CN104558064A - Preparation method of iron sucrose - Google Patents
Preparation method of iron sucrose Download PDFInfo
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- CN104558064A CN104558064A CN201310517696.0A CN201310517696A CN104558064A CN 104558064 A CN104558064 A CN 104558064A CN 201310517696 A CN201310517696 A CN 201310517696A CN 104558064 A CN104558064 A CN 104558064A
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Abstract
The invention belongs to the field of medicinal chemistry and specifically provides an iron sucrose complex which is stable in quality, prone to industrialization and relatively narrow in molecular weight. A trivalent iron salt and an inorganic base are reacted under the reaction of 5-20 DEG C to prepare a ferric hydroxide colloid; a complex reaction is performed on the ferric hydroxide colloid and cane sugar under the condition of 100-120 DEG C to obtain an iron sucrose liquid; the iron sucrose liquid is spray-dried to obtain a solid; and the invention also relates to an application of the iron sucrose in pharmaceutical preparations for treating iron-deficiency anemia.
Description
Technical field
The invention belongs to medicinal chemistry art, be specially the preparation method of iron sucrose solution and iron sucrose solid.
Background technology
The patient for the treatment of to hypoferric anemia of iron deficiency is necessary, wherein intravenous injection is specially adapted to those and can not tolerates Oral Iron Preparations treatment, dietary iron can not be absorbed completely or have the crowd of hematopoietic disorders, in intravenous injection chalybeate, Iron Dextran is widely used, but it has obvious untoward reaction, it is reported, accept in the patient of Iron Dextran treatment, there is side effect in the patient close to 26%, cause the basic reason of this serious side reaction also indefinite, but, the known anaphylaxis to dextran is the reason causing this serious side effects, the intravenous injection chalybeate that so there is no dextran can reduce or avoid these side effects.Sucrose complex is exactly a kind of intravenous injection chalybeate not having dextran, iron sucrose is called Venofer (a kind of iron sucrose injection) list marketing in nineteen fifty by Luitpold drugmaker with medicine, a kind of medicine for using the long-term hemodialysis patients of erythropoietin to carry out iron supplement therapy, since nineteen ninety-two 66 national list marketings.
It is reported that sucrose complex adverse reaction rate is low, 77 routine patient accept altogether in 757 agent quantifier elimination, 4 routine patients are only had to experienced by untoward reaction owing to having injected iron sucrose injection, adverse events be diarrhoea, stomachache, feel sick, constipation and the of short duration sense of taste malfunctioning, in research, 10 examples have the patient of irritated record to dextran, its none experience anaphylaxis when using iron sucrose.Sucrose complex usually comprise auxiliary material, free sucrose and complexing time the by product that produces, can be detected by technology such as gel permeation chromatographies, the analytical procedure detecting sucrose complex has report in American Pharmacopeia.
The chromatographic process of abstraction and purification sucrose complex is disclosed in United States Patent (USP) 20020076821 and 20030153086.Also disclose a kind of molecular weight and be less than 5000 dalton, substantially the sucrose complex of auxiliary material is not had, on molecular structure and composition, little change just can determine that a kind of active iron complex compound does not have side reaction, another kind of iron complex then may cause side reaction (Raising the Bar for Quality Drugs, P26 ~ 31, Chemical and Engineering News, American Chemical Society, Mar.19, 2001), the toxicity of sucrose complex and higher molecular weight and complex compound difference in size correlate (Fishbane et al., Semin Dial.2000November-December, 13 (6): 3814), sucrose complex comprises a narrower molecular weight distribution, safer, the more effective treatment result of one can be produced, need a kind of preparation method of sucrose complex of necessity, make it compared with existing complex compound, the product of molecular weight distribution in a narrower scope can be produced.
United States Patent (USP) 20050209187 reports and makes iron(ic) chloride and alkali effect generate ironic hydroxide at 20 DEG C, then sucrose complex is obtained by reacting with sucrose, molecular-weight average 20000 to about 400000 dalton, preferable range 30000 to 60000 dalton, and obtain sucrose complex non-type solid by the method for organic solvent crystallization, prove that the sucrose complex solution that aforesaid method obtains needs to use a large amount of organic solvents that its solid just can be made to separate out by experiment, and need to use some 2 kind solvents as methyl alcohol, acetone etc., the quality product heterogeneity simultaneously obtained, by preparation high-temperature sterilization, molecular weight can increase, in view of the shortcoming of aforesaid method, need a kind of pollution of exploitation little, steady quality, reaction safety is high, cost is low, be easy to industrialized preparation method and the complex compound compared with narrow molecular-weight.
