CN109513018A - A kind of endotoxic minimizing technology of polysaccharide superparamagnetic iron oxide - Google Patents
A kind of endotoxic minimizing technology of polysaccharide superparamagnetic iron oxide Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K33/24—Heavy metals; Compounds thereof
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
- A61L2/0017—Filtration
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- A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
- A61L2202/20—Targets to be treated
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Abstract
The present invention provides a kind of endotoxic methods in simple and effective removal superparamagnetic iron oxide bulk pharmaceutical chemicals.This method is that superparamagnetic iron oxide bulk pharmaceutical chemicals are carried out ultrafiltration using macromolecule ultrafiltration membrane.The macromolecule ultrafiltration membrane is 400kD PAN ultrafiltration membrane and 500kD PVDF ultrafiltration membrane.
Description
Technical field
The invention belongs to field of medicinal chemistry, are related to the preparation process of vein iron preparation bulk pharmaceutical chemicals, and in particular to polysaccharide
Endotoxic minimizing technology in superparamagnetic iron oxide bulk pharmaceutical chemicals.
Background technique
Polysaccharide superparamagnetic iron oxide (Ferumoxytol) is by the package superparamagnetic oxidation of polydextrose sorbierite carboxylic methyl ether
The nano particle that iron is formed, the injection of the drug were ratified to list in 2009 by FDA, for treat chronic kidney disease (CKD) at
The hypoferric anemia of human patient.
Hypoferric anemia (IDA) is that the storage of internal iron is not able to satisfy the needs of normocyte generation and occurs poor
Blood.Be due to iron intake is insufficient, uptake is reduced, requirement increases, iron Use barriers or lose it is excessive caused by.Morphology table
It is now microcytic hypochromic anemia.Not a kind of disease of hypoferric anemia, the symptom of disease, symptom and severity of anemia and
The emergency of onset is related.
Iron deficiency and anaemia are the common complication of many serious diseases, these diseases include chronic kidney disease, chronic heart failure
It exhausts, anaemia caused by chemotherapy of tumors, inflammatory bowel disease, a large amount of menstrual bleedings and postpartum haemorrhage.Patients with Chronic Renal Disease, reproduction age woman
Female, pregnant woman, in puberty children be hypoferric anemia people at highest risk.
Hypoferric anemia can seriously reduce the quality of life of patient, increase even dead risk of being hospitalized, while also increasing
The medical burden of patient.Data show that the payment for medical care for merging the chronic of hypoferric anemia will increase 30-40%.Cause
It is an important content of patient blood management that this, which uses effective therapeutic scheme,.
The treatment of IDA mainly have Oral Iron Preparations, parenteral formulation (i.e. Intravenous Iron in Maintenance), treatment of blood transfusion and diet adjustment and
The treatment of other classes.Treating IDA first choice is Oral Iron Preparations, for not being resistant to Oral Iron Preparations, not sufficiently responding to Oral Iron Preparations
Patient, and the patient with intestinal absorption disease can take Intravenous Iron in Maintenance.American market mainstream vein iron preparation has:
1. Iron dextran injection (iron dextran)；2. iron sucrose injection (iron sucrose)；3. carboxyl maltose iron
Injection (ferric carboxymaltose)；4. complex glucose acid sodium iron (sodium ferric gluconate
complex)；5. polysaccharide superparamagnetic iron oxide injection (ferumoxytol).Chinese market mainstream Intravenous Iron in Maintenance has dextrose
Acid anhydride injection and iron sucrose injection.
Ferumoxytol is colloidal iron-carbohydrate compound.The molecule is cladded with poly- grape centered on iron oxide
Sugar-sorbierite-sodium carboxymethylcellulose shell, in this way can drug reach liver, spleen, marrow macrophage before prevent have life
The active ferrous iron of object is contacted with plasma composition.Iron ion is released from compound in macrophage, subsequently into thin
Iron holding pond (e.g., ferritin) intracellular is transported to erythroid progenitor cells synthesis hemoglobin by plasma transferrins.
Research shows that molecular weight and iron oxide core are smaller, iron preparation is more unstable, and the release of active iron is faster, by active iron
Caused adverse reaction is more, is also easier to be removed by body, and clinical application interval time and single dosage also can only be smaller.
And the iron preparation with higher molecular weight and larger iron oxide core particle then means more safety and conveniently.Superparamagnetic oxidation
The molecular weight of iron reaches 750kD, safety with higher.
