CN105520955B - A kind of carboxyl maltose iron Pharmaceutical composition and preparation method thereof - Google Patents
A kind of carboxyl maltose iron Pharmaceutical composition and preparation method thereof Download PDFInfo
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
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- A61K33/26—Iron; Compounds thereof
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- 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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- A61K9/0012—Galenical forms characterised by the site of application
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Abstract
The invention discloses a kind of carboxyl maltose iron Pharmaceutical composition and preparation method thereof.Carboxyl maltose iron Pharmaceutical composition, the meglumine of carboxyl maltose iron, 1~15 parts by weight containing 10~30 parts by weight and pharmaceutically acceptable one or more pH adjusting agents and water for injection.The preparation method of composition of the present invention, comprises the following steps：A, carboxyl maltose iron is added in water for injection with meglumine and dissolved；B, a resulting solutions pH adjusting agent is adjusted into pH value；C, the made solution of b is filtered into filling sterilizing.The present invention Pharmaceutical composition have iron ion be not easy to dissociate, free iron is low, and stability is good, it is safe the characteristics of.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, is related to a kind of carboxyl maltose iron Pharmaceutical composition and preparation method thereof.
Background technology
Hypoferric anemia is still the universal and important health problem in the whole world, especially developing country so far.Defended according to the world
Raw tissue statistics, the whole world there are about 4,000,000,000 people and is in iron-deficient status, and about 1,500,000,000 people suffer from hypoferric anemia.China is iron deficiency in the world
Property one of the higher area of anaemia incidence, Chinese 4th nutrition survey the result shows that, Chinese residents hypoferric anemia is diseased
Rate is 20.1%, wherein<2 years old infants,>60 years old the elderlys and the hypoferric anemia illness rate difference of the 15-50 Sui women of child-bearing age
31.1%th, 29.1% and 19.9%.
The treatment method of hypoferric anemia is generally using benefit iron drug therapy, it is therefore intended that supplemental blood is lacked with tissue
Iron, makes hemoglobin recover normal level, and supplies storage iron.Oral iron of mending is effective, inexpensive and safe, is hypoferric anemia
Choice drug.But Oral Iron Preparations iron content rate is low, and bioavilability is low, often there is obvious gastrointestinal discomfort symptom, also by food into
The interference of part and the influence of internal Blood lipids, so as to influence the absorption and utilization of iron, Oral Iron Preparations effect is often very poor at this time
It is or absolutely void.Especially in many chronic diseases (including chronic heart failure, renal failure etc.) and tumor patient,
Internal inflammatory cellular mediators increase, and inflammatory mediator (such as interleukin-6) can induce liver synthesis Fe regulatory protein, the latter
Intestines and stomach and the in vivo expression of storage siderocyte skin covering of the surface iron transporter are lowered, so as to influence the absorption and utilization of iron, mouth at this time
It is often very poor or absolutely void to take chalybeate effect, even if taking 200mg elemental irons daily, cannot still meet hematopoietin
(EPO) needs of iron deficiency when treating.At this time, injection chalybeate becomes choice drug, it can more quickly restore iron storage, and rise is blood red
Protein level.
At present in the world for clinical practice injection chalybeate include iron-dextrin, complex glucose acid sodium iron, iron sucrose,
Iron Sorbitex, isomaltose acid anhydride iron 1000, Ferumoxytol (polysaccharide superparamagnetic iron oxide) and carboxyl maltose iron.Wherein
Carboxyl maltose iron, can be effectively by iron transfer to internal due to good degradation rate and physicochemical characteristics
Storage and transport protein, are a kind of more satisfactory injection chalybeates.Carboxyl maltose iron can safely and fast mend iron and alternative
Blood transfusion, which overcomes oral iron (representative products turn of speed phenanthrene and Niferex) course for the treatment of length (often wanting more than half a year), effective slow, expense
With it is high, gastrointestinal reaction is big, more than a day secondary medication poor resistance the shortcomings that, even anaemia caused by disease of digestive tract can also make
With；Compared with the compound such as Iron Sorbitex of low molecular weight, this product is more effective, and toxicity smaller；This product from iron sucrose and
The same high ph-values of complex glucose acid sodium iron phase and osmotic pressure limitation, and cause dosage to be limited, in addition, other Intravenous Iron in Maintenance are such as
Iron sucrose needs to be transfused when 3.5 is small (500mg iron) every time due to pH value and osmotic pressure limitation；It is steady from iron transfer and compound
From the point of view of qualitative, this product is comparable with dextran, but it greatly reduces dextran and antibody occurs in clinical practice
Formation or anaphylactoid risk.In addition, this product, which also overcomes blood transfusion, may trigger the infection risks such as AIDS, hepatitis and haemolysis
Reaction, and expense also remain high the shortcomings that.
