)C(O)=C1CO VFEKMAOUJHONFD-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000007689 inspection Methods 0.000 description 8
- 206010061218 Inflammation Diseases 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 208000007536 Thrombosis Diseases 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 210000001612 chondrocyte Anatomy 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 229960000935 dehydrated alcohol Drugs 0.000 description 7
- 210000003725 endotheliocyte Anatomy 0.000 description 7
- 210000002615 epidermis Anatomy 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 230000008595 infiltration Effects 0.000 description 7
- 238000001764 infiltration Methods 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 238000012856 packing Methods 0.000 description 7
- 206010033675 panniculitis Diseases 0.000 description 7
- 229940023488 pill Drugs 0.000 description 7
- 239000006187 pill Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000010025 steaming Methods 0.000 description 7
- 230000002792 vascular Effects 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 239000008215 water for injection Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 229940093181 glucose injection Drugs 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- 230000001575 pathological effect Effects 0.000 description 6
- 235000019633 pungent taste Nutrition 0.000 description 6
- 235000014347 soups Nutrition 0.000 description 6
- 238000013270 controlled release Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000011265 semifinished product Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 208000032843 Hemorrhage Diseases 0.000 description 4
- -1 absorption carrier Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- BYTCDABWEGFPLT-UHFFFAOYSA-L potassium;sodium;dihydroxide Chemical compound [OH-].[OH-].[Na+].[K+] BYTCDABWEGFPLT-UHFFFAOYSA-L 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 240000007711 Peperomia pellucida Species 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229910052788 barium Inorganic materials 0.000 description 3
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000011082 depyrogenation Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000011179 visual inspection Methods 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 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
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 230000003727 cerebral blood flow Effects 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- 229940068682 chewable tablet Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000007919 dispersible tablet Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940100688 oral solution Drugs 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
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- 239000008174 sterile solution Substances 0.000 description 2
- 235000020985 whole grains Nutrition 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- OXUMVEOKAMNGER-UHFFFAOYSA-N C.OC=1C=CC=NC1C Chemical compound C.OC=1C=CC=NC1C OXUMVEOKAMNGER-UHFFFAOYSA-N 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010057315 Daydreaming Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- XQAXGZLFSSPBMK-UHFFFAOYSA-M [7-(dimethylamino)phenothiazin-3-ylidene]-dimethylazanium;chloride;trihydrate Chemical compound O.O.O.[Cl-].C1=CC(=[N+](C)C)C=C2SC3=CC(N(C)C)=CC=C3N=C21 XQAXGZLFSSPBMK-UHFFFAOYSA-M 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000037354 amino acid metabolism Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
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- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000003085 diluting agent 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
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- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
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Abstract
The invention belongs to the field of medical technology, relating to a metal salt and the hydrate of the pyritinol, the drug combination containing the pyritinol and the application of the pyritinol in the treatment and virgule or prevention of the cerebrovascular disease; the invention also provides the preparation method. The pharmacological experiments show that the alkaline metal salt of the pyritinol of the invention can reduce the irritation and can be chosen as the substitute of the hydrochloride in the existing market.
Description
1, technical field
The invention belongs to medical technical field, relate to the metal-salt of pyritinol and hydrate thereof and its preparation method, contain its pharmaceutical composition and the application in treating and/or preventing cerebrovascular disease.
2, background technology
Pyritinol is the derivative of vitamin B6, be the brain metabolism improving medicine, can promote glucose and amino acid metabolism in the brain, improve the whole body assimilation, increase the carotid artery flow amount, improve cerebral blood flow (CBF), be applicable to the dizzy distending pain, insomnia, hypomnesis of cerebral trauma sequela, encephalitis and meningitis sequela etc., the improvement of absent minded, emotional change; Also be used for cerebral arteriosclerosis, senile dementia mental symptom etc.The structural formula of pyritinol is as follows:
A kind of known salts of pyritinol is a hydrochloride, is specially hydrochloride monohydrate, and its chemical name is 3, and 3-(dithio methylene radical) two (5-hydroxyl-6-methyl-pyridine methane) dihydrochloride monohydrate records in " Chinese Pharmacopoeia version in 2005 ".The preparation of listing has sheet, capsule and powder injection, and its injection causes venous stimulation easily when clinical application, limited clinical application greatly.