In " CKD patient's hypoferric anemia " third stage studies have shown that compared with Oral Iron Preparations, double injection
Ferumoxytol can more significant raising hemoglobin content, while tolerance is good.It compares, surpasses with iron sucrose than Oral Iron Preparations
Paramagnetic iron oxide effect is more preferable, because its amount of iron load is high compared with iron sucrose, and easy to use, need to only inject twice, improve patient
Compliance, reduce medical care precess, and reduce departmental cost.
Endotoxin is one of gram-negative bacterial cell wall ingredient, is called lipopolysaccharides.Lipopolysaccharides is to have to host
Toxicity.The method of common endotoxin removal has high concentration soda acid removal method, ultrafiltration membrane and a charged microporous membrane method, asbestos and
Active carbon adsorption, chemical degradation method, ion-exchange chromatography, affinity chromatography.
Contain a large amount of free sugars in polysaccharide superparamagnetic iron oxide bulk pharmaceutical chemicals, and PH is neutrality, is very suitable to microorganism
Growth and the extremely difficult control of endotoxin require production environment harsh, high production cost.Endotoxin condition is controlled by environment
Harsh and failure rate is high；If selection, which removes endotoxin with active carbon, worries that can active carbon remove completely completely again.
Yuan Yan company removes free sugar and inorganic impurity in product using 100kD molecular weight ultrafiltration membrane, but can not be effective
Endotoxin is removed, makes level of endotoxin except limits.
Summary of the invention
The characteristic that the present invention mainly utilizes polysaccharide superparamagnetic iron oxide molecular weight relatively high, by selecting high molecular weight super
Filter membrane can not only play the effect of purification, moreover it is possible to remove most of endotoxin in product.The invention avoids increasing in other removals
The step of toxin, reduces production cost so that operation is simpler.Meanwhile it is endotoxic simultaneously in removal, iron content is not
It declines to a great extent.
Polysaccharide superparamagnetic iron oxide molecular weight is about 750kD, and endotoxin molecular weight is probably differed thousands of to hundreds of thousands,
With macromolecule ultrafiltration membrane (400kD~500kD molecular weight), product cannot pass through ultrafiltration membrane, but the endotoxin overwhelming majority can
To penetrate, to reach separation product and endotoxic purpose.
High molecular weight ultrafiltration membrane can not only remove PSC extra in reaction solution (polydextrose sorbierite carboxylic methyl ether), moreover it is possible to
Endotoxin content in product is greatly reduced.
It is using macromolecular that the present invention, which removes the endotoxic specific method that polysaccharide superparamagnetic iron oxide bulk pharmaceutical chemicals contain,
It measures ultrafiltration membrane (400kD~500kD molecular weight) and ultrafiltration is carried out to polysaccharide superparamagnetic iron oxide bulk pharmaceutical chemicals.
Wherein the preparation method of polysaccharide superparamagnetic iron oxide bulk pharmaceutical chemicals is Dextran 10 reduction and carboxylated, is obtained
PSC, PSC are aoxidized after reacting with ferric chloride (FeCl36H2O) and four water frerrous chlorides, obtain polysaccharide superparamagnetic iron oxide raw material
Medicine.
The 400kD ultrafiltration membrane is PAN (polyacrylonitrile) ultrafiltration membrane, and the 500kD ultrafiltration membrane is PVDF (poly- inclined
Vinyl fluoride) ultrafiltration membrane.
Specific embodiment
It present invention will be described in detail below.However, the present invention may be embodied as many different forms,
And it is not necessarily limited in embodiment described herein, and providing the purpose in these embodiments is to make disclosure
More completely and comprehensively.Agents useful for same and raw material, except providing preparation method, remaining is commercially available.Unless otherwise defined,
Otherwise all scientific and technical terminologies have herein meaning and the normally understood meaning of claim theme technical field personnel
It is identical.
The preparation of 1 polysaccharide superparamagnetic iron oxide of embodiment
100g Dextran 10 is dissolved in 200ml water, 50% sodium hydroxide solution 2g is added, puts into sodium borohydride amount
1.6g is reacted at room temperature 4 hours, and 50% sodium hydroxide 80.0g, bromoacetic acid 27.8g, room temperature reaction 16 are added at not higher than 25 DEG C
System PH is adjusted to 6.2 with 6M hydrochloric acid after hour, 5000ml ethyl alcohol is added and forms white precipitate, removes supernatant, residue
It is dissolved in 240ml water, 800mg sodium chloride is added, 120ml ethyl alcohol is added, form white precipitate, it will after repeating above-mentioned purification 2 times
Residue is dissolved in 120ml water, be added 1L ethyl alcohol, white solid be precipitated, filtering, 50 DEG C drying 24 hours obtain PSC.
