CN100509787C - New pharmaceutically acceptable salt of pyritinol, and a preparation method thereof - Google Patents
New pharmaceutically acceptable salt of pyritinol, and a preparation method thereof Download PDFInfo
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- CN100509787C CN100509787C CNB2006100795771A CN200610079577A CN100509787C CN 100509787 C CN100509787 C CN 100509787C CN B2006100795771 A CNB2006100795771 A CN B2006100795771A CN 200610079577 A CN200610079577 A CN 200610079577A CN 100509787 C CN100509787 C CN 100509787C
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Abstract
This invention relates to new pharmaceutically acceptable salts and solvates of pyritinol, drug composition containing them, and their application in treating diseases. This invention also provides a method for preparing them. The salts and solvates of pyritinol can be used as an alternative for commercialized hydrochloride drug. The salts and solvates of pyritinol have such advantages as high stability, high solubility, little stimulation and high safety, and can satisfy clinical requirements.
Description
1, technical field
The invention belongs to medical technical field, relate to new pharmacy acceptable salt of pyritinol and preparation method thereof, contain its pharmaceutical composition and it is in the purposes of treatment in the medical conditions.
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 this product listing has sheet, capsule and sterile powder injection, and its injection causes venous stimulation easily when clinical application, limited clinical application greatly.
3, summary of the invention
The objective of the invention is to improve the higher new compound of patient's tolerance and clinical safety in utilization, i.e. the new pharmacy acceptable salt of pyritinol in order to provide a kind of littler than pyritinol hydrochloride pungency.
Through a large amount of screening operations, we are surprised to find the mesylate of pyritinol and the surrogate selection that hydrobromate can be used as existing commercially available hydrochloride, these two kinds of compounds are compared with the pyritinol hydrochloride, have good stability, solvability is strong, pungency is little and medicinal safe characteristics.
Technical scheme of the present invention is as follows:
The present invention relates to a kind of suc as formula the described pyritinol of I new pharmacy acceptable salt and hydrate thereof:
The pharmacy acceptable salt that pyritinol of the present invention is new can be inorganic acid salt or organic acid salt, preferred especially mesylate and hydrobromate.
The new pharmacy acceptable salt of pyritinol of the present invention can also with corresponding co-reactant, promptly contact and form hydrate with water and/or with solvent phase, for example: semihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, preferred especially pyritinol mesylate monohydrate and pyritinol hydrobromide monohydrate.
Another object of the present invention provides the method for preparing above-claimed cpd.
The step for preparing the new pharmacy acceptable salt of pyritinol of the present invention comprises: pyritinol is mixed in solvent with mineral acid or organic acid, form a solution, isolate the formed solid of solution thus subsequently.Promptly can in appropriate solvent, pyritinol with mineral acid or organic acid processing as defined above, be formed required acid such as methylsulfonic acid or Hydrogen bromide additive salt solution, in solution, be settled out this salt subsequently, thereby make compound of the present invention.Pyritinol is 10:1～1:10 with the mole proportion optimization of acid (as methylsulfonic acid, Hydrogen bromide); Described solvent is the mixture or the lower alcohol of water, lower alcohol and water, is preferably in-10～100 ℃ of temperature ranges and is stirred churning time 0.1～10h; Solution is concentrated into to be done or adds after ether, ketone stirs, and separates obtaining solid.This solid can be by refining in water, water-containing organic solvent or organic solvent.Can be randomly with gac, silica gel, diatomite or other suitable material processing solution to be purified.
The preparation method of pyritinol mesylate can for: get pyritinol 10g (27mmol), drop in the reaction flask, add the 100ml deionized water then, stir into suspension, under agitation drip 6g methylsulfonic acid (62mmol)/50ml aqueous solution then, dropwise back stirring reaction 10 minutes, then reaction solution is concentrated into driedly, obtain off-white color pyritinol mesylate crude product.Crude product is joined in the 100ml90% ethanolic soln, is heated with stirring to backflow, treat solid complete molten after, activated carbon decolorizing, the filtrate cooling crystallization obtains white crystalline powder, is pyritinol mesylate monohydrate through structural identification, molecular formula is C
16H
20N
2O
4S
22CH
3SO
3HH
2O.This product can also obtain its no hydrate by the following method: with dissolving crude product in dehydrated alcohol, decolouring rear filtrate cooling crystallization, if also contain small amount of crystalline water by detecting in the product, available dehydrated alcohol periodic crystallisation is not then contained the methylsulfonic acid pyritinol of crystal water.
