CN103340827B - Iron sucrose injection and preparation method thereof - Google Patents
Iron sucrose injection and preparation method thereof Download PDFInfo
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Abstract
The invention relates to iron sucrose injection and a preparation method thereof. The iron sucrose injection comprises iron sucrose serving as an active ingredient, an optional acidifying or alkalizing agent and water for injection. The iron sucrose injection is characterized in that the pH value is 10.0-11.5, the osmotic pressure is 1100-1400mOsmol/L, 1ml of iron sucrose injection contains 15-25mg of iron and 240-400g of sucrose, the turbid point is in the range from 4.4-5.3 based on pH, the weight-average molecular weight (MW) is in the range from 34000-60000Da, the number-average molar mass (Mn) is no less than 24000Da, and the molecular weight distribution is less than 1.7 by Mw/Mn. The iron sucrose injection can be used for specially treating iron-deficiency anemia, can be used for intravenous administration in an instillation or slow injection manner and is suitable for patients which do not have good response to oral iron preparations and need to undergo intravenous iron preparation treatment, such as patients which cannot tolerate the oral iron preparations and cannot absorb the oral iron preparations well.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition of iron content, particularly relate to a kind of pharmaceutical composition that contains iron sucrose, relate more particularly to a kind of injection that contains iron sucrose.The invention still further relates to the preparation method of said composition.The present composition can be used for treating iron deficiency anemia especially, particularly this compositions can be applicable to the bad patient who needs Intravenous Iron in Maintenance treatment of Oral Iron Preparations effect by the mode intravenously administrable instiling or slowly inject, and the not tolerant patient of for example Oral Iron Preparations and Oral Iron Preparations absorb bad patient.
Background technology
As everyone knows, ferrum is the necessary trace element of human body, due to Deficiency of Intake, utilizes iron deficiency limited or that other reasons causes quite general, and iron deficiency anemia is the widest Deficiency disease that distributes in the world today.Therefore, except actively carrying out meals adjustment, increase outside the absorption of rich ferrum food, the research of various iron supplement agent and iron fortified food product is also very necessary.At present conventional chalybeate, as ferrous sulfate, exists the raw meat astringent taste of iron ion, causes mouthfeel not good, has again GI irritation, easily causes shortcoming nauseating, vomiting, is difficult to adhere to use; And ferrous iron is easily oxidized to high ferro, cause declined bioavailability of oral administration; And utilize the haemachrome of animal proteinum extraction as iron supplement agent, good absorbing effect, but raw material sources are few, and cost is high.Use the injection that makes of sucrose there is no the shortcoming of above-mentioned oral ferrum, and rapidly and efficiently, accurate positioning, dangerous low.Iron sucrose is prepared by ferric hydroxide colloid and sucrose complexation, is a kind of water miscible FHSC, and its ferrum comprising is in nonionic state.Ferric hydroxide colloid composition multinuclear ferrum parent nucleus in molecule, and sucrose replaces the hydrone combination with it on ferrum parent nucleus surface by its active hydroxyl, the adhesion of the two is non-covalent bond molecular separating force.In iron sucrose, sucrose exists as the solubilizing agent of ferric hydroxide colloid, and sucrose and ferric hydroxide colloid exist a dynamic balance.This Duo He Approximately hydrated ferric oxide. core is by simple the holding of sucrose molecule of a large amount of non-covalent bonds, thereby the macromolecular complex (particularly the molecular weight of iron sucrose (Mw) is conventionally within the scope of approximately 34000 to 60000 dalton) that forms an about 43Kda, is similar to naturally occurring ferritin in the iron complexes structure of this multi-core.This material has good stability, and can ensure not have ionic iron to discharge under physiological status, and this stability can well adapt to absorbing of physiological ferrum, and therefore, local organization reaction and other untoward reaction almost do not occur.The control of iron sucrose stability is mainly realized by controlling its cloud point.
Having suitable molecular weight ranges and having suitable stability is that iron sucrose discharges in order physiological ferrum and the very important precondition of avoiding untoward reaction under physiological status.Ensure that it is also the condition that ensures injection safety to the general stipulation of injection that the injection obtaining meets pharmacopeia in the indexs such as particulate matter, thermal source, microbial limit simultaneously.But as mentioned above, in iron sucrose molecule, the combination of sucrose and ferrum core is the non-covalent bond that bond energy is relatively little, so how to ensure in the preparation process of iron sucrose injection, it is very important that the molecular weight of crude drug active component iron sucrose molecule and stability do not change.
