CN106727662A - 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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- CN106727662A CN106727662A CN201611186277.3A CN201611186277A CN106727662A CN 106727662 A CN106727662 A CN 106727662A CN 201611186277 A CN201611186277 A CN 201611186277A CN 106727662 A CN106727662 A CN 106727662A
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- iron
- carboxyl maltose
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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
- A61K31/716—Glucans
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
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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, carboxyl maltose iron, the niacinamide of 1~15 weight portion and pharmaceutically acceptable one or more pH adjusting agent and water for injection containing 10~30 weight portions.The preparation method of composition of the present invention, comprises the following steps：A, will carboxyl maltose iron and niacinamide add water for injection in dissolve；B, by a resulting solutions with pH adjusting agent adjust pH value；C, by b made solution filtering filling sterilizing.Pharmaceutical composition of the invention has good stability, and carboxyl maltose iron is not degradable during long-term storage, suppresses reduced sugar the characteristics of produce.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, it is related to a kind of carboxyl maltose iron Pharmaceutical composition and preparation method thereof.
Background technology
Hypoferric anemia is one of four big nutritive diseases of most serious in the world today, is also to include China all over the world
Most common one kind in interior anaemia type, its incidence of disease is very high, especially in developing country.Research prevention and treatment iron deficiency
Property anaemia method be always numerous medical personals concern focus.
Treatment hypoferric anemia, it is the most commonly used with oral or injection chalybeate, it is also most effective.Oral iron of mending is because effective, inexpensive
And safety, frequently as the choice drug of hypoferric anemia, at home still orally mending based on iron.But Oral Iron Preparations often have substantially
Gastrointestinal discomfort symptom, have patient that treatment is interrupted because not tolerating, additionally, its also by food component interference and internal iron
The influence of deposit, especially in many chronic diseases and tumor patient, internal inflammatory cellular mediators increase, and inflammatory mediator can be lured
Liver synthesis Fe regulatory protein is led, the latter lowers intestines and stomach and the in vivo expression of storage siderocyte skin covering of the surface iron transporter, so that
The absorption and utilization of iron are influenceed, now Oral Iron Preparations effect is often very poor or absolutely void.Additionally, in enterogastric diseases, needing
When wanting fast quick-recovery iron to store and being orally sufficient to compensate for human body and need, situations such as not being resistant to Oral Iron Preparations, can not complied with
Under must apply intravenous iron.
The conventional Intravenous Iron in Maintenance in the world for clinical practice includes iron-dextrin, complex glucose acid sodium iron, sugarcane at present
Sugared iron, isomaltose acid anhydride iron 1000, Ferumoxytol and carboxyl maltose iron.Iron is with stabilization in carboxyl maltose rail injection liquid
Ferric state and carbohydrate polymer be complexed with discharge available iron to internal iron transfer and storage protein (ferritin and
Transferrins).Clinical research shows that hematology reaction and Blood lipids supplement are faster than oral right after carboxyl maltose iron intravenously administrable
According to medicine.Carboxyl maltose iron is granted invalid for Oral Iron Preparations in the whole world or cannot use the hypoferric anemia of Oral Iron Preparations
Treatment.At present, the multinomial clinical efficacy and safety research of this product has been carried out, has involved a need to be corrected using Intravenous Iron in Maintenance
The different field of hypoferric anemia, including Gastroenterology dept., gynaecology, kidney section etc..Supporting carboxyl maltose iron efficacy and saferry
In crucial Journal of Sex Research, all main and secondary treatment response parameters are confirmed, can effectively be treated using the treatment of carboxyl maltose iron
Hypoferric anemia caused by the various causes of disease.
Carboxyl maltose rail injection liquid is researched and developed by Vifor companies of Switzerland, is listed in Germany first in 2007, May next year
In Britain's listing, trade name Ferinject is invalid for Oral Iron Preparations or cannot controlling using the hypoferric anemia of Oral Iron Preparations
Treat.By the end of the end of the year 2014, carboxyl maltose rail injection liquid is including numerous European countries and the U.S., Australia, A Gen
The court of a feudal ruler, South Korea, Singapore are in interior global 63 national registrations, wherein 54 country's listings.Carboxyl maltose iron be it is a kind of with
Compound CI (III) hydroxide of carboxyl maltose, is a kind of sugared polymers for discharging iron, and its chemical name is multinuclear iron
(III) hydroxide 4 (R)-[poly- (1 → 4)-O- α-D- glucopyranosyls]-epoxide -2 (R), 3 (S), 5 (R), 6- tetrahydroxys
Caproic acid compound, 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 part) relative molecular weights：About 150,000Da.