The preparation method of pyritinol hydrobromate can for: get pyritinol 10g (27mmol), drop in the reaction flask, add the 100ml deionized water then, stir into suspension, Dropwise 5 g Hydrogen bromide (61.8mmol)/50ml aqueous solution under agitation then, dropwise back stirring reaction 10 minutes, then reaction solution is concentrated into driedly, obtain off-white color Hydrogen bromide pyritinol crude product.Crude product is joined in the 100ml90% ethanolic soln, is heated with stirring to backflow, treat solid complete molten after, activated carbon decolorizing, the filtrate cooling crystallization obtains white crystalline powder, is the pyritinol hydrobromide monohydrate through structural identification, molecular formula is C
16H
20N
2O
4S
22HBrH
2O.This product can also obtain its no hydrate by the following method: with dissolving crude product in dehydrated alcohol, decolouring rear filtrate cooling crystallization, if also contain small amount of crystalline water by detecting in the product, available dehydrated alcohol periodic crystallisation is not then contained the Hydrogen bromide pyritinol of crystal water.
The pharmaceutical composition that the new pharmacy acceptable salt of pyritinol of the present invention and hydrate thereof can be made into different dosage form is used for the treatment of disease, as can be made into oral preparations or injection.Pharmaceutical composition of the present invention can only contain the The compounds of this invention of effective dose, or share with pharmaceutically acceptable carrier or thinner, and effective dosage ranges is that 0.04g～0.5g is (with C herein
16H
20N
2O
4S
2Meter), as make oral preparations, its unitary dose can be 0.04g～0.4g, and as 0.08g, 0.16g is (with C
16H
20N
2O
4S
2Meter), as make injection, its unitary dose can be 0.04g～0.4g, as 0.083g, and 0.166g, 0.332g is (with C
16H
20N
2O
4S
2Meter).
The low irritant of The compounds of this invention, the stability of high temperature, high humidity, illumination has been guaranteed the security of injection in clinical application; The highly water-soluble of The compounds of this invention also guaranteed to have high-dissolution based on the solid preparation of The compounds of this invention in the release in vitro process, and also guaranteed behind the oral administration good biological availability in vivo.
Below example further specifies beneficial effect of the present invention by experiment:
Test example 1 pyritinol hydrobromate, mesylate and pyritinol hydrochloride injection liquid compare the vein irritating test of rabbit
Test objective is observed the pyritinol hydrobromate, pyritinol mesylate injection liquid has nonirritant to blood vessel.
Be subjected to reagent thing pyritinol hydrobromate injection liquid, specification: 2ml; Pyritinol mesylate injection liquid, specification: 2ml; Pyritinol hydrochloride injection liquid, specification: 2ml, three samples all contain the pyritinol of equivalent, all self-control.
Contrast medicine 5% glucose injection, Sanjiu Yimin Pharmaceutic Co., Ltd., Jinan produces, lot number: 0407160301.
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 27 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.
The results are shown in 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 mesylate 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 hydrobromate 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 mesylate 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 hydrobromate 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 mesylate, hydrobromate and the hydrochloride of pyritinol compare, pungency to vein significantly reduces, substantially there is not pungency, wonderful effect has appearred in the mesylate, the hydrobromate that show pyritinol of the present invention, and this is that those of ordinary skill in the art institute is beyond thought.
The visual inspection result of table 1 pyritinol mesylate, pyritinol hydrobromate and pyritinol hydrochloride injection liquid rabbit ear vein injection back 24h and 3d
Pathological examination results after table 2 pyritinol hydrobromate and the injection of pyritinol hydrochloride injection liquid rabbit ear vein
The solubleness of test example 2 pyritinol mesylates, hydrobromate and pyritinol hydrochloride and stability are relatively
The generally very stable and no hygroscopicity of compound of the present invention.Below be and the solubleness comparative result of pyritinol hydrochloride and the comparative result of 10 days stability, method is operated with reference to two appendix of version pharmacopeia in 2000, and the result sees Table 3,4 respectively:
The comparison of table 3 pyritinol mesylate, pyritinol hydrobromate and pyritinol, pyritinol hydrochloride physico-chemical property
As can be seen from Table 3, compare with pyritinol, pyritinol hydrochloride, the solubleness of pyritinol mesylate in water has had extremely significantly to be improved, very easily dissolving in water; Water-soluble and the hydrochloride of pyritinol hydrobromate is close, and is easily molten in water.