Iron sucrose has had longer service time as Intravenous Iron in Maintenance, the commodity that have of for example applying on Chinese Clinical are called the iron sucrose injection (medicine registration certificate H20080403, specification is 5ml:100mg ferrum and 1.6g sucrose) of Wei Lefu (Venofer) and the product of some other manufacturer production.Although iron sucrose injection is being totally chemically stable, but known iron sucrose injection occurs the phenomenon of physical instability, for example there is sedimentary phenomenon, particularly in the situation that there is fluctuation in reserve temperature, for example, in Wei Lefu commercially available product description, clearly recording its holding conditions is: " at 4 DEG C～25 DEG C temperature, be stored in original-pack carton box.Avoid overheated, not freezing.The storage of mistake can cause forming macroscopic precipitate ".And in the Venofer injection package insert of FDA approval, also clearly recorded its more strict holding conditions: " under 20 ° of C～25 ° C, preserve, allow to fluctuate between 15 °～30 ° C, must not be freezing ".In addition, the inventor has been found that more existing products have the precipitation discovery of larger probability while storage in the lower situation of temperature.
Therefore, this area still needs to have a kind of new method to prepare iron sucrose injection, expects that this iron sucrose injection has for example physical stability of good performance and/or chemical stability.
Summary of the invention
The object of the present invention is to provide a kind of new method to prepare iron sucrose injection, expect that this iron sucrose injection has for example physical property of good performance and/or chemical property.The inventor is surprisingly found out that and uses the iron sucrose injection of specific treatment process preparation to demonstrate at least one beat all beneficial effect aspect physical property and/or chemical property.The present invention is based on this discovery and be accomplished.
For this reason, first aspect present invention provides a kind of iron sucrose injection, wherein comprises the iron sucrose as active component, optional acid-base modifier (also can be described as in the present invention pH adjusting agent), and water for injection.
According to the iron sucrose injection of the arbitrary embodiment of first aspect present invention, its pH value is 10.0～11.5, for example, be 10.5～11.1, for example, be 10.5～11.0, for example, be 10.7～10.9.
According to the iron sucrose injection of the arbitrary embodiment of first aspect present invention, its osmotic pressure is 1100～1400mOsmol/L, for example, be 1150～1350mOsmol/L, for example, be 1200～1300mOsmol/L, for example, be about 1250mOsmol/L.
According to the iron sucrose injection of the arbitrary embodiment of first aspect present invention, in its every 1ml, contain 15～25mg ferrum, for example in every 1ml, contain 18～22mg ferrum, for example in every 1ml, contain 19～21mg ferrum, for example in every 1ml, contain the 20mg ferrum of having an appointment.
According to the iron sucrose injection of the arbitrary embodiment of first aspect present invention, in its every 1ml, contain 240～400mg sucrose, for example in every 1ml, contain 260～380mg sucrose, for example in every 1ml, contain 270～330mg sucrose, for example in every 1ml, contain 300～330mg sucrose, for example, in every 1ml, contain the 320mg sucrose of having an appointment.
According to the iron sucrose injection of the arbitrary embodiment of first aspect present invention, in its every 1ml, contain iron sucrose and count 15～25mg (for example 18～22mg, for example 19～21mg, for example about 20mg) with ferrum.
According to the iron sucrose injection of the arbitrary embodiment of first aspect present invention, in its every 1ml, contain iron sucrose and count 240～400mg (for example 260～380mg, for example 270～330mg, for example 300～330mg, for example about 320mg) with sucrose.
According to the iron sucrose injection of the arbitrary embodiment of first aspect present invention, in its every 1ml, contain iron sucrose and count 15～25mg (for example 18～22mg with ferrum, for example 19～21mg, for example about 20mg), count 240～400mg (for example 260～380mg with sucrose, for example 270～330mg, for example 300～330mg, for example about 320mg).
According to the iron sucrose injection of the arbitrary embodiment of first aspect present invention, wherein said acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, for example 1M hydrochloric acid solution or 1M sodium hydroxide solution.In one embodiment, described acid-base modifier is sodium hydroxide solution, for example 1M sodium hydroxide solution.