Summary of the invention
Object of the present invention provides a kind of sucrose complex had compared with narrow molecular-weight, and preparation method is simple, saves and environmental friendliness.
Iron sucrose molecular formula of the present invention: [Na
2fe
5o
8(OH) 3 (H
2o)]
nm (C
12h
22o
11), weight-average molecular weight: about 43kDa.
Be specifically as follows: Mw (weight-average molecular weight)=34,000 ~ 60,000 dalton (D), Mn (number-average molecular weight)=24,000 ~ 36000 dalton (D), Mw/Mn (molecular weight distribution) should be not more than 1.7.
The preparation method of iron sucrose solution of the present invention, comprises following steps:
A trivalent iron salt and mineral alkali react and prepare ferric hydroxide colloid by ();
B ferric hydroxide colloid and sucrose are carried out complex reaction and obtain iron sucrose solution by ();
Wherein step (a) temperature of reaction is 5 ~ 20 DEG C, and research preferred steps (b) complex reaction temperature is 100 ~ 120 DEG C.
The preparation method of iron sucrose solid of the present invention, above-mentioned iron sucrose solution drying obtains, drying means can be vacuum-drying, preferably spray drying, spray-dired parameter can according to equipment, process condition adjustment, preferably spray drying inlet temperature is 130 ~ 150 DEG C, and air outlet temperature is 80 ~ 100 DEG C.
The present invention also comprises: iron sucrose prepared by the inventive method, the application in hypoferric anemia pharmaceutical preparation; The present invention can also comprise iron sucrose medicinal compositions, comprises the iron sucrose of above-mentioned any preparation for the treatment of significant quantity, and the pharmaceutically acceptable carrier of at least one.
Wherein method (a) prepares the method for ferric hydroxide colloid, is 5 ~ 20 DEG C of reactions in temperature, preferable temperature 10 ~ 20 degree reaction, and trivalent iron salt can be iron(ic) chloride, iron nitrate, ferric sulfate; Preferred iron(ic) chloride.Mineral alkali can be one in sodium carbonate, sodium bicarbonate, sodium hydroxide or mixed base, preferred sodium carbonate, in preparation process, find that temperature controls particularly important, if reacting the ferric hydroxide colloid that obtains and sucrose in temperature higher than 20 DEG C, to be obtained by reacting the molecular weight of product wider, be specially number-average molecular weight 38533, weight-average molecular weight 66044; Temperature lower than 5 DEG C, iron sucrose as number-average molecular weight 41021, weight-average molecular weight 62313.
Method (b) prepares the sucrose complex aqueous solution, ferric hydroxide colloid can first mix with sucrose by preparation at room temperature crosses 40 ~ 200 mesh sieves, then by solution heating slowly heating, until temperature steams moisture content to 120 DEG C of insulations, until cloud point qualified after, stop heating, temperature easily makes iron sucrose molecular weight increase higher than 120 DEG C, thus molecular weight is broadened, and the low meeting of temperature makes cloud point defective.
Prepared by iron sucrose solid preferably spray drying method, the drying of sucrose complex solution is obtained pulverulent solids, not only avoids in this way using organic solvent, and dried powder quality is homogeneous, and molecular weight ranges is narrow.Because sucrose complex is soluble in water, and draw by force moist, strictly will control inlet temperature and the air outlet temperature of spray drying device, preferable temperature is inlet temperature 130 ~ 150 DEG C, air outlet temperature 80 ~ 100 DEG C.
Prepare iron sucrose solid for sodium carbonate and iron(ic) chloride, reaction equation is:
Iron sucrose molecular weight and molecular weight distribution of the present invention, cloud point measuring method are:
1, molecular weight and molecular weight distribution measures according to the molecular weight and molecular weight distribution assay method (Chinese Pharmacopoeia 2101 editions two annex V H) of polysaccharide.
Chromatographic condition and system suitability test are with special gel post (Shodex Ohpak SB-804HQ); Be dissolved in for moving phase in 2000ml water with 14.31g Sodium phosphate dibasic, 6.35g SODIUM PHOSPHATE, MONOBASIC and 0.40g sodiumazide, column temperature 45 DEG C; Flow velocity 0.5ml/min; Adopt differential refraction detector.Number of theoretical plate calculates should be not less than 5000 by glucose peaks.Standard specimen is the dextran of known molecular amount, and weight-average molecular weight is respectively 5,900,11,800,22,800,47,300 and 112,000.