Carboxyl maltose iron is researched and developed by Vifor companies of Switzerland, is listed first in Germany in 2007, trade name
Ferinject.Carboxyl maltose iron is a kind of and the compound colloidal iron of carboxyl maltose (III) hydroxide, is a kind of release
The sugared polymers of iron, its chemical name are multinuclear iron (III) hydroxide 4 (R)-[poly- (1 → 4)-O- α-D- glucopyranoses
Base]-epoxide -2 (R), 3 (S), 5 (R), 6- tetrahydroxy caproic acid compounds, molecular formula：[FeOx(OH)y(H2O)z]n[{(C6H10O5)m
(C6H12O7)}l]k, wherein n ≈ 103, m ≈ 8, l ≈ 11, k ≈ 4 (l represents the average branchiness of ligand), relative molecular weight：About
150,000Da。
Carboxyl maltose iron is in preparation process, due to the change of production, storage requirement etc., it may appear that a small amount of free iron
Ion, the generations of these free irons can bring a series of adverse reactions to patient, and most common adverse reaction is oxidative stress, group
Knit the risk of accumulation (triggering atherosclerosis, tissue accumulation/impaired, cell dysfunction) and increase infection.
The control method of the free iron in carboxyl maltose iron is had no in the prior art, is only related to carboxyl maltose iron
Patent (the ZL200380101802.1 of synthesis technique, treatment method and application field；ZL 200780002006.0；ZL
200880017862.8), and European Union is necessary on proposing to need in the research guideline of injection chalybeate to carry out free iron
Control, (A comparative study of the physicochemical properties of iron
isomaltoside1000(Monofer_),a new intravenous iron preparation and its
Clinical implications, European Journal of Pharmaceutics and
Biopharmaceutics).It is desirable that suppression trip can be played by adding certain specific material or suitable preparation process
The effect produced from iron.Pass through the screening to various materials, it has been found that add meglumine in carboxyl maltose iron ferrous solution
It can play the role of suppressing free iron generation, meanwhile, control suitable solution ph to play more preferably effect.
The content of the invention
The purpose of the present invention is the drawbacks described above for the prior art, there is provided a kind of carboxyl maltose iron Pharmaceutical composition.
It is a further object of the present invention to provide the preparation method of said composition.
The purpose of the present invention can be achieved through the following technical solutions：
Carboxyl maltose iron Pharmaceutical composition, it is characterised in that the carboxyl maltose iron containing 10~30 parts by weight, 1~15
The meglumine of parts by weight and pharmaceutically acceptable one or more pH adjusting agents and water for injection.
The carboxyl maltose iron of the Pharmaceutical composition preferably 15~25 parts by weight, the meglumine of 1~10 parts by weight and
Pharmaceutically acceptable one or more pH adjusting agent and water for injection.
Acceptable one or more pH adjusting agent preferably is selected from potassium hydroxide, hydrogen-oxygen in the Pharmaceutical composition Chinese pharmacology
Change the one or more in sodium, disodium hydrogen phosphate, sodium acetate, further preferred sodium hydroxide.
The preparation method of the Pharmaceutical composition, comprises the following steps：
A. carboxyl maltose iron is added in water for injection with meglumine and dissolved；
B. it is 5.0~8.0 a resulting solutions pH adjusting agent to be adjusted pH value, is preferably 5.0~7.0；
C. the made solution of b is filtered, filling, sterilizing；
Wherein carboxyl maltose iron is 10~30 parts by weight, preferably 15~25 parts by weight；Meglumine is 1~15 parts by weight,
It is preferred that 1~10 parts by weight.
In the present invention, meglumine is that alias is N- meglumins, chemical formula：H3NHCH2(CHOH)4CH2OH, chemical name：
1- deoxidations -1- methylaminos-D-Glucose alcohol.
Meglumine can be used as diagnostic reagent, can also improve the dissolubility of medicine with some drugs into salt or be directly dissolved in
In some drugs solution, as cosolvent.It has been unexpectedly discovered that meglumine can also stablize the water of carboxyl maltose iron
Property pharmaceutical composition, stablize the iron ion in the material, be not easy to dissociate, and then form free iron, while coordinate suitable pH
Value, it is better.Beneficial effect
The present invention is by adding a certain amount of meglumine, and after adjusting pH value with sodium hydroxide, carboxyl maltose rail injection
Liquid occurs unexpected as a result, the free iron i.e. in carboxyl maltose rail injection liquid can be controlled in very low model in preparing
In enclosing, and growth is had no during long-term storage.It is probably the meglumine energy stable colloid iron in suitable pH value range
(III) associative key of hydroxide, while compensate on locus the free possible approach of iron ion.