The stability of table 4 pyritinol mesylate, pyritinol hydrobromate and pyritinol hydrochloride is (10 days) relatively
As can be seen from Table 4, compare with the pyritinol hydrochloride, pyritinol mesylate and pyritinol hydrobromate also are significantly increased to the stability of high temperature, illumination and high humidity, beyond thought effect occurred.
In sum, illustrate that pyritinol mesylate, hydrobromate have reduction extremely significantly to the pungency of vein, its solubleness, stability all are significantly increased and improve in addition, have solved the difficult problem of this product tolerance difference in clinical application, have produced positively effect.
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 experimental example and 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.
4, embodiment
Embodiment 1 prepares pyritinol mesylate monohydrate by pyritinol
Get pyritinol 10g (27mmol), drop in the reaction flask, add the 100ml deionized water then, stir into suspension, under agitation drip 6g methylsulfonic acid (62mmol)/50ml aqueous solution then, dropwise back stirring reaction 10 minutes, then reaction solution is concentrated into driedly, obtain off-white color pyritinol mesylate crude product.Crude product is joined in the 100ml aqueous ethanolic solution (90%), is heated with stirring to backflow, treat solid complete molten after, activated carbon decolorizing, the filtrate cooling crystallization obtains white crystalline powder 12.1g.Yield: 79.6%.
Purity: 99.8% (HPLC).
m.p.：152～155℃
IR spectrum (KBr, cm
-1): 2956,2924,2855,1460,1377,1260,1112
Ultimate analysis (C
16H
20N
2O
4S
22CH
3SO
3HH
2O): C:37.44% H:5.14% N:4.93% S:22.24% (theory: C:37.36% H:5.22% N:4.841% S:22.16%)
1H-NMR(600MHz，DMSO)δ：2.35(5H，s)，2.52(6H，d)，3.91(2H，w)，4.16(4H，s)，4.84(4H，s)，6.04(1H，w)，8.21(2H，s)，10.82(1H，w)，15.37(1H，w)
Embodiment 2 prepares the pyritinol hydrobromide monohydrate by pyritinol
Get pyritinol 10g (27mmol), drop in the reaction flask, add the 100ml deionized water then, stir into suspension, Dropwise 5 g Hydrogen bromide (61.8mmol)/50ml aqueous solution under agitation then, dropwise back stirring reaction 10 minutes, then reaction solution is concentrated into driedly, obtain off-white color Hydrogen bromide pyritinol crude product.Crude product is joined in 90ml/10ml ethanol-aqueous solution, is heated with stirring to backflow, treat solid complete molten after, activated carbon decolorizing, the filtrate cooling crystallization obtains white crystalline powder 11.5g, yield: 80%.
Fusing point: 202 ℃ (decomposition)
1H-NMR(600MHz，DMSO)δ：2.57(6H，d)，4.23(4H，s)，4.85(4H，s)，6.05(2H，w)，8.32(2H，s)，10.82(2H，w)，15.49(1H，w)
IR(KBr)cm-1：2961，2924，2854，1261，1093，1020，800
Ultimate analysis (C
16H
20N
2O
4S
22HBrH
2O): C:35.12% H:4.31% N:5.19%S:11.82% Br:29.24% (theory: C:35.05% H:4.41% N:5.11% S:11.70% Br:29.15%)
The preparation of embodiment 3 pyritinol mesylate aqueous injections
Prescription
Preparation technology:
1, the container of earlier dosing being used, ampoule, the plant-scale equipment, instrument etc. carry out pre-treatment.
2, recipe quantity takes by weighing raw material and auxiliary material (raw material give money as a gift pure then feed intake).
3, stirring and dissolving in the water for injection of raw material adding dosing amount 80%, the needle-use activated carbon temperature control of adding 0.1% stirred filtering decarbonization 10 minutes for 50 ℃.
4, survey the pH value of solution, add water and be settled to cumulative volume.
5, with the filtering with microporous membrane of 0.45 μ m.
6, check the clarity of solution.
7, the 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 pyritinol mesylate tablets
Prescription
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, 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, particle is dried under 50 ℃ condition.
6, dried 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 pyritinol in the mensuration particle.
8, compressing tablet.
9, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 5 injection pyritinol mesylates
Prescription
Preparation technology:
In aseptic weighing room, take by weighing aseptic pyritinol mesylate monohydrate by prescription, packing is sealed, promptly.
The preparation of embodiment 6 pyritinol mesylate sodium chloride injections
Prescription
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 pyritinol mesylate monohydrate, stirring and dissolving.