PSC (40g) is dissolved in 850ml water, and four water of six water of ferric trichloride (29.9g) and frerrous chloride (14.9 g) is molten
It in 373ml water, after 0.2um membrane filtration, is mixed, in reaction flask, is cooled to 10 DEG C, lead to nitrogen protection,
Under stirring, 114ml is added, 28% ammonium hydroxide after being added dropwise, is heated to 78 DEG C, under the conditions of 78 DEG C, keeps the temperature 60min, then
Under the conditions of 78 DEG C of temperature, it is passed through air oxidation, after oxidation, adds water 1.5L to dilute, is reacted using 0.2um membrane filtration
Liquid obtains the filtrate containing polysaccharide superparamagnetic iron oxide bulk pharmaceutical chemicals.
Embodiment 2
The filtrate containing polysaccharide superparamagnetic iron oxide bulk pharmaceutical chemicals that embodiment 1 is obtained is surpassed with 100kD molecular weight PES
Ultrafiltration through membranes purifying, concentration, concentrate test PSC content and iron content.
Embodiment 3
The filtrate containing polysaccharide superparamagnetic iron oxide bulk pharmaceutical chemicals that embodiment 1 is obtained is surpassed with 200kD molecular weight PES
Ultrafiltration through membranes purifying, concentration, concentrate test PSC content and iron content.
Embodiment 4
The filtrate containing polysaccharide superparamagnetic iron oxide bulk pharmaceutical chemicals that embodiment 1 is obtained is surpassed with 300kD molecular weight PES
Ultrafiltration through membranes purifying, concentration, concentrate test PSC content and iron content.
Embodiment 5
The filtrate containing polysaccharide superparamagnetic iron oxide bulk pharmaceutical chemicals that embodiment 1 is obtained is surpassed with 400kD molecular weight PAN
Ultrafiltration through membranes purifying, concentration, concentrate test PSC content and iron content.
Embodiment 6
The filtrate containing polysaccharide superparamagnetic iron oxide bulk pharmaceutical chemicals that embodiment 1 is obtained is surpassed with 500kD molecular weight PVDF
Ultrafiltration through membranes purifying, concentration, concentrate test PSC content and iron content.
Above-described embodiment 2-6 carries out measuring endotoxin in accordance with the following methods:
Bacterial endotoxins test (Chinese Pharmacopoeia version general rule 1143 in 2015)
Operating process:
(1) instrument and equipment
Vortex mixer, accurate pipettor, electric thermostat.
(2) test toolss
Without heat source sample spoon, without heat source sky ampoule, disposably without heat source suction nozzle.
(3) reagent
The reagents of λ=0.125EU/ml, bacterial endotoxin working standard, baterial endotoxin test water
(4) process is tested
Detection of bacterial endotoxin is carried out according to " Chinese Pharmacopoeia " version Chinese Pharmacopoeia general rule 1143 in 2015, the method is as follows:
According to interference test as a result, this test selects sensitivity of the limulus reagent for 0.125EU/ml, test sample is maximum effectively dilute
Releasing multiple is 100 times.
(4-1) reacts item setup
(4-2) each reaction solution preparation
Solution C: bacterial endotoxin working standard is dissolved with baterial endotoxin test with water, is mixed on vortex mixer
15 minutes, then gradually dilution was prepared into 2 λ bacterial endotoxin standard solution.One step of every dilution should all mix on vortex mixer
Even 30s.