3, summary of the invention
The problem of the serious venous stimulation that in clinical application, causes for the injection that solves Pyrithioxine hydrochloride, the inventor is through a large amount of screening operations, the metal-salt (alkaline metal ions wherein be a kind of in lithium, sodium, potassium, barium, calcium, magnesium, the zinc or any two kinds) that is surprised to find pyritinol is less to the pungency of vein, can improve patient's the tolerance and the security of clinical use greatly, and the surrogate that can be used as existing commercially available hydrochloride is selected.
Technical scheme of the present invention is as follows:
The invention provides a kind ofly 3,3-(dithio methylene radical) two (5-hydroxyls-6-methyl-pyridine methane) is the metal-salt of pyritinol, and metal ion wherein is a kind of in lithium, sodium, potassium, barium, calcium, magnesium, the zinc or any two kinds.Be preferably sodium salt, sylvite, natrium potassium salt.Optimum is a sodium salt.
The present invention also provides the method for preparing above-mentioned pyritinol metal-salt: get pyritinol, Yu Shuizhong, ice-water bath stirs down, oxyhydroxide or oxide compound with certain density lithium, sodium, potassium, barium, calcium, magnesium, zinc are regulated pH value to 10, it is molten entirely to be stirred to solid, obtain clarifying the colourless aqueous solution, the 70 ℃ of evaporates to dryness that reduce pressure get white solid.Dried solid is joined in the dehydrated alcohol, reflux, solid is molten entirely, pressure reducing and steaming 2/3 solvent, cooling crystallization obtains white solid.Solution behind the crystallization is filtered, and filter cake is off-white color, uses absolute ethanol washing 2 times, gets off-white powder in 5 hours in 45 ℃ of drying under reduced pressure, promptly.
The present invention is the hydrate of the metal-salt of claimed pyritinol recited above further, can be semihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate.
The present invention is claimed metal-salt and the medicinal compound of hydrate thereof that comprises pyritinol recited above further; especially the sodium salt of pyritinol, sylvite, natrium potassium salt; the amount of its effective constituent is 0.05g～1.0g (in a pyritinol); as being 0.05g, 0.08g, 0.1g, 0.13g, 0.15g, 0.18g, 0.22g, 0.25g, 0.3g, 0.34g, 0.38g, 0.41g, 0.45g, 0.5g, 0.6g, 0.8g, 1.0g; being preferably 0.1g～0.5g, especially is 0.1g, 0.2g, 0.3g, 0.4g.Said composition is clinical or pharmaceutically acceptable arbitrary formulation.
Aforementioned pharmaceutical compositions can be applied to the patient who needs treatment in modes such as oral or administered parenterallys.Be used for when oral, can be made into conventional solid preparation, as sheet, capsule, soft capsule, dispersible tablet, oral liquid, particle, chewable tablet, orally disintegrating tablet, dripping pill, slow releasing tablet, slow releasing capsule, controlled release tablet, controlled release capsule etc.; Also can be made into liquid preparation, as oral liquid, syrup etc.When being used for administered parenterally, can be made into solution, water or the oil-suspending agent etc. of injection, as liquid drugs injection, freeze-dried powder, aseptic powder injection, transfusion etc.Preferred oral preparations commonly used and injection among the present invention are as sheet, capsule, particle, powder pin, liquid drugs injection, transfusion etc.
The preparation of aforementioned pharmaceutical compositions can adopt the ordinary method production in the existing pharmacy field, can add various pharmaceutically acceptable carriers when needing.Described carrier comprises vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant of pharmaceutical field routine etc.
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, comprises 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, it indicates loading amount can be 0.5ml, 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and the large volume injection liquid of using for intravenous drip that generally is not less than 100ml 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 that sterilized powder can make 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 being used for oral administration, conventional solid preparation be can be made into, tablet, capsule, granule, pill and oral solution etc. comprised.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form; Tablet is based on oral ordinary tablet, and 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; Capsule 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 according to its dissolving and release characteristics.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size; Granule 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.Pill means medicine and suitable auxiliary material uniform mixing, the spherical or near-spherical solid preparation made from proper method; Pill comprises dripping pill, sugar-pill, piller etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.