According to the iron sucrose injection of the arbitrary embodiment of first aspect present invention, it is after cold cycling is disposed, check according to the first method (lamp test) in two (can be called for short in the present invention " 2010 editions two of Chinese Pharmacopoeias " or similar abbreviation) annex IX H visible foreign matters inspection techniques of version Pharmacopoeia of People's Republic of China in 2010 (the method in the present invention also can referred to as " lamp test " or similar abbreviation), visible foreign matters recall rate is less than 8%, particularly be less than 5%, be more especially less than 3%.
In the present invention, above-mentioned " cold cycling disposal " refer to, makes to detect through above-mentioned lamp test at least 100 bottles of injection that visible foreign matters all do not detected, places 3 days at the temperature of 25 ± 1 ° of C, then transfer at the temperature of 4 ± 1 ° of C and place 3 days, complete cold cycling one time; So repeat in 30 days, to have amounted to freeze cycle five times.
In the present invention, above-mentioned " visible foreign matters " comprises the two summation of obvious visible foreign matters and fine visible foreign matters.
In the present invention, above-mentioned " visible foreign matters recall rate " refers to, detect at least 100 bottles of injection that visible foreign matters all do not detected through lamp test, after the described cold cycling of five freeze cycle of experience is disposed, check the visible foreign matters in each bottle of injection through lamp test again, the injection bottle number that detects visible foreign matters accounts for the percent of overall test bottle number.
Have been surprisingly found that, the iron sucrose injection preparing through the inventive method have than significantly lower visible foreign matters recall rate of the iron sucrose injection obtaining in prior art.
According to the iron sucrose injection of the arbitrary embodiment of first aspect present invention, it is to prepare according to the method for following steps substantially:
(a) by prescription amount of calculation iron sucrose with being dissolved in appropriate water for injection;
(b) in step (a) gained medicinal liquid, add 0.05～0.2% (w/v) active carbon, under agitation use again pH value to 5.5～6.5 of 1M hydrochloric acid solution regulator solution, then make medicinal liquid at 60-70 DEG C of temperature, be incubated absorption 20～30 minutes; Use again 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9, continue to make medicinal liquid at 60-70 DEG C of temperature, to be incubated absorption 10～15 minutes, filtering decarbonization;
(c) mend and inject water to prescription full dose, check the pH value of solution, use if desired in pH value to 10.7～10.9 scope of acid-base modifier regulator solution; Make medicinal liquid use successively 0.4 μ m and 0.22 μ m filtering with microporous membrane, medicinal liquid is divided and installed in vial, sealing, 115 ° of C pressure sterilizing 30min, to obtain final product.
According to the iron sucrose injection of the arbitrary embodiment of first aspect present invention, wherein in step (a), appropriate water for injection can be 30～60% water for injection of prescription full dose, can be for example 45～55% water for injection of prescription full dose, for example, can be approximately 50% water for injection of prescription full dose.
According to the iron sucrose injection of the arbitrary embodiment of first aspect present invention, wherein in step (b), use pH value to 5.8～6.2 of 1M hydrochloric acid solution regulator solution.
Further, second aspect present invention provides the method for preparing iron sucrose injection (for example, described in the arbitrary embodiment of first aspect present invention iron sucrose injection), and it consists essentially of following steps:
(a) by prescription amount of calculation iron sucrose with being dissolved in appropriate water for injection;
(b) in step (a) gained medicinal liquid, add 0.05～0.2% (w/v) active carbon, under agitation use again pH value to 5.5～6.5 of 1M hydrochloric acid solution regulator solution, then make medicinal liquid at 60-70 DEG C of temperature, be incubated absorption 20～30 minutes; Use again 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9, continue to make medicinal liquid at 60-70 DEG C of temperature, to be incubated absorption 10～15 minutes, filtering decarbonization;
(c) mend and inject water to prescription full dose, check the pH value of solution, use if desired in pH value to 10.7～10.9 scope of acid-base modifier regulator solution; Make medicinal liquid use successively 0.4 μ m and 0.22 μ m filtering with microporous membrane, medicinal liquid is divided and installed in vial, sealing, 115 ° of C pressure sterilizing 30min, to obtain final product.