Carboxyl maltose iron does not have reproducibility in itself, but its facile hydrolysis in production and storage process is produced and has reduction
Property end (free aldehyde or ketone group) carbohydrate, it is this kind of sugar be collectively referred to as reduced sugar.We have been surprisingly found that in research process, in carboxylic
Niacinamide is added in base maltose ferrous solution can be such that it more stablizes, and facile hydrolysis, does not suppress the generation of reduced sugar, meanwhile, control
The suitable solution ph of system can play more preferably effect.
Niacinamide alias is Nicotinic Acid Amide, vitamin B3, nicotinic acid, chemical formula：C6H6N2O, chemical name：3- pyridines
Formamide.
Niacinamide is the part of cozymase and codehydrogenase Ⅱ, various metabolic processes in vivo is participated in, except for preventing and treating pellagra
It is mainly used in cosolvent in pharmaceutical preparation, to improve the water solubility of insoluble medicine, there is not yet niacinamide can suppress carboxyl malt
The relevant report of sugared molten iron solution.
The content of the invention
The purpose of the present invention is directed to the drawbacks described above of prior art, there is provided a kind of carboxyl maltose iron Pharmaceutical composition.
The purpose of the present invention can be achieved through the following technical solutions：
A kind of carboxyl maltose iron Pharmaceutical composition, it is characterised in that the carboxylic first maltose iron containing 10-30 weight portions, 1-
The niacinamide of 15 weight portions and pharmaceutically acceptable one or more pH adjusting agent and water for injection.
A kind of described carboxyl maltose iron Pharmaceutical composition preferably the carboxyl maltose of weight portion containing 15-25 iron, 5-12 weights
Amount part niacinamide and pharmaceutically acceptable one or more pH adjusting agent and water for injection.
Acceptable pH adjusting agent is sodium acetate, phosphoric acid in a kind of described carboxyl maltose iron Pharmaceutical composition Chinese pharmacology
One or more in disodium hydrogen, NaOH, potassium hydroxide, further preferred NaOH.
Above technical scheme, carboxyl maltose iron content is 50mg/ml or 75mg/ml in the composition.
It is a further object of the present invention to provide the preparation method of said composition.
Described preparation method, comprises the following steps：
A. dissolved in carboxyl maltose iron and niacinamide being added into water for injection；
B. a resulting solutions are adjusted into pH to 4.0-8.0 with pH adjusting agent；
C. by the made solution filtering filling sterilizings of b；
The wherein preferred 5.0-7.0 of pH adjustable ranges.
Application of the niacinamide in carboxyl maltose iron liquid body preparation is prepared；It is preferred that niacinamide is reducing carboxyl maltose iron
Application in injection in content of reducing sugar.
Beneficial effect：We have been surprisingly found that in research process, add a certain amount of niacinamide, and with hydrochloric acid or hydrogen-oxygen
After changing the suitable pH value of sodium regulation, carboxyl maltose rail injection liquid occurs in that unexpected result, i.e. carboxyl malt in preparing
Sugared iron is more stablized in the solution, not facile hydrolysis, so that suppress the generation of reduced sugar, and content of reducing sugar is in long-term storage process
In also have no growth.
Specific embodiment
Embodiment 1
Proportioning and following techniques according to table 1 prepare parenteral solution, determine content of reducing sugar, and data are listed in the table below：Weigh place
The carboxyl maltose iron and auxiliary material of side's amount, add in water for injection, are stirred to dissolve, regulation parenteral solution pH value 5.0 to 7.0, then
Filtered with 0.22 micron membrane filter, filtrate is filling in ampoule, sterilizing.Take the parenteral solution after sterilizing and determine reduced sugar in parenteral solution
Content.
Table 1
Research discovery, different auxiliary materials are added in carboxyl maltose ferrous solution, only when adding using niacinamide, injection
Content of reducing sugar in liquid is less than 0.19%, better than the carboxyl maltose rail injection liquid that Vifor companies of Switzerland produce.
