CN101121696B - Metal salt of pyritinol and hydrate of the same - Google Patents

Metal salt of pyritinol and hydrate of the same Download PDF

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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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pyritinol
salt
injection
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prescription
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CN101121696A (en
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黄振华
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Jilin Jinsheng Pharmaceutical Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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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

The metal-salt of pyritinol and hydrate thereof
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:
Figure S06169695420060829D000011
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,
Figure S06169695420060829D00003114155QIETU
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
Figure S06169695420060829D000041
Table 2 pyritinol sodium, potassium, natrium potassium salt and pyritinol hydrochloride injection liquid
Pathological examination results after the rabbit ear vein administration
Figure S06169695420060829D000051
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:
Figure S06169695420060829D000081
Prescription 2:
Prescription 3:
Figure S06169695420060829D000083
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:
Figure S06169695420060829D000084
Prescription 2:
Figure S06169695420060829D000085
Prescription 3:
Figure S06169695420060829D000086
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:
Figure S06169695420060829D000091
Prescription 2:
Figure S06169695420060829D000092
Prescription 3:
Figure S06169695420060829D000093
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:
Figure S06169695420060829D000101
Prescription 2:
Figure S06169695420060829D000102
Prescription 3:
Figure S06169695420060829D000111
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:
Figure S06169695420060829D000112
Prescription 2:
Figure S06169695420060829D000121
Prescription 3:
Figure S06169695420060829D000122
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:
Figure S06169695420060829D000131
Prescription 2:
Figure S06169695420060829D000132
Prescription 3:
Figure S06169695420060829D000133
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:
Figure S06169695420060829D000141
Prescription 2:
Figure S06169695420060829D000142
Prescription 3:
Figure S06169695420060829D000143
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.
CN2006100696954A 2006-08-11 2006-08-11 Metal salt of pyritinol and hydrate of the same Active CN101121696B (en)

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CN1679565A (en) * 2004-04-06 2005-10-12 王玫 Injection of pyritinol hydrochloride and its preparation

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