CN106236707A - A kind of preparation method of carboxylic maltose ferrum - Google Patents
A kind of preparation method of carboxylic maltose ferrum Download PDFInfo
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- CN106236707A CN106236707A CN201610871679.0A CN201610871679A CN106236707A CN 106236707 A CN106236707 A CN 106236707A CN 201610871679 A CN201610871679 A CN 201610871679A CN 106236707 A CN106236707 A CN 106236707A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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Abstract
The present invention disclose a kind of by carboxylic maltose ferrum building-up process add sucrose suppress carboxylic maltose rail injection liquid during pressure sterilizing molecular weight increase method, its consumption is the 0.25 20% of carboxylic maltose ferrum refined solution total iron content, and preferable amount is 0.25 10%.
Description
Technical field
The open one of the present invention suppresses carboxylic maltose rail injection liquid molecule during pressure sterilizing by adding sucrose
The method that amount increases, belongs to pharmaceutical technology.
Background technology
Ferrum is one of indispensable trace element of human body, the ferrum of the most about 70% be present in hemoglobin, Myoglobin,
In haemachrome enzyme, cofactor, it is again functional ferrum；Remaining ferrum is as internal storage ferrum, mainly with ferritin and iron content
Presented in xanthematin in liver, spleen and bone marrow, it is to constitute hemoglobin, Myoglobin and the important component of multiple enzyme.Lack
Ferrum can cause Various Tissues functional disorder, as affected adenoid normal development and supporting the decline of anti-infective ability, usual table
It it is now iron deficiency anemia.
As a kind of common food deficiency disease, chalybeate is the common medicine for the treatment of iron deficiency anemia, the iron ion of its release
Can be combined to play a role with iron transporter and ferritin, be used for treating or preventing iron deficiency anemia.Classify by dosage form, chalybeate
Oral Iron Preparations and injection chalybeate can be divided into.At present, the Oral Iron Preparations on market mainly have ferrous sulfate, Ferrous gluconate,
The ferrous salt such as ferrous fumarate, though taking convenience, but digestive tract is had obvious zest.It addition, the easy oxygen of principal agent ferrous salt
Changing, bioavailability is low, and ferrous ion is easily generated endogenous (OH) free radical in vivo, causes Cell membrane lipids peroxide
Change and cause damage.Injection chalybeate mainly includes the iron-carbohydrate networks such as iron dextran, iron sucrose, carboxylic maltose ferrum
Compound；For comparing Oral Iron Preparations, injection chalybeate is not only without GI irritation, and can realize quick iron supplement, the most in recent years
Obtain clinical practice widely.Iron dextran stable chemical nature, can be used for intramuscular injection, intravenous injection and vein and drips
Note.But the existence due to dextran, in fact it could happen that anaphylaxis, such as shock, asthma, respiratory failure etc..Iron sucrose structure is steady
Fixed, Avobenzone, but its part free iron can be directly entered blood, there is the risk of oxidative stress and infection.
Carboxylic maltose ferrum is a kind of novel intravenous injection chalybeate, for trivalent multinuclear ferrum core (β-FeOOH) by carboxyl Fructus Hordei Germinatus
The complex (code name is " VIT-45 ") that dextrin (i.e. maltodextrin oxidation product) surrounds and formed, this nucleocapsid structure can be by ferrum
Stable complexation and control the release of ferrum, the iron transporter, the ferritin that cause owing to blood concentration of iron is too high therefore can be prevented saturated
And the nitrous oxide produced.In carboxylic maltose ferrum, (24-32%, in its injection, iron content is 47.5-to iron content height
52.5mg/mL, can rapidly input 500-1500mg ferrum in 15min), administration number of times is few, and iron supplement is effective, largely carries
The high compliance of patient, is a kind of good Intravenous Supplement chalybeate.
Optimum molecular weight and synthesis technique about carboxylic maltose iron complex have involved in the domestic and international patent of many
And, WO2007/081744 discloses Ferinject/InjectaferTMThe molecular weight of active component carboxylic maltose ferrum should be
Between 100kDa and 350kDa, optimum is 150kDa；Patent US7612109, US2006/0205691, US2012/0412986 etc.
(one or more maltodextrins use time chlorine in the basic conditions by trivalent iron salt and maltodextrin oxidation product to disclose one
Hydrochlorate oxidation obtain) reaction to the method preparing carboxylic maltose ferrum.