Embodiment
Refer to that the assay method of free iron and iron content is as follows in following embodiments：
The assay method of free iron：Carboxyl maltose rail injection liquid is diluted to 20mgFe/ with 0.9% sodium chloride solution
Ml, takes 7.5ml dilutions to be added in the dialysis tubing of molecular weight 8,000-14,000, and outside is molten with 0.9% sodium chloride of 100ml
Liquid is used as dialyzate, and the 24h that dialyses at 20 DEG C ± 1 DEG C is as test solution.Blood lipids liquid separately is taken, 5 to 6 is diluted to and covers
The concentration rank of its limit is covered, puts the transmitting light intensity of former inductive coupling plasma emission spectrograph parametric measurement ferro element respectively
Degree, using concentration as X-axis, emitted luminescence intensity is Y-axis linear standard curve.Take the transmitting light intensity of test sample measure ferro element
Emitted luminescence intensity, is brought into the concentration of equation calculation sample institute iron content, so as to calculate the content of sample institute iron content by degree.
Methods For The Determination of Iron：This product 1ml is measured with pipette is accurate, puts in 500ml conical flask with cover, adds hydrochloric acid
10ml, shakes transparent to solution, in faint yellow, adds hydrogenperoxide steam generator 1ml, water 100ml and glacial acetic acid 10ml, and shaking mixes,
PH value is adjusted to 2.2~2.5 with 32% sodium hydroxide solution, adds Tiron indicator solutions (to take 4,5- dihydroxy benzenes -1,3- disulfonic acid
Sodium-hydrate 2.0g, is diluted with water to 100ml) 2.5ml, titrated with Calcium Disodium Versenate titrating solution (0.05mol/L)
Gilvous is shown to solution, iron content is calculated as follows.
In formula：V is consumption titrating solution volume；
C is Calcium Disodium Versenate titrating solution concentration (mol/L)；
1 is test sample volume (ml)；
50 or 75 be parenteral solution concentration of iron (50mg/ml or 75mg/ml)；
Per the Fe of 1ml Calcium Disodium Versenates titrating solution (0.05mol/L) equivalent to 2.7925mg.
Embodiment 1,
Proportioning and following techniques according to table 1 prepare parenteral solution, measure free iron content, and data are listed in the table below：Weigh place
The carboxyl maltose iron and auxiliary material just measured, add in water for injection, are stirred to dissolve, and adjust parenteral solution pH value 6 to 7, then use
0.22 micron of membrane filtration, filtrate is filling in ampoule, sterilizing.Take free iron in the parenteral solution measure parenteral solution after sterilizing
Content.
Table 1
Research is found, uses different auxiliary materials and the iron standby parenteral solution of carboxyl maltose, only when using meglumine, note
The free iron in liquid is penetrated below 0.4%, less than the carboxyl maltose rail injection liquid of Vifor companies of Switzerland production.
Embodiment 2,
Proportioning and following techniques according to table 2 prepare parenteral solution, measure free iron content, and data are listed in the table below：Weigh place
The carboxyl maltose iron and auxiliary material just measured, add in water for injection, are stirred to dissolve, then with 0.22 micron of membrane filtration, filter
Liquid is filling in ampoule, sterilizing.Take the content of the parenteral solution measure free iron after sterilizing.
Table 2
Research is found, in the carboxyl maltose rail injection liquid of various concentrations, adding the meglumine of various concentrations can rise
To the effect for reducing free iron content.
Embodiment 3,
Parenteral solution is prepared according to prescription in table 3 and following techniques, the free iron content of parenteral solution measure, is listed in the table below：
The carboxyl maltose iron and auxiliary material of recipe quantity are weighed, adds in water for injection, is stirred to dissolve, then with 0.22 micron
Membrane filtration, filtrate is filling in ampoule, sterilizing.Take the content of the parenteral solution measure free iron after sterilizing.
Table 3
Research found using meglumine and when adjusting pH value in the range of 5.0-8.0, the content of free iron 0.3% with
It is interior, hence it is evident that better than the 0.46% of the carboxyl maltose rail injection liquid of Vifor companies of Switzerland production.Preferable ph scope is in 5.0-
7.0, the free iron of carboxyl maltose rail injection liquid is within 0.2%.
Embodiment 4,
Proportioning according to table 4 prepares parenteral solution, and the meglumine of carboxyl maltose iron and different amounts is added water for injection
In, be stirred to dissolve, pH value adjusted using different pH adjusting agent, then with 0.22 micron of membrane filtration, filtrate it is filling in
In ampoule, sterilizing, takes the parenteral solution after sterilizing to measure the content of free iron.