The assay method of content of reducing sugar：
Blank test：Water intaking 1.0ml, puts in 10ml tool plug teat glasses, plus DNS reagents (take 3,5- dinitrosalicylic acids
6.5g, puts in 1000ml measuring bottles, adds water appropriate, and ultrasound makes dissolving, is adding the sodium hydroxide solution 325ml and glycerine of 2mol/L
45g, lets cool, and is diluted with water to scale, shakes up, and obtains final product) 4.0ml, shake up, heat 10 minutes in a water bath immediately, used after taking-up
Frozen water is cooled down rapidly, and add water 5.0ml, shakes up, used as blank solution.According to UV-VIS spectrophotometry (Chinese Pharmacopoeia 2010
Two A of annex annex IV of version), returned to zero with blank solution at 540nm wavelength.
The drafting of standard curve：Take D- DEXTROSE ANHYDROUSs reference substance appropriate, it is accurately weighed, it is diluted to water dissolves and quantitatively
The solution containing 2.0mg in every 1ml is made, as reference substance stock solution.Take reference substance storing solution 0ml, 0.1ml, 0.2ml,
0.3ml, 0.4ml, 0.5ml are put in 6 test tubes, and add water 1.0ml, 0.9ml, 0.8ml, 0.7ml, 0.6ml, 0.5ml respectively, shakes
It is even.Add DNS reagent 4.0ml respectively in above-mentioned test tube, shake up, heat 10 minutes in a water bath immediately, it is fast with frozen water after taking-up
But, add water quickly cooling 5.0ml, shakes up, used as calibration curve solution, the mensuration absorbance at 540nm wavelength.With calibration curve solution
Concentration (mg/ml) is abscissa, with absorbance as ordinate, draws standard curve, calculates regression equation and coefficient correlation, related
Coefficient should be not less than 0.99.
The measure of test sample：This product 4.0ml is taken, in putting 10ml measuring bottles, plus saturation sodium dihydrogen phosphate 3.0ml, mix,
Placement makes generation gelatinous precipitate in 5 minutes, is diluted with water to scale, shakes up, and continuation is placed in 5 minutes rearmounted centrifuge tubes, with every point
The centrifugation that 4000 turns of clock 20 minutes, takes supernatant 1.0ml, plus DNS reagent 4.0ml, shakes up, and heats 10 in a water bath immediately
Minute, cooled down rapidly with frozen water after taking-up, add water 5.0ml, shakes up, used as need testing solution.Extinction is determined at 540nm wavelength
Degree, brings standard curve regression equation calculation need testing solution concentration into, is calculated as follows the reduced sugar in this product.
Computing formula：
In formula：C brings the concentration (mg/ml) that standard curve regression equation calculation goes out into for test sample absorbance.
The detection method detection method of content of reducing sugar is carried out as stated above in following examples.
Embodiment 2
Proportioning and following techniques according to table 2 prepare parenteral solution, determine content of reducing sugar, and data are listed in the table below：Weigh place
The carboxyl maltose iron and auxiliary material of side's amount, 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 that the parenteral solution after sterilizing determines reduced sugar.
Table 2
Research finds, in the carboxyl maltose rail injection liquid of various concentrations, adding the niacinamide of various concentrations can rise
To the effect for reducing content of reducing sugar.
Embodiment 3
Parenteral solution is prepared according to prescription in table 3 and following techniques, parenteral solution determines content of reducing sugar, is listed in the table below：
The carboxyl maltose iron and auxiliary material of recipe quantity are weighed, is added in water for injection, be stirred to dissolve, then with 0.22 micron
Membrane filtration, filtrate is filling in ampoule, sterilizing.Take the content that the parenteral solution after sterilizing determines reduced sugar.
Table 3
Research found using niacinamide and when adjusting pH value in the range of 4.0-8.0, the content of reduced sugar 0.15% with
It is interior, hence it is evident that the 0.19% of the carboxyl maltose rail injection liquid produced better than Vifor companies of Switzerland.Preferable ph scope is in 5.0-
7.0, the content of reducing sugar of carboxyl maltose rail injection liquid is within 0.1%.
Embodiment 4
Proportioning according to table 4 prepares parenteral solution, and by carboxyl maltose iron and niacinamide addition water for injection, stirring makes molten
Solution, pH value is adjusted using different pH value regulator, then with 0.22 micron of membrane filtration, filtrate is filling in ampoule, sterilizing,
Take the content that the parenteral solution after sterilizing determines reduced sugar.
Table 4
When research hair currently uses pH value regulator, conventional pH value regulator can coordinate niacinamide to play suppression also
The effect that raw sugar is produced, optimal pH value regulator is NaOH, and now the content of reduced sugar is minimum.