According to the method for the arbitrary embodiment of second aspect present invention, wherein in step (a), appropriate water for injection can be 30～60% water for injection of prescription full dose, can be for example 45～55% water for injection of prescription full dose, for example, can be approximately 50% water for injection of prescription full dose.
According to the method for the arbitrary embodiment of second aspect present invention, wherein in step (b), use pH value to 5.8～6.2 of 1M hydrochloric acid solution regulator solution.
According to the method for the arbitrary embodiment of second aspect present invention, wherein said iron sucrose infusion pump is containing the iron sucrose as active component, optional acid-base modifier (also can be described as in the present invention pH adjusting agent), and water for injection.
According to the method for the arbitrary embodiment of second aspect present invention, the pH value of wherein said iron sucrose injection is 10.0～11.5, for example, be 10.5～11.1, for example, be 10.5～11.0, for example, be 10.7～10.9.
According to the method for the arbitrary embodiment of second aspect present invention, the osmotic pressure of wherein said iron sucrose injection is 1100～1400mOsmol/L, for example, be 1150～1350mOsmol/L, for example, be 1200～1300mOsmol/L, for example, be about 1250mOsmol/L.
According to the method for the arbitrary embodiment of second aspect present invention, in its every 1ml of wherein said iron sucrose injection, contain 15～25mg ferrum, for example in every 1ml, contain 18～22mg ferrum, for example in every 1ml, contain 19～21mg ferrum, for example in every 1ml, contain the 20mg ferrum of having an appointment.
According to the method for the arbitrary embodiment of second aspect present invention, in its every 1ml of wherein said iron sucrose injection, contain 240～400mg sucrose, for example in every 1ml, contain 260～380mg sucrose, for example in every 1ml, contain 270～330mg sucrose, for example in every 1ml, contain 300～330mg sucrose, for example, in every 1ml, contain the 320mg sucrose of having an appointment.
According to the method for the arbitrary embodiment of second aspect present invention, in its every 1ml of wherein said iron sucrose injection, contain iron sucrose and count 15～25mg (for example 18～22mg, for example 19～21mg, for example about 20mg) with ferrum.
According to the method for the arbitrary embodiment of second aspect present invention, in its every 1ml of wherein said iron sucrose injection, contain iron sucrose and count 240～400mg (for example 260～380mg with sucrose, for example 270～330mg, for example 300～330mg, for example about 320mg).
According to the method for the arbitrary embodiment of second aspect present invention, in its every 1ml of wherein said iron sucrose injection, contain iron sucrose and count 15～25mg (for example 18～22mg with ferrum, for example 19～21mg, for example about 20mg), count 240～400mg (for example 260～380mg with sucrose, for example 270～330mg, for example 300～330mg, for example about 320mg).
According to the method for the arbitrary embodiment of second aspect present invention, wherein said acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, for example 1M hydrochloric acid solution or 1M sodium hydroxide solution.In one embodiment, described acid-base modifier is sodium hydroxide solution, for example 1M sodium hydroxide solution.
According to the method for the arbitrary embodiment of second aspect present invention, its prepared iron sucrose injection is after cold cycling is disposed, check according to the first method (lamp test) in two (can be called for short in the present invention " 2010 editions two of Chinese Pharmacopoeias " or similar abbreviation) annex IX H visible foreign matters inspection techniques of version Pharmacopoeia of People's Republic of China in 2010 (the method in the present invention also can referred to as " lamp test " or similar abbreviation), visible foreign matters recall rate is less than 8%, particularly be less than 5%, be more especially less than 3%.In the present invention, above-mentioned " cold cycling disposal " refer to, makes to detect through above-mentioned lamp test at least 100 bottles of injection that visible foreign matters all do not detected, places 3 days at the temperature of 25 ± 1 ° of C, then transfer at the temperature of 4 ± 1 ° of C and place 3 days, complete cold cycling one time; So repeat in 30 days, to have amounted to freeze cycle five times.In the present invention, above-mentioned " visible foreign matters " comprises the two summation of obvious visible foreign matters and fine visible foreign matters.In the present invention, above-mentioned " visible foreign matters recall rate " refers to, detect at least 100 bottles of injection that visible foreign matters all do not detected through lamp test, after the described cold cycling of five freeze cycle of experience is disposed, check the visible foreign matters in each bottle of injection through lamp test again, the injection bottle number that detects visible foreign matters accounts for the percent of overall test bottle number.