Solution A: absorption superparamagnetic iron oxide is appropriate, and BET water is then added, and gradually dilutes 100 times of test solution.Often
30s should all be mixed on vortex mixer by diluting a step.It can refer to following dilution step:
Solution B: S50 the and E0.5 solution of 0.5ml is drawn respectively into no heat source sky ampoule bottle, vortex mixing 30s is obtained
Test sample positive solution S 50E0.5.Schematically as follows:
(4-3) sample-adding:
The reagents original ampoule of 0.1ml/ branch after taking 8 redissolution, wherein it is S100's that 2, which are added 0.1ml diluted concentrations,
Solution A is as test sample pipe；22 λ endotoxin working standard solution 0.1ml of addition are as positive control pipe；2 are added carefully
Bacterium tiny electrolytic cell uses water 0.1ml as negative control pipe；2 are added the solution B that 0.1ml concentration is S100E0.25 and are used as confession
Test product positive control pipe.It after sample-adding, is sealed, is mixed gently with sealed membrane, avoided generating bubble, be put into 37 together with rack for test tube
In DEG C ± 1 DEG C of water-bath or suitable thermostat, rack for test tube keeps horizontality, keeps the temperature 60 ± 2 minutes, observes result.It keeps the temperature and takes
Taking test tube process should be avoided to be vibrated and causes false negative result.
(4-4) determines:
Test tube is gently taken out from thermostat, slowly reverses 180 °, if forming gel in pipe, and gel is indeformable, no
It is the positive from tube wall slippage person, is recorded as (+)；The not formed gel or gel of formation is solid, deformation and from tube wall slippage person
For feminine gender, it is recorded as (-).
If the parallel pipe of negative control solution D is feminine gender, the parallel pipe of test sample positive control solution B is the positive,
The parallel pipe of positive control solution C is the positive, and test is effective.If two parallel pipes of solution A are feminine gender, test sample is determined
Meet regulation.If two parallel pipes of solution A are the positive, determine that test sample is against regulation.If two parallel pipes of solution A
One pipe is the positive, and another pipe is feminine gender, need to carry out retrial.Solution A need to make 4 parallel pipes when retrial, if all parallel pipes are
Feminine gender, determines that test sample meets regulation, otherwise determines that test sample is against regulation.
The endotoxic quality standard of superparamagnetic iron oxide is less than 12.5Eu/ml.
After measured, level of endotoxin and iron content are as follows in the bulk pharmaceutical chemicals that embodiment 2-6 is obtained:
| Example | Sample | Level of endotoxin | API weight (in terms of iron) |
| Example 2 | 100000 ultrafiltration | 50Eu/ml~100EU/ml | 7.83g |
| Example 3 | 200000 ultrafiltration | 25Eu/ml~50Eu/ml | 7.47g |
| Example 4 | 300000 ultrafiltration | 12.5Eu/ml~25Eu/ml | 7.56g |
| Example 5 | 400000 ultrafiltration | < 12.525Eu/ml | 7.50g |
| Example 6 | 500000 ultrafiltration | < 12.525Eu/ml | 7.48g |
Claims (8)
1. a kind of endotoxic minimizing technology of superparamagnetic iron oxide, this method is that superparamagnetic iron oxide bulk pharmaceutical chemicals are used macromolecular
Measure ultrafiltration membrane ultrafiltration.
2. the method as described in claim 1, the macromolecule ultrafiltration membrane is 400kD PAN ultrafiltration membrane.
3. the method as described in claim 1, the macromolecule ultrafiltration membrane is 500kD PVDF ultrafiltration membrane.
4. method a method according to any one of claims 1-3, the superparamagnetic iron oxide bulk pharmaceutical chemicals are prepared by following methods: dextrose
The reduction of acid anhydride 10 and carboxylated, obtain PSC, PSC is aoxidized after reacting with ferric chloride (FeCl36H2O) and four water frerrous chlorides, obtained more
Glycan superparamagnetic iron oxide bulk pharmaceutical chemicals.
5. method as claimed in claim 4, this method are as follows:
(1) Dextran 10 is soluble in water, 50% sodium hydroxide solution is added, puts into sodium borohydride amount, room temperature reaction, not
50% sodium hydroxide is added at higher than 25 DEG C, bromoacetic acid is adjusted system PH to 6-7 after room temperature reaction, and addition ethyl alcohol forms white
Color precipitating, removes supernatant, and residue is soluble in water, and sodium chloride is added, and ethyl alcohol is added, and forms white precipitate, repeats above-mentioned mention
It is dissolved the residue in water after pure 2 times, ethyl alcohol is added, white solid is precipitated, filtering, dry PSC；
(2) PSC is soluble in water, and six water of ferric trichloride and four water of frerrous chloride are soluble in water, uses 0.2um membrane filtration
Afterwards, it is mixed, in reaction flask, is cooled to 10 DEG C, logical nitrogen protection is added 28% ammonium hydroxide, is added dropwise under stiring
Afterwards, 78 DEG C are heated to, under the conditions of 78 DEG C, heat preservation then under the conditions of 78 DEG C of temperature, is passed through air oxidation, oxidation finishes
Afterwards, it is diluted with water, using 0.2um membrane filtration reaction solution, obtains the filtrate containing polysaccharide superparamagnetic iron oxide bulk pharmaceutical chemicals；
(3) it will be concentrated after filtrate obtained above macromolecule ultrafiltration membrane ultrafiltration.