We use synthetic method disclosed in US7612109 to prepare carboxylic maltose ferrum, but use this raw material to inject use
Injection prepared by water is after pressure sterilizing (about 121 DEG C of sterilizing 8-30min), and weight average molecular weight (Mw) is increased dramatically about 20-
30%, sterilization stability is poor.We prepare the higher carboxylic of sterilization stability by adjusting synthesis technique disclosed in this patent at plan
Maltose ferrum, as extended the complex reaction time, rising high reaction temperature, purified feed stock maltodextrin, control byproduct of reaction chlorination
The amount etc. of sodium, but all it is not reaching to preferable effect.In test, we have surprisingly found that, when adding in carboxylic maltose ferrum refined solution
After entering a small amount of sucrose, after prepared injection pressure sterilizing, weight average molecular weight without significant change or only has slight increase (1-
5%) problem that molecular weight increases during this injection pressure sterilizing, is significantly improved.
The present invention discloses a kind of in the building-up process of carboxylic maltose ferrum, suppresses carboxylic maltose ferrum to note by adding sucrose
Penetrate the liquid method that molecular weight increases during pressure sterilizing.Use carboxylic maltose ferrum sterilization stability prepared by the method more
High.
Summary of the invention
The present invention discloses and a kind of suppresses carboxylic maltose iron molecule amount during pressure sterilizing to increase by adding sucrose
Method.The technical scheme used comprises the following steps:
Step A: take carboxylic maltose ferrum crude reaction liquid, filters, and uses dialysis or ultrafiltration to remove the sodium chloride in filtrate
Deng small-molecule substance, obtain carboxylic maltose ferrum refined solution.
Step B: add suitable amount of sucrose, stirring and dissolving in the carboxylic maltose ferrum refined solution of step A；Then salt it is slowly added to
Acid-conditioning solution pH value is to 5-7, after continuously stirred 0.5-3h, and 0.22 μm filtering with microporous membrane, collect filtrate；It is spray-dried filtrate
Obtain pressed powder.
Step C: the pressed powder taking the acquisition of step B is dissolved in water for injection, 0.22 μm filtering with microporous membrane, embedding, heat
Pressure sterilizing 8-30min i.e. obtains carboxylic maltose rail injection liquid (concentration is calculated as 50mg/mL with iron content).
Carboxylic maltose ferrum crude reaction liquid used in step A of the present invention is according to method system disclosed in patent US7612109
Standby gained, does not repeats at this；Available bag filter dialysis or ultrafiltration reactant liquor, to remove the little molecules such as sodium chloride in solution, thoroughly
Analysis bag molecular cut off is at least 8-14kDa, and no more than 50kDa.
Step B of the present invention adds the 0.25-20% that consumption is carboxylic maltose ferrum refined solution total iron content of sucrose, preferably
Consumption is 0.25-10%；The concentration of hydrochloric acid of regulation solution ph is 0.5-20%, preferably 5-10%.
Using autoclaving that injection is carried out sterilizing in step C of the present invention, sterilising conditions is 121 DEG C, 8-30min,
Preferably sterilization time is 10-20min, F0At least up to more than 12.
The more detailed implementation of the present invention can be found in embodiment.
Accompanying drawing explanation
Fig. 1 and Fig. 2 is respectively the carboxylic maltose rail injection liquid (lot number using the method for the invention to prepare
2015112601) HPLC (GPC) chromatogram before sterilizing and after sterilizing and graph of molecular weight distribution.
Fig. 3 is that each embodiment middle-molecular-weihydroxyethyl increases percentage ratio summary.
Detailed description of the invention
Embodiment 1
Under room temperature, by stirring, 100g maltodextrin (glucose equivalent is 19.4) and 2g sodium bromide are dissolved in 420mL water
In, add appropriate 3% sodium hydroxide solution regulation pH value to 8-12；Under stirring, add 60mL liquor natrii hypochloritis (have
Effect chlorine is about 140g/L) maltodextrin is aoxidized, oxidization time is 2-6h；Then to the oxidation maltodextrin solution of gained
Middle addition 420g liquor ferri trichloridi (35%w/w), is slowly added to 706g sodium carbonate liquor (17.3%w/w) regulation pH value to 2-
3；Then it is slowly added to sodium hydroxide solution (30%w/w) regulation pH value and rises to 8-14, be heated to 60-100 DEG C, react 2-
6h, filtered while hot, obtain about 1750g carboxylic maltose ferrum crude reaction liquid.
Taking 100g carboxylic maltose ferrum crude reaction liquid, 0.22 μm filtering with microporous membrane, is that 8-14kDa bag filter is saturating with interception
Analysis filtrate removes the little molecules such as the sodium chloride in solution；Being slowly added to 5% hydrochloric acid conditioning solution pH value under stirring is 5-6,
Filter；Filtrate is spray-dried and obtains pressed powder；Take pressed powder to inject and be formulated as the solution containing 50mg/mL ferrum with water,
Filter, embedding, 121 DEG C of pressure sterilizing 20min, obtain carboxylic maltose rail injection liquid；Before measuring carboxylic maltose rail injection liquid sterilizing
After molecular weight.