Standardized solution gets 20mg known molecular amount, and (weight-average molecular weight is 5,900 ~ 112,000) dextran, accurately weighed, put in 5ml volumetric flask respectively, add 2ml moving phase, below 25 DEG C place more than 12 hours, make fully swelling after, slow jolting every bottle solution, make it slowly dissolve, to obtain final product.
Assay method gets each 20 μ l of above-mentioned standardized solution respectively, injection liquid chromatography, record color atlas, separately get this product appropriate (being equivalent to 40mg iron) to put in 10ml measuring bottle, add moving phase and dissolve and be diluted to scale, obtain need testing solution, get 20 μ l injection liquid chromatographies, record color atlas, data acquisition GPC special software process, to obtain final product.
2, cloud point is got this product appropriate (being equivalent to 10mg iron) and is put in 150ml beaker, the 100ml that adds water dilutes, the hydrochloric acid soln slowly dripping 0.1mol/L is under continuous stirring about 6.0 to pH value, remove pH meter, light source is regulated to make light beam from 2cm under liquid level parallel across solution, solution in light path must not see muddiness (measure and carry out in darkroom as far as possible), slowly drip the hydrochloric acid soln of 0.1mol/L under continuous stirring, to light path, solution occurs continuing muddiness, stop stirring, record pH value (Chinese Pharmacopoeia version in 2010 two annex VI H), be the cloud point of sample, should be 4.4 ~ 5.3.
Embodiment
Following examples just further illustrate the present invention, and the present invention is not limited in the content of following examples.
Embodiment 1
1.04kg ferric chloride hexahydrate (3.85mol) is joined in 3L purified water and dissolves, taking anhydrous sodium carbonate 670g (6.3mol) is dissolved in 7L purified water, be cooled to 12 DEG C, by in above-mentioned sodium carbonate solution instillation ferric chloride Solution under stirring, stir 1 hour, filter to obtain ironic hydroxide solid, this solid was mixed 100 mesh sieves with 3kg sucrose, then 110 DEG C are heated to, the distribution of sampling detection molecules amount; Weight-average molecular weight (Mw) should be 49705Da, and number-average molecular weight (Mn) should be 30968Da, Tile Width (Mw/Mn) 1.6, by the dry inlet temperature 140 DEG C of spray-dryer; Air outlet temperature 90 DEG C, obtains iron sucrose powder 3.3kg, and weight-average molecular weight (Mw) should be 49660Da, and number-average molecular weight (Mn) should be 30668Da, Tile Width (Mw/Mn) 1.6.
Embodiment 2
1.04kg ferric chloride hexahydrate (3.85mol) is joined in 3L purified water and dissolves, taking anhydrous sodium carbonate 670g (6.3mol) is dissolved in 7L purified water, be cooled to 18 DEG C, by in above-mentioned sodium carbonate solution instillation ferric chloride Solution under stirring, stir 1 hour, filter to obtain ironic hydroxide solid, this solid was mixed 150 mesh sieves with 3kg sucrose, then 110 DEG C are heated to, the distribution of sampling detection molecules amount, weight-average molecular weight (Mw) should be 49632Da, number-average molecular weight (Mn) should be 32007Da, Tile Width (Mw/Mn) 1.55, by the dry inlet temperature 130 DEG C of spray-dryer, air outlet temperature 100 DEG C, obtains iron sucrose powder 3.2kg, and weight-average molecular weight (Mw) should be 49771Da, and number-average molecular weight (Mn) should be 32168Da, Tile Width (Mw/Mn) 1.55.
Embodiment 3
1.04kg ferric chloride hexahydrate (3.85mol) is joined in 3L purified water and dissolves, taking anhydrous sodium carbonate 670g (6.3mol) is dissolved in 7L purified water, room temperature 24 DEG C, by in above-mentioned sodium carbonate solution instillation ferric chloride Solution under stirring, stir 1 hour, filter to obtain ironic hydroxide solid, this solid was mixed 100 mesh sieves with 3kg sucrose, then 110 DEG C are heated to, the distribution of sampling detection molecules amount, weight-average molecular weight (Mw) should be 66044Da, number-average molecular weight (Mn) should be 38533Da, Tile Width (Mw/Mn) 1.71, by the dry inlet temperature 140 DEG C of spray-dryer, air outlet temperature 90 DEG C, obtain iron sucrose powder 3.3kg, weight-average molecular weight (Mw) should be 66102Da, number-average molecular weight (Mn) should be 38620Da, Tile Width (Mw/Mn) 1.71.