The sodium salt of the metal-salt of the further claimed pyritinol of the present invention, especially pyritinol, sylvite, natrium potassium salt and hydrate thereof preparation be used for the treatment of and/or the medicine of prevention of brain vascular disease in application.
The metal-salt of pyritinol of the present invention and hydrate thereof compared with prior art, its advantage is:
(1) the present invention provides the metal-salt and the hydrate thereof of pyritinol first, especially its sodium salt, sylvite, natrium potassium salt, venous stimulation test to rabbit shows, compare with commercially available pyritinol hydrochloride, seriously become nonirritant by stimulating, guarantee safety of clinical administration, obtained beyond thought effect.
(2) preparation technology of the metal-salt of pyritinol 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.
(3) good water solubility of pyritinol sodium salt of the present invention, sylvite, natrium potassium salt, especially sodium salt is easy to make the above formulation of any pharmaceutics.
Below example further specifies beneficial effect of the present invention by experiment:
The metal-salt of experimental example pyritinol and pyritinol hydrochloride injection liquid compare the vein irritating test of rabbit
The metal-salt injection liquid that test objective is observed pyritinol has nonirritant to blood vessel.
Be subjected to the reagent thing
The pyritinol sodium injection, specification: 2ml:0.2g, self-control;
Pyritinol potassium injection liquid, specification: 2ml:0.2g, self-control;
Pyritinol sodium potassium injection liquid, specification: 2ml:0.2g, self-control.
The contrast medicine
5% glucose injection, Sanjiu Yimin Pharmaceutic Co., Ltd., Jinan produces, lot number: 0407160301;
Pyritinol hydrochloride injection, Tri-Lion Pharmaceutical Co., Ltd., Harbin, specification: 2ml:0.2g.
The animal rabbit, body weight 2.1～2.4kg,
Dual-purpose, anti-medical Group Co.,Ltd provides by the Shandong, Shandong.Animal conformity certification number: SCXK (Shandong) 20030006.
Dosage is provided with quiet of branch and quietly pushes away 2 kinds of route of administration.Quiet: sample thief 4ml is diluted in the 250ml glucose injection, and 30ml/ only; Quiet pushing away: each 2～4ml stoste.Quiet consumption is 20ml/kg (diluent).
Method is got 30 of healthy rabbits, is divided at random for reagent group and 5% glucose injection control group, 3 every group.Before the administration rabbit is put in the fixed case, instil respectively, inject for reagent and 5% glucose injection by above-mentioned grouping in auricular vein, drip velocity be 1ml/min (20/min), the speed of injecting is slow, observe administration after the 24h injection site have or not hyperemia, oedema, hemorrhage, downright bad.Successive administration 3 days, 24h does pathological examination getting the rabbit ear 10% formalin fixed away from the entad end of injection site 1cm after the last administration.The blood vessel of visual inspection agents area and surrounding tissue have or not hyperemia, oedema, sex change, scleroma and necrosis, relatively have or not significant difference with the position of 5% glucose injection; Originally, cut into slices then during pathologic finding away from the sampling of injection site 1cm place.
Table 1 pyritinol sodium, potassium, natrium potassium salt and pyritinol hydrochloride injection liquid
The visual inspection result of 24h and 3d after the rabbit ear vein administration
Table 2 pyritinol sodium, potassium, natrium potassium salt and pyritinol hydrochloride injection liquid
Pathological examination results after the rabbit ear vein administration
Test-results and conclusion test-results see Table 1,2.
5% glucose injection control group: the blood vessel of 6 rabbit visual inspection agents areas and surrounding tissue are not seen hyperemia, oedema, hemorrhage, the pathological tissue result proves that vascular tissue's structure is normal, epidermis does not have and thickens, and subcutis and corium do not have hyperemia, oedema, inflammation and necrosis; The auricular vein endotheliocyte is arranged normal, does not find mural thrombus and cell infiltration in the tube chamber; Chondrocyte's marshalling of cartilaginous tissue is not seen changes such as sex change, necrosis.