It is 15.931kDa before carboxylic maltose rail injection liquid weight average molecular weight Mw sterilizing, is 20.682kDa after sterilizing, increase
29.8%.
Embodiment 2
Taking 100g carboxylic maltose ferrum crude reaction liquid, 0.22 μm filtering with microporous membrane, is that 8-14kDa bag filter is saturating with interception
Analysis filtrate removes the little molecules such as the sodium chloride in solution, obtains carboxylic maltose ferrum refined solution；Sucrose (carboxylic Fructus Hordei Germinatus is added in refined solution
The 4% of sugar ferrum refined solution total iron content), stirring and dissolving；Being slowly added to 5% hydrochloric acid conditioning solution pH value under stirring is 5-6,
Filter；Filtrate is spray-dried and obtains pressed powder；Take pressed powder to inject and be formulated as the solution containing 50mg/mL ferrum with water,
Filter, embedding, 121 DEG C of pressure sterilizing 20min, obtain carboxylic maltose rail injection liquid；Before measuring carboxylic maltose rail injection liquid sterilizing
After molecular weight.
It is 15.207kDa before carboxylic maltose rail injection liquid weight average molecular weight Mw sterilizing, is 15.822kDa after sterilizing, increase
4.0%.
Embodiment 3
Taking 100g carboxylic maltose ferrum crude reaction liquid, 0.22 μm filtering with microporous membrane, is that 8-14kDa bag filter is saturating with interception
Analysis filtrate removes the little molecules such as the sodium chloride in solution, obtains carboxylic maltose ferrum refined solution；Sodium chloride (carboxylic wheat is added in refined solution
The 4% of bud sugar ferrum refined solution total iron content), stirring and dissolving；Being slowly added to 5% hydrochloric acid conditioning solution pH value under stirring is 5-
6, filter；Filtrate is spray-dried and obtains pressed powder；Take pressed powder inject with water be formulated as containing 50mg/mL ferrum molten
Liquid, filters, embedding, 121 DEG C of pressure sterilizing 20min, obtains carboxylic maltose rail injection liquid；Measure carboxylic maltose rail injection liquid sterilizing
Molecular weight front and back.
It is 14.945kDa before carboxylic maltose rail injection liquid weight average molecular weight Mw sterilizing, is 20.231kDa after sterilizing, increase
35.4%.
Embodiment 4
Taking 100g carboxylic maltose ferrum crude reaction liquid, 0.22 μm filtering with microporous membrane, is that 8-14kDa bag filter is saturating with interception
Analysis filtrate removes the little molecules such as the sodium chloride in solution, obtains carboxylic maltose ferrum refined solution；Sodium chloride (carboxylic wheat is added in refined solution
The 0.25% of bud sugar ferrum refined solution total iron content), stirring and dissolving；5% hydrochloric acid conditioning solution pH value it is slowly added under stirring
For 5-6, filter；Filtrate is spray-dried and obtains pressed powder；Take pressed powder to inject and be formulated as containing 50mg/mL ferrum with water
Solution, filters, embedding, 121 DEG C of pressure sterilizing 20min, obtains carboxylic maltose rail injection liquid；Measure carboxylic maltose rail injection liquid to go out
Molecular weight before and after bacterium.
It is 15.017kDa before carboxylic maltose rail injection liquid weight average molecular weight Mw sterilizing, is 15.612kDa after sterilizing, increase
4.0%.
Embodiment 5
Taking 100g carboxylic maltose ferrum crude reaction liquid, 0.22 μm filtering with microporous membrane, is that 8-14kDa bag filter is saturating with interception
Analysis filtrate removes the little molecules such as the sodium chloride in solution, obtains carboxylic maltose ferrum refined solution；Sucrose (carboxylic Fructus Hordei Germinatus is added in refined solution
The 20% of sugar ferrum refined solution total iron content), stirring and dissolving；Being slowly added to 5% hydrochloric acid conditioning solution pH value under stirring is 5-
6, filter；Filtrate is spray-dried and obtains pressed powder；Take pressed powder inject with water be formulated as containing 50mg/mL ferrum molten
Liquid, filters, embedding, 121 DEG C of pressure sterilizing 20min, obtains carboxylic maltose rail injection liquid；Measure carboxylic maltose rail injection liquid sterilizing
Molecular weight front and back.
It is 15.158kDa before carboxylic maltose rail injection liquid weight average molecular weight Mw sterilizing, is 15.559kDa after sterilizing, increase
2.6%.
The amount and the molecular weight that add sucrose in each embodiment increase percentage ratio and are summarized in table 1.