Embodiment 5
Proportioning and following techniques according to table 5 prepare parenteral solution, determine content of reducing sugar, and data are listed in the table below：Weigh place
The carboxyl maltose iron and niacinamide of side's amount, 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 that the parenteral solution after sterilizing determines free iron.
Table 5
Research found in the specification of 75mg iron, using in the parenteral solution that niacinamide and NaOH adjust obtained by pH value also
The content of raw sugar is also very low, illustrates that the 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：The carboxyl maltose iron and niacinamide of recipe quantity are weighed, plus
Enter in water for injection, be stirred to dissolve, parenteral solution pH is to 5.0-7.0 for regulation, then with 0.22 micron of membrane filtration, filtrate is filling
In ampoule, sterilizing.Gained sample is carried out into Acceleration study in 40 DEG C, respectively in 0 day, 1 month, 3 months, sampling inspection in 6 months
Survey the content of reducing sugar of parenteral solution.
Table 6
Research hair is when currently using niacinamide and adjusting pH value in the range of 5.0-7.0, the content of reduced sugar 0.1% with
It is interior, and 40 DEG C accelerate 6 months after reduced sugar substantially without raise phenomenon, hence it is evident that better than Vifor companies of Switzerland production carboxyl malt
Sugared rail injection liquid.
Claims (9)
1. a kind of carboxyl maltose iron Pharmaceutical composition, it is characterised in that composition includes the carboxyl maltose of 10-30 weight portions
Iron, the niacinamide of 1-15 weight portions and pharmaceutically acceptable one or more pH adjusting agent and water for injection.
2. a kind of carboxyl maltose iron Pharmaceutical composition according to claim 1, it is characterised in that carboxylic in the composition
Base maltose iron is 15-25 weight portions, niacinamide is 5-12 weight portions.
3. a kind of carboxyl maltose iron Pharmaceutical composition according to claim 1, it is characterised in that pH adjusting agent is selected from vinegar
One or more in sour sodium, disodium hydrogen phosphate, NaOH, potassium hydroxide.
4. a kind of carboxyl maltose iron Pharmaceutical composition according to claim 3, it is characterised in that pH adjusting agent is hydrogen-oxygen
Change sodium.
5. a kind of carboxyl maltose iron Pharmaceutical composition according to claim 1, it is characterised in that iron in the composition
Content is 50mg/ml or 75mg/ml.
6. the preparation method of the carboxyl maltose iron Pharmaceutical composition any one of Claims 1 to 5, it is characterised in that bag
Include following steps：
A. dissolved in carboxyl maltose iron and niacinamide being added into water for injection；
B. a resulting solutions are adjusted into pH to 4.0-8.0 with pH adjusting agent；
C. by the made solution filtering filling sterilizings of b.
7. the preparation method of carboxyl maltose iron Pharmaceutical composition according to claim 6, it is characterised in that the step b
It is middle to adjust pH value to 5.0-7.0.
8. application of the niacinamide in carboxyl maltose iron liquid body preparation is prepared.
9. application according to claim 8, it is characterised in that niacinamide is reduced in carboxyl maltose rail injection agent is reduced
Application in sugared content.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105520955A (en) * | 2015-12-21 | 2016-04-27 | 南京生命能科技开发有限公司 | Ferric carboxymaltose pharmaceutical composition and preparation method thereof |
| WO2016151367A1 (en) * | 2015-03-23 | 2016-09-29 | Suven Life Sciences Limited | Preparation of water soluble trivalent iron carbohydrate complexes |
| CN106008408A (en) * | 2016-05-18 | 2016-10-12 | 江苏神龙药业有限公司 | Carboxyl iron maltose injection and biomedical application thereof |
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- 2016-12-20 CN CN201611186277.3A patent/CN106727662B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016151367A1 (en) * | 2015-03-23 | 2016-09-29 | Suven Life Sciences Limited | Preparation of water soluble trivalent iron carbohydrate complexes |
| CN105520955A (en) * | 2015-12-21 | 2016-04-27 | 南京生命能科技开发有限公司 | Ferric carboxymaltose pharmaceutical composition and preparation method thereof |
| CN106008408A (en) * | 2016-05-18 | 2016-10-12 | 江苏神龙药业有限公司 | Carboxyl iron maltose injection and biomedical application thereof |
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