The quiet group that pushes away of pyritinol hydrochloride injection liquid: when 3 rabbit were injected beginning, animal occurred restless, injected the back naked eyes and saw capillary injection, and is no hemorrhage, reddens around the capillary vessel.Preliminary judgement all has serious pungency.The pathological replacement result has also confirmed this point.
The quiet group that pushes away of pyritinol sodium injection: 3 rabbit vascular tissue structures are normal, and epidermis does not have and thickens, and subcutis and corium do not have hyperemia, oedema, inflammation and necrosis; The auricular vein endotheliocyte is arranged normal, does not find mural thrombus and cell infiltration in the tube chamber; Chondrocyte's marshalling of cartilaginous tissue is not seen changes such as sex change, necrosis.
The quiet group that pushes away of pyritinol potassium injection liquid: 3 rabbit vascular tissue structures are normal, and epidermis does not have and thickens, and subcutis and corium do not have hyperemia, oedema, inflammation and necrosis; The auricular vein endotheliocyte is arranged normal, does not find mural thrombus and cell infiltration in the tube chamber; Chondrocyte's marshalling of cartilaginous tissue is not seen changes such as sex change, necrosis.
The quiet group that pushes away of pyritinol sodium potassium injection liquid: 3 rabbit vascular tissue structures are normal, and epidermis does not have and thickens, and subcutis and corium do not have hyperemia, oedema, inflammation and necrosis; The auricular vein endotheliocyte is arranged normal, does not find mural thrombus and cell infiltration in the tube chamber; Chondrocyte's marshalling of cartilaginous tissue is not seen changes such as sex change, necrosis.
Quiet group of pyritinol hydrochloride injection liquid: naked eyes see that capillary vessel is slightly congested, no hemorrhage behind quiet of 3 rabbit.The pathological replacement result has also confirmed pungency.
Quiet group of pyritinol sodium injection: 3 rabbit vascular tissue structures are normal, and epidermis does not have and thickens, and subcutis and corium do not have hyperemia, oedema, inflammation and necrosis; The auricular vein endotheliocyte is arranged normal, does not find mural thrombus and cell infiltration in the tube chamber; Chondrocyte's marshalling of cartilaginous tissue is not seen changes such as sex change, necrosis.
Quiet group of pyritinol potassium injection liquid: 3 rabbit vascular tissue structures are normal, and epidermis does not have and thickens, and subcutis and corium do not have hyperemia, oedema, inflammation and necrosis; The auricular vein endotheliocyte is arranged normal, does not find mural thrombus and cell infiltration in the tube chamber; Chondrocyte's marshalling of cartilaginous tissue is not seen changes such as sex change, necrosis.
Quiet group of pyritinol sodium potassium injection liquid: 3 rabbit vascular tissue structures are normal, and epidermis does not have and thickens, and subcutis and corium do not have hyperemia, oedema, inflammation and necrosis; The auricular vein endotheliocyte is arranged normal, does not find mural thrombus and cell infiltration in the tube chamber; Chondrocyte's marshalling of cartilaginous tissue is not seen changes such as sex change, necrosis.
Above-mentioned experimental result shows that sodium, potassium, the injection liquid of natrium potassium salt and the injection liquid of hydrochloride of pyritinol compare, pungency to vein significantly reduces, substantially do not have pungency, show that sodium, potassium, the natrium potassium salt of pyritinol of the present invention can reduce the pungency to vein, be worth clinical application.
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 metal-salt of the pyritinol described in following examples comprises its hydrate, and its weight is by its dry product.
4, embodiment
The preparation of embodiment 1 pyritinol metal-salt
1, the preparation of pyritinol sodium
Method one:
Take by weighing pyritinol 8g, be suspended in the 100ml water, ice-water bath stirs down, regulates pH value to 13 with 5% sodium hydroxide, and it is molten entirely to be stirred to solid, obtains clarifying the colourless aqueous solution, and the 70 ℃ of evaporates to dryness that reduce pressure get white solid.Dried solid is joined in the 80ml dehydrated alcohol, reflux, solid is molten entirely, pressure reducing and steaming 2/3 solvent, cooling crystallization obtains white solid.Solution behind the crystallization is filtered, and filter cake is off-white color, uses absolute ethanol washing 2 times, gets off-white powder 5.6g, yield 62.5% in 5 hours in 45 ℃ of drying under reduced pressure.