5, survey the pH value of solution, 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, the 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 pyritinol mesylate glucose injections
Prescription
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 pyritinol mesylate monohydrate, stirring and dissolving.
5, survey the pH value of solution, 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, the 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 pyritinol hydrobromate aqueous injections
Prescription
Preparation technology:
1, the 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 (raw material give money as a gift pure then feed intake) by recipe quantity.
3, with stirring and dissolving in the water for injection of pyritinol hydrobromide monohydrate adding dosing amount 80%, the needle-use activated carbon temperature control of adding 0.1% stirred filtering decarbonization 10 minutes for 50 ℃.
4, survey the pH value of solution, add water and be settled to cumulative volume.
5, with the filtering with microporous membrane of 0.45 μ m.
6, check the clarity of solution.
7, the 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 9 pyritinol hydrobromate tablets
Prescription
Pyritinol hydrobromide monohydrate 80g is (with C
16H
20N
2O
4S
2Meter)
Starch 20.0g
Microcrystalline Cellulose 35.0g
2%HPMC (50% ethanol) solution 50ml
Magnesium Stearate 1.2g
Prepare 1000 altogether
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, HPMC is soaked dissolving and make 2% 50% ethanolic soln, standby.
3, take by weighing raw material and auxiliary material according to recipe quantity.
4, pyritinol hydrobromide monohydrate and Microcrystalline Cellulose, starch are mixed, add the tackiness agent of getting ready, stir, make suitable softwood, cross 20 mesh sieve system particles.
5, particle is dried under 50 ℃ condition.
6, dried particle is crossed the whole grain of 18 mesh sieves, adds Magnesium Stearate and mixes.
7, sampling, work in-process chemical examination, the content of Hydrogen bromide pyritinol in the mensuration particle.
8, compressing tablet.
9, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 10 injection pyritinol hydrobromates
Prescription
Preparation technology: in aseptic weighing room, take by weighing aseptic Hydrogen bromide pyritinol by prescription, packing is sealed, promptly.
The preparation of embodiment 11 pyritinol hydrobromate sodium chloride injections
Prescription
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 pyritinol hydrobromide monohydrate, stirring and dissolving.
5, survey the pH value of solution, 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, the 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 12 pyritinol hydrobromate glucose injections
Prescription
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 Hydrogen bromide pyritinol, stirring and dissolving.
5, survey the pH value of solution, 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, the 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.
Claims (5)
1, the hydrate of pyritinol pharmacy acceptable salt is characterized in that, is pyritinol mesylate monohydrate.
2, a kind of pharmaceutical composition is characterized in that, comprises the pyritinol mesylate monohydrate as claimed in claim 1 and the pharmaceutical carrier/thinner of significant quantity.
3, pharmaceutical composition as claimed in claim 2, the effective dose of pyritinol is 0.04g～0.5g, with C
16H
20N
2O
4S
2Meter.
4, pharmaceutical composition as claimed in claim 3, it is oral preparations or non-oral formulation.
5, pharmaceutical composition as claimed in claim 4, non-oral formulation wherein are injection.
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| CN103992268A (en) * | 2014-06-06 | 2014-08-20 | 浙江永宁药业股份有限公司 | Pyritinol maleate and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3010966A (en) * | 1958-03-21 | 1961-11-28 | Merck Ag E | Derivatives of vitamin b6 |
| GB1153555A (en) * | 1967-03-25 | 1969-05-29 | Merck Ag E | Preparation of a Sulphur-Containing Pyridine Derivative |
| 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 |
-
2006
- 2006-05-04 CN CNB2006100795771A patent/CN100509787C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3010966A (en) * | 1958-03-21 | 1961-11-28 | Merck Ag E | Derivatives of vitamin b6 |
| GB1153555A (en) * | 1967-03-25 | 1969-05-29 | Merck Ag E | Preparation of a Sulphur-Containing Pyridine Derivative |
| 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 |
Non-Patent Citations (4)
| Title |
|---|
| 吡硫醇合成中硫化的工业改进. 宋宪梓.中国医药工业杂志，第21卷第1期. 1990 |
| 吡硫醇合成中硫化的工业改进. 宋宪梓.中国医药工业杂志，第21卷第1期. 1990 * |
| 盐酸吡硫醇的合成工艺改进. 陈文华.化学试剂，第27卷第10期. 2005 |
| 盐酸吡硫醇的合成工艺改进. 陈文华.化学试剂，第27卷第10期. 2005 * |
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| CN101003509A (en) | 2007-07-25 |
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