The ratio of the amount and molecular weight increase that add sucrose in each embodiment of table 1 is summed up
Upper table result shows, sucrose can the most substantially suppress the molecular weight after carboxylic maltose rail injection liquid sterilizing to increase
Adding, its effect of Inhibitory molecules amount effect in the range of 0.25% to 20% is the most notable, and sodium chloride is without obvious effect.
Claims (5)
1. one kind is suppressed carboxylic maltose rail injection liquid at pressure sterilizing by addition sucrose in carboxylic maltose ferrum building-up process
During molecular weight increase method, it is characterised in that comprise the following steps: step A: take carboxylic maltose ferrum crude reaction liquid, mistake
Filter, uses dialysis or ultrafiltration to remove the small-molecule substances such as the sodium chloride in filtrate, obtains carboxylic maltose ferrum refined solution；Step
B: add suitable amount of sucrose, stirring and dissolving in carboxylic maltose ferrum refined solution, be slowly added to hydrochloric acid conditioning solution pH value to 5-7, hold
After continuous stirring 0.5-3h, 0.22 μm filtering with microporous membrane, collect filtrate, then be spray-dried filtrate acquisition pressed powder；Step C:
Taking pressed powder to be dissolved in water for injection, 0.22 μm filtering with microporous membrane, embedding, pressure sterilizing i.e. obtains carboxylic maltose rail injection liquid
(concentration is calculated as 50mg/mL with iron content).
One the most according to claim 1 suppresses carboxylic maltose by adding sucrose in carboxylic maltose ferrum building-up process
The rail injection liquid method that molecular weight increases during pressure sterilizing, it is characterised in that in described step A, purification filtrate is adopted
Bag filter molecular cut off be at least 8-14kDa, and no more than 50kDa.
One the most according to claim 1 suppresses carboxylic maltose by adding sucrose in carboxylic maltose ferrum building-up process
The rail injection liquid method that molecular weight increases during pressure sterilizing, it is characterised in that in described step B, the consumption of sucrose
0.25-20%, preferably 0.25-10% for carboxylic maltose ferrum refined solution total iron content.
One the most according to claim 1 suppresses carboxylic maltose by adding sucrose in carboxylic maltose ferrum building-up process
The rail injection liquid method that molecular weight increases during pressure sterilizing, it is characterised in that in described step B, regulates pH value of solution
The concentration of hydrochloric acid of value is 0.5-20%, preferably 5-10%.
One the most according to claim 1 suppresses carboxylic maltose by adding sucrose in carboxylic maltose ferrum building-up process
The rail injection liquid method that molecular weight increases during pressure sterilizing, it is characterised in that in described step C, uses hot pressing to go out
Bacterium method carries out sterilizing to injection, and sterilising conditions is 121 DEG C, and 8-30min, preferably sterilization time are 10-20min, F0At least up to
To more than 12.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111077252A (en) * | 2019-12-30 | 2020-04-28 | 东营天东制药有限公司 | Method for detecting content of carbohydrate in carboxyl maltose iron |
| CN113018256A (en) * | 2019-12-25 | 2021-06-25 | 金陵药业股份有限公司 | Preparation process of ferric carboxymaltose injection |
| TWI784646B (en) * | 2021-07-29 | 2022-11-21 | 台耀化學股份有限公司 | Method for preparing ferric carboxymaltose |
Citations (1)
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| CN105125577A (en) * | 2015-07-29 | 2015-12-09 | 南京生命能科技开发有限公司 | Stable sugar-iron compound and preparation method thereof |
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2016
- 2016-09-27 CN CN201610871679.0A patent/CN106236707B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105125577A (en) * | 2015-07-29 | 2015-12-09 | 南京生命能科技开发有限公司 | Stable sugar-iron compound and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 毛凯等: "低聚异麦芽糖铁配合物的制备工艺优化", 《食品科学》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113018256A (en) * | 2019-12-25 | 2021-06-25 | 金陵药业股份有限公司 | Preparation process of ferric carboxymaltose injection |
| CN113018256B (en) * | 2019-12-25 | 2023-02-17 | 金陵药业股份有限公司 | Preparation process of ferric carboxymaltose injection |
| CN111077252A (en) * | 2019-12-30 | 2020-04-28 | 东营天东制药有限公司 | Method for detecting content of carbohydrate in carboxyl maltose iron |
| TWI784646B (en) * | 2021-07-29 | 2022-11-21 | 台耀化學股份有限公司 | Method for preparing ferric carboxymaltose |
| US11731998B2 (en) | 2021-07-29 | 2023-08-22 | Formosa Laboratories, Inc | Method of preparing ferric carboxymaltose |
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