Embodiment 4
1.04kg ferric chloride hexahydrate (3.85mol) is joined in 3L purified water and dissolves, taking anhydrous sodium carbonate 670g (6.3mol) is dissolved in 7L purified water, be cooled to 2 DEG C, by in above-mentioned sodium carbonate solution instillation ferric chloride Solution under stirring, stir 1 hour, filter to obtain ironic hydroxide solid, this solid was mixed 150 mesh sieves with 3kg sucrose, then 110 DEG C are heated to, the distribution of sampling detection molecules amount, weight-average molecular weight (Mw) should be 62313Da, number-average molecular weight (Mn) should be 41021Da, Tile Width (Mw/Mn) 1.52, by the dry inlet temperature 130 DEG C of spray-dryer, air outlet temperature 100 DEG C, obtain iron sucrose powder 3.3kg, weight-average molecular weight (Mw) should be 62275Da, number-average molecular weight (Mn) should be 41165Da, Tile Width (Mw/Mn) 1.55.
Embodiment 5
1.6kg iron nitrate (3.85mol) is joined in 3L purified water and dissolves, weighing sodium hydroxide 504g (12.6mol) is dissolved in 7L purified water, be cooled to 12 DEG C, by in above-mentioned sodium carbonate solution instillation iron nitrate solution under stirring, stir 1 hour, filter to obtain ironic hydroxide solid, this solid was mixed 100 mesh sieves with 3kg sucrose, then 110 DEG C are heated to, the distribution of sampling detection molecules amount, weight-average molecular weight (Mw) should be 43495Da, number-average molecular weight (Mn) should be 30236Da, Tile Width (Mw/Mn) 1.438, by the dry inlet temperature 140 DEG C of spray-dryer, air outlet temperature 90 DEG C, obtain iron sucrose powder 3.3kg, weight-average molecular weight (Mw) should be 43560Da, number-average molecular weight (Mn) should be 30168Da, Tile Width (Mw/Mn) 1.4.
Embodiment 6
1.04kg ferric chloride hexahydrate (3.85mol) is joined in 3L purified water and dissolves, taking anhydrous sodium carbonate 670g (6.3mol) is dissolved in 7L purified water, be cooled to 12 DEG C, by in above-mentioned sodium carbonate solution instillation ferric chloride Solution under stirring, stir 1 hour, filter to obtain ironic hydroxide solid, this solid was mixed 100 mesh sieves with 3kg sucrose, then 95 DEG C are heated to, the distribution of sampling detection molecules amount, weight-average molecular weight (Mw) should be 71060Da, number-average molecular weight (Mn) should be 46859Da, Tile Width (Mw/Mn) 1.52, by the dry inlet temperature 140 DEG C of spray-dryer, air outlet temperature 90 DEG C, obtain iron sucrose powder 3.2kg, weight-average molecular weight (Mw) should be 69862Da, and number-average molecular weight (Mn) should be 45821Da, Tile Width (Mw/Mn) 1.5, but it is defective to detect cloud point.
Embodiment 7
1.04kg ferric chloride hexahydrate (3.85mol) is joined in 3L purified water and dissolves, taking anhydrous sodium carbonate 670g (6.3mol) is dissolved in 7L purified water, be cooled to 12 DEG C, by in above-mentioned sodium carbonate solution instillation ferric chloride Solution under stirring, stir 1 hour, filter to obtain ironic hydroxide solid, this solid was mixed 100 mesh sieves with 3kg sucrose, then 125 DEG C are heated to, the distribution of sampling detection molecules amount, weight-average molecular weight (Mw) should be 88544Da, number-average molecular weight (Mn) should be 48446Da, Tile Width (Mw/Mn) 1.83, by the dry inlet temperature 140 DEG C of spray-dryer, air outlet temperature 90 DEG C, obtain iron sucrose powder 3.1kg, weight-average molecular weight (Mw) should be 88351Da, and number-average molecular weight (Mn) should be 48541Da, Tile Width (Mw/Mn) 1.8.