Ultimate analysis (C
16H
18N
2Na
2O
4S
2): C, 46.54%; H, 4.43%; N, 6.78%; Na, 11.13%; S, 15.54% (theory: C, 46.59%; H, 4.40%; N, 6.79%; Na, 11.15%; S, 15.55%)
Method two:
Take by weighing pyritinol 8g, be suspended in the 100ml water, ice-water bath stirs down, regulates pH value to 13 with 10% sodium hydroxide, and it is molten entirely to be stirred to solid, obtains clarifying the colourless aqueous solution, and the 70 ℃ of evaporates to dryness that reduce pressure get white solid.Dried solid is joined in the 70ml dehydrated alcohol, reflux, solid is molten entirely, pressure reducing and steaming 2/3 solvent, cooling crystallization obtains white solid.Solution behind the crystallization is filtered, and filter cake is off-white color, uses absolute ethanol washing 2 times, gets buff powder 5.9g, yield 65.9% in 5 hours in 45 ℃ of drying under reduced pressure.
2, the preparation of pyritinol potassium
Method one:
Take by weighing pyritinol 8g, be suspended in the 100ml water, ice-water bath stirs down, regulates pH value to 13 with 5% potassium hydroxide, and it is molten entirely to be stirred to solid, obtains clarifying the colourless aqueous solution, and the 70 ℃ of evaporates to dryness that reduce pressure get white solid.Dried solid is joined in the 90ml dehydrated alcohol, reflux, solid is molten entirely, pressure reducing and steaming 2/3 solvent, cooling crystallization obtains white solid.Solution behind the crystallization is filtered, and filter cake is off-white color, uses absolute ethanol washing 2 times, gets off-white powder 4.5g, yield 46.6% in 4 hours in 45 ℃ of drying under reduced pressure.
Ultimate analysis (C
16H
18K
2N
2O
4S
2): C, 43.18%; H, 4.12%; K, 17.56%; N, 6.29%; S, 14.40% (theory: C, 43.22%; H, 4.08%; K, 17.59%; N, 6.30%; S, 14.42%)
Method two:
Take by weighing pyritinol 8g, be suspended in the 100ml water, ice-water bath stirs down, regulates pH value to 13 with 10% potassium hydroxide, and it is molten entirely to be stirred to solid, obtains clarifying the colourless aqueous solution, and the 70 ℃ of evaporates to dryness that reduce pressure get white solid.Dried solid is joined in the 90ml dehydrated alcohol, reflux, solid is molten entirely, pressure reducing and steaming 2/3 solvent, cooling crystallization obtains white solid.Solution behind the crystallization is filtered, and filter cake is off-white color, uses absolute ethanol washing 2 times, gets off-white powder 4.2g, yield 43.5% in 4 hours in 45 ℃ of drying under reduced pressure.
3, the preparation of pyritinol natrium potassium salt
Method one:
Take by weighing pyritinol 8g, be suspended in the 100ml water, ice-water bath stirs down, with 5% potassium hydroxide sodium hydroxide mixing solutions (potassium hydroxide sodium hydroxide mol ratio 1:1) adjust pH to 13, it is molten entirely to be stirred to solid, obtains clarifying the colourless aqueous solution, and the 70 ℃ of evaporates to dryness that reduce pressure get white solid.Dried solid is joined in the 80ml dehydrated alcohol, reflux, solid is molten entirely, pressure reducing and steaming 2/3 solvent, cooling crystallization obtains white solid.Solution behind the crystallization is filtered, and filter cake is off-white color, uses absolute ethanol washing 2 times, gets yellow powder 5.2g, yield 55.9% in 5 hours in 45 ℃ of drying under reduced pressure.