Table 4
Research finds that when using pH adjusting agent, common pH adjusting agent can coordinate meglumine to play suppression trip
The effect produced from iron, optimal pH adjusting agent is sodium hydroxide, and the content of free iron is minimum at this time.
Embodiment 5,
Proportioning and following techniques according to table 5 prepare parenteral solution, measure free iron content, and data are listed in the table below：Weigh place
The carboxyl maltose iron and meglumine just measured, add in water for injection, are stirred to dissolve, and adjust parenteral solution to different pH value, then
With 0.22 micron of membrane filtration, filtrate is filling in ampoule, sterilizing.Take the content of the parenteral solution measure free iron after sterilizing.
Table 5
Research is found in the specification of 75mg iron, and the parenteral solution middle reaches obtained by pH value are adjusted using meglumine and sodium hydroxide
It is also very low from the content of iron, illustrate that this method is equally effective to the parenteral solution of 75mg iron specifications.
Embodiment 6,
Proportioning and following techniques according to table 6 prepare parenteral solution, measure 0 day free iron content, parenteral solution is placed in 45 DEG C
1st, 3,6 months measure free irons and iron content.Stability data is listed in the table below：Weigh the carboxyl maltose iron and Portugal's first of recipe quantity
Amine, adds in water for injection, is stirred to dissolve, and adjusts parenteral solution to different pH value, then with 0.22 micron of membrane filtration, filtrate
It is filling in ampoule, sterilizing.Take parenteral solution measure free iron and iron content after sterilizing.
Table 6
Research found using meglumine and when adjusting pH value in the range of 5.0-7.0, the content of free iron 0.2% with
It is interior, and in 45 DEG C of resting periods of 6 months free iron substantially without rise phenomenon, hence it is evident that better than the carboxyl of Vifor companies of Switzerland
Maltose rail injection liquid, iron content is substantially unchanged, consistent with the carboxyl maltose rail injection liquid of Vifor companies of Switzerland.
Claims (8)
1. carboxyl maltose iron Pharmaceutical composition, it is characterised in that carboxyl maltose iron, 1 ~ 15 weight containing 10 ~ 30 parts by weight
Measure the meglumine and pharmaceutically acceptable one or more pH adjusting agents and water for injection of part.
2. carboxyl maltose iron Pharmaceutical composition according to claim 1, it is characterised in that contain 15 ~ 25 parts by weight
The meglumine and pharmaceutically acceptable one or more pH adjusting agents and water for injection of carboxyl maltose iron, 1 ~ 10 parts by weight.
3. carboxyl maltose iron Pharmaceutical composition according to claim 1, it is characterised in that described is pharmaceutically acceptable
One or more of one or more pH adjusting agents in potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, sodium acetate.
4. carboxyl maltose iron Pharmaceutical composition according to claim 3, it is characterised in that described is pharmaceutically acceptable
One or more pH adjusting agents be selected from sodium hydroxide.
5. the preparation method of the Pharmaceutical composition any one of claim 1 ~ 4, comprises the following steps：
A. carboxyl maltose iron is added in water for injection with meglumine and dissolved；
B. a resulting solutions pH adjusting agent is adjusted into pH value；
C. the made solution of b is filtered into filling sterilizing；
It is characterized in that：PH value 5.0 ~ 8.0 is adjusted in b step.
6. preparation method according to claim 5, it is characterised in that pH adjusting agent is selected from potassium hydroxide, sodium hydroxide, phosphorus
Sour disodium hydrogen, sodium acetate.
7. preparation method according to claim 6, it is characterised in that pH adjusting agent is sodium hydroxide, adjusts the pH value of solution
For 5.0 ~ 7.0.
8. the preparation method according to claim 5, it is characterised in that iron content is 50mg/ml in prepared composition
Or 75mg/ml.
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| CN115177625A (en) * | 2022-06-28 | 2022-10-14 | 金陵药业股份有限公司 | Carboxyl ferric maltose pharmaceutical composition and preparation method thereof |
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| CN1705682A (en) * | 2002-10-23 | 2005-12-07 | 维福（国际）股份公司 | Water-soluble iron-carbohydrate complexes, production thereof, and medicaments containing said complexes |
| CN101679530A (en) * | 2007-05-29 | 2010-03-24 | 维福（国际）股份公司 | Water-soluble iron-carbohydrate derivates-complex compound, its preparation and contain the medicine of this complex compound |
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| CN1705682A (en) * | 2002-10-23 | 2005-12-07 | 维福（国际）股份公司 | Water-soluble iron-carbohydrate complexes, production thereof, and medicaments containing said complexes |
| CN101679530A (en) * | 2007-05-29 | 2010-03-24 | 维福（国际）股份公司 | Water-soluble iron-carbohydrate derivates-complex compound, its preparation and contain the medicine of this complex compound |
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