6. method as claimed in claim 5, this method are as follows:
(1) 100g Dextran 10 is dissolved in 200ml water, 50% sodium hydroxide solution 2g is added, put into sodium borohydride amount
1.6g is reacted at room temperature 4 hours, and 50% sodium hydroxide 80.0g, bromoacetic acid 27.8g, room temperature reaction 16 are added at not higher than 25 DEG C
System PH is adjusted to 6.2 with 6M hydrochloric acid after hour, 5000ml ethyl alcohol is added and forms white precipitate, removes supernatant, residue
It is dissolved in 240ml water, 800mg sodium chloride is added, 120ml ethyl alcohol is added, form white precipitate, it will after repeating above-mentioned purification 2 times
Residue is dissolved in 120ml water, be added 1L ethyl alcohol, white solid be precipitated, filtering, 50 DEG C drying 24 hours obtain PSC；
(2) 40g PSC is dissolved in 850ml water, and six water of 29.9g ferric trichloride and 14.9g frerrous chloride four are water-soluble in 373ml
It in water, after 0.2um membrane filtration, is mixed, in reaction flask, is cooled to 10 DEG C, lead to nitrogen protection, under stiring,
114ml is added, 28% ammonium hydroxide after being added dropwise, is heated to 78 DEG C, under the conditions of 78 DEG C, 60min is kept the temperature, then at 78 DEG C
Temperature under the conditions of, be passed through air oxidation, after oxidation, add water 1.5L dilute, using 0.2um membrane filtration reaction solution, obtain
To the filtrate containing polysaccharide superparamagnetic iron oxide bulk pharmaceutical chemicals；
(3) it will be concentrated after filtrate obtained above macromolecule ultrafiltration membrane ultrafiltration.
7. method as claimed in claim 6, the macromolecule ultrafiltration membrane is 400kD PAN ultrafiltration membrane.
8. method as claimed in claim 6, the macromolecule ultrafiltration membrane is 500kD PVDF ultrafiltration membrane.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104769426A (en) * | 2012-07-27 | 2015-07-08 | 卢特波尔德药品公司 | Method of treating iron deficiency anemia |
| CN104822391A (en) * | 2012-04-04 | 2015-08-05 | 柏林夏洛蒂医科大学 | Magnetic nanoparticles dispersion, its preparation and diagnostic and therapeutic use |
| CN108675356A (en) * | 2018-05-30 | 2018-10-19 | 博瑞生物医药（苏州）股份有限公司 | The endotoxic minimizing technology of superparamagnetic iron oxide |
| CN108743616A (en) * | 2018-05-30 | 2018-11-06 | 博瑞生物医药（苏州）股份有限公司 | A kind of endotoxic minimizing technology of superparamagnetic iron oxide |
| CN108862398A (en) * | 2018-07-16 | 2018-11-23 | 东南大学 | A kind of minimum ferric oxide nanometer particle and preparation method thereof |
-
2018
- 2018-12-29 CN CN201811637740.0A patent/CN109513018A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104822391A (en) * | 2012-04-04 | 2015-08-05 | 柏林夏洛蒂医科大学 | Magnetic nanoparticles dispersion, its preparation and diagnostic and therapeutic use |
| CN104769426A (en) * | 2012-07-27 | 2015-07-08 | 卢特波尔德药品公司 | Method of treating iron deficiency anemia |
| CN108675356A (en) * | 2018-05-30 | 2018-10-19 | 博瑞生物医药（苏州）股份有限公司 | The endotoxic minimizing technology of superparamagnetic iron oxide |
| CN108743616A (en) * | 2018-05-30 | 2018-11-06 | 博瑞生物医药（苏州）股份有限公司 | A kind of endotoxic minimizing technology of superparamagnetic iron oxide |
| CN108862398A (en) * | 2018-07-16 | 2018-11-23 | 东南大学 | A kind of minimum ferric oxide nanometer particle and preparation method thereof |
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Application publication date: 20190326 |