Ultimate analysis (C
16H
18KN
2NaO
4S
2): C, 44.80%; H, 4.26%; K, 9.12%; N, 6.52%; Na, 5.34%; S, 14.95% (theory: C, 44.84%; H, 4.23%; K, 9.12%; N, 6.54%; Na, 5.36%; S, 14.96%)
Method two:
Take by weighing pyritinol 8g, be suspended in the 100ml water, ice-water bath stirs down, with 10% potassium hydroxide sodium hydroxide mixing solutions (potassium hydroxide sodium hydroxide mol ratio 1:1) adjust pH to 13, it is molten entirely to be stirred to solid, obtains clarifying the colourless aqueous solution, and the 70 ℃ of evaporates to dryness that reduce pressure get white solid.Dried solid is joined in the 80ml dehydrated alcohol, reflux, solid is molten entirely, pressure reducing and steaming 2/3 solvent, cooling crystallization obtains white solid.Solution behind the crystallization is filtered, and filter cake is off-white color, uses absolute ethanol washing 2 times, gets yellow powder 4.8g, yield 51.6% in 5 hours in 45 ℃ of drying under reduced pressure.
The preparation of embodiment 2 aseptic powder of the present invention
1, prescription
Prescription 1:
Prescription 2:
Prescription 3:
2, preparation technology:
In aseptic weighing room, take by weighing aseptic The compounds of this invention by prescription, packing is sealed, promptly.
The system of embodiment 3 aqueous injections of the present invention respectively
1, prescription
Prescription 1:
Prescription 2:
Prescription 3:
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 and auxiliary 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 4 powder pins of the present invention
1, prescription:
Prescription 1:
Prescription 2:
Prescription 3:
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 system of embodiment 5 sodium chloride injections of the present invention respectively
1, prescription
Prescription 1:
Prescription 2:
Prescription 3:
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 in case of necessity with adjust pH about 4.0～5.0.
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 6 glucose injections of the present invention
1, prescription
Prescription 1:
Prescription 2:
Prescription 3:
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 in case of necessity with adjust pH about 4.0～5.0.
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 7 tablets of the present invention
1, prescription
Prescription 1:
Prescription 2:
Prescription 3:
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 8 capsules of the present invention
1, prescription
Prescription 1:
Prescription 2:
Prescription 3:
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 (7)
1. the metal-salt of pyritinol, its described metal-salt is sodium salt, sylvite, natrium potassium salt.
2. the metal-salt of pyritinol as claimed in claim 1, its described metal-salt is a sodium salt.
3. a pharmaceutical composition is characterized in that, comprises the metal-salt in the pyritinol as claimed in claim 1 or 2 of pyritinol 0.05g～1.0g significant quantity.
4. pharmaceutical composition as claimed in claim 3 is characterized in that, comprises the metal-salt in the pyritinol as claimed in claim 1 or 2 of pyritinol 0.1g～0.5g significant quantity.
5. as claim 3 or 4 described pharmaceutical compositions, be clinical or pharmaceutically acceptable arbitrary formulation.
6. pharmaceutical composition as claimed in claim 5 is oral preparations or injection.
The metal-salt of pyritinol as claimed in claim 1 or 2 preparation be used for the treatment of and/or the medicine of prevention of brain vascular disease in application.
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| US3010966A (en) * | 1958-03-21 | 1961-11-28 | Merck Ag E | Derivatives of vitamin b6 |
| CN1491648A (en) * | 2003-09-18 | 2004-04-28 | 伟 熊 | Pyrithioxine hydrochloride freeze-dried power injection and its preparing method |
| CN1679565A (en) * | 2004-04-06 | 2005-10-12 | 王玫 | Injection of pyritinol hydrochloride and its preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3010966A (en) * | 1958-03-21 | 1961-11-28 | Merck Ag E | Derivatives of vitamin b6 |
| CN1491648A (en) * | 2003-09-18 | 2004-04-28 | 伟 熊 | Pyrithioxine hydrochloride freeze-dried power injection and its preparing method |
| CN1679565A (en) * | 2004-04-06 | 2005-10-12 | 王玫 | Injection of pyritinol hydrochloride and its preparation |
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