Claims (4)
1. a preparation method for iron sucrose solution, comprises following steps:
A trivalent iron salt and mineral alkali react and prepare ferric hydroxide colloid by ();
B ferric hydroxide colloid and sucrose are carried out complex reaction and obtain iron sucrose solution by ();
It is characterized in that, step (a) temperature of reaction is 5 ~ 20 DEG C, and step (b) complex reaction temperature is 100 ~ 120 DEG C.
2. a preparation method for iron sucrose solid, is characterized in that: use claim 1 iron sucrose solution is spray-dried to be obtained.
3. the preparation method of iron sucrose solid according to claim 2, it is characterized in that: spray-dired inlet temperature is 130 ~ 150 DEG C, air outlet temperature is 80 ~ 100 DEG C.
4. the iron sucrose prepared of claim 1-3 any one, the application in hypoferric anemia pharmaceutical preparation.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106234774A (en) * | 2016-08-01 | 2016-12-21 | 南宁市泽威尔饲料有限责任公司 | The preparation method of sucrose magnesium complex |
| EP3302504A4 (en) * | 2015-05-29 | 2019-01-23 | Sun Pharmaceutical Industries Limited | Composition of iron sucrose and process for its preparation |
| CN110551019A (en) * | 2019-09-12 | 2019-12-10 | 天津医科大学 | Ferrous sugar (II) compound, preparation method and application thereof |
| CN112168844A (en) * | 2020-09-29 | 2021-01-05 | 神奈纳米医药技术(珠海)有限公司 | Preparation method of iron hydroxide carbohydrate compound |
| JP2022522009A (en) * | 2019-02-28 | 2022-04-13 | レニバス・セラピューティクス・インコーポレイテッド | New iron composition and its manufacturing method and usage method |
| CN115317494A (en) * | 2022-07-22 | 2022-11-11 | 康瑞鑫(天津)药物研究院有限公司 | Sucrose ferric oxide hydroxide with high phosphate bonding force and preparation method thereof |
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| WO2006061685A1 (en) * | 2004-12-06 | 2006-06-15 | Emcure Pharmaceuticals Limited | A cost-effective process for preparation of manufacture of iron sucrose |
| CN1895260A (en) * | 2006-06-23 | 2007-01-17 | 杭州平和堂医药科技有限公司 | Sucrose-ferri aseptic powdery injection and its preparation |
| CN103059072A (en) * | 2013-01-18 | 2013-04-24 | 常州工程职业技术学院 | Preparation method of raw medicine of environment-friendly iron sucrose |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20050209187A1 (en) * | 2004-03-16 | 2005-09-22 | Navinta Llc | Iron sucrose complexes and method of manufacture thereof |
| WO2006061685A1 (en) * | 2004-12-06 | 2006-06-15 | Emcure Pharmaceuticals Limited | A cost-effective process for preparation of manufacture of iron sucrose |
| CN1895260A (en) * | 2006-06-23 | 2007-01-17 | 杭州平和堂医药科技有限公司 | Sucrose-ferri aseptic powdery injection and its preparation |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3302504A4 (en) * | 2015-05-29 | 2019-01-23 | Sun Pharmaceutical Industries Limited | Composition of iron sucrose and process for its preparation |
| CN106234774A (en) * | 2016-08-01 | 2016-12-21 | 南宁市泽威尔饲料有限责任公司 | The preparation method of sucrose magnesium complex |
| JP2022522009A (en) * | 2019-02-28 | 2022-04-13 | レニバス・セラピューティクス・インコーポレイテッド | New iron composition and its manufacturing method and usage method |
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| CN110551019A (en) * | 2019-09-12 | 2019-12-10 | 天津医科大学 | Ferrous sugar (II) compound, preparation method and application thereof |
| CN112168844A (en) * | 2020-09-29 | 2021-01-05 | 神奈纳米医药技术(珠海)有限公司 | Preparation method of iron hydroxide carbohydrate compound |
| CN115317494A (en) * | 2022-07-22 | 2022-11-11 | 康瑞鑫(天津)药物研究院有限公司 | Sucrose ferric oxide hydroxide with high phosphate bonding force and preparation method thereof |
| CN115317494B (en) * | 2022-07-22 | 2024-02-13 | 康瑞鑫(天津)药物研究院有限公司 | Sucrose ferric hydroxide with high phosphate binding force and preparation method thereof |
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