In the step of the above-mentioned preparation method of the present invention, although the step of the concrete steps of its description in some details or described in the preparation example of language description up and down literary composition detailed description of the invention part distinguished to some extent, but, detailed open the above method step of completely can summarizing of those skilled in the art's full text according to the present invention.
Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characterictic goes for this technical characterictic in other embodiment, as long as they there will not be contradiction.The invention will be further described below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
In the present invention, symbol %, the linguistic context using according to it, can have those skilled in the art and hold intelligible implication.
In the time of preparation medicinal liquid of the present invention, as well known to those skilled in the art, can example according to appointment the microporous filter membrane of 0.45um carry out coarse filtration filtration, by liquid medicine filling to before in vial, can example according to appointment the microporous filter membrane of 0.22um carry out fine straining filtration with degerming, can filter repeatedly if desired.
The invention provides a kind of iron sucrose injection for intravenous iron treatment iron deficiency anemia.The pH value of iron sucrose injection of the present invention conventionally 10.0～11.5, for example, is 10.5～11.1, for example, be 10.5～11.0, for example, be 10.7～10.9.
The cloud point of iron sucrose injection of the present invention (for example can with reference to American Pharmacopeia USP35-NF30 iron sucrose injection cloud point (Turbidity) lower definition and detection method mensuration) with pH meter in 4.4～5.3 scopes.
The weight average molecular weight (Mw) of iron sucrose injection of the present invention is within the scope of 34000 – 60000Da, for example, within the scope of 34000 – 54000Da.
The number-average molecular weight (Mn) of iron sucrose injection of the present invention is not less than 24000Da.
The molecular weight distribution (in Mw/Mn) of iron sucrose injection of the present invention is less than 1.7.
In the process of preparation iron sucrose injection of the present invention, when medicinal liquid is filtered, microporous filter membrane used is hydrophilic film, this class hydrophilic film is such as but not limited to cellulose acetate film (being all hereinafter to use cellulose acetate film if not otherwise specified in the present invention), nitrocellulose membrane, polypropylene film, poly (ether sulfone) film or nylon membrane, and typically the different choice of these several films does not have harmful effect to the preparation of injection.
The iron sucrose injection that the inventive method prepares has good performance, and particularly the parameter such as the pH value of such as injection of its many physical and chemical parameter, cloud point, weight average molecular weight, number-average molecular weight, molecular weight distribution all meets the regulation of American Pharmacopeia and/or British Pharmacopoeia.
Have been surprisingly found that, use the iron sucrose injection that the inventive method prepares after cold cycling is disposed, to show extremely low visible foreign matters recall rate; Also have been surprisingly found that, these iron sucrose injection are showing lower cloud point rate of change after cold cycling is disposed.This is that prior art was not instructed completely.
According to iron sucrose injection of the present invention, its injection that is solution-type is injection.In one embodiment, this injection is single-dose preparations (injection of for example glass bottle), the iron sucrose comprising in per unit dosage can be within the scope of 10～500mg, such as but not limited to about 10mg, about 20mg, about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 400mg or about 500mg in its amount of ferrum (Fe).
For example iron deficiency anemia of iron deficiency is clinical common disease.Previously, iron dextran is developed and is used for the treatment of iron deficiency disease, and it is applied to the Patients with iron deficiency anemia that can not tolerate various oral iron salt preparations through intramuscular injection at first.Referring to for example Lawrence, " development of dextran iron product and comparison " PDA Journal of Pharmaceutical Science & Technology52 (5): 190-197 (1998).Afterwards, iron dextran was also used through intravenous, and found to produce similar beneficial effect.
Develop multiple containing iron preparation.Intravenous injection colloid hydrated ferric oxide. preparation, particularly iron sucrose are applicable to clinically treatment and accept the iron deficiency anemia of supplementing epo treatment, carrying out the patient of chronic hemodialysis.
Iron sucrose is prepared to colloidal suspension and uses as prodrug, and it,, by the cellular uptake of reticuloendothelial system, discharges iron ion.Iron ion is combined with transferrin, transferrin and then be transported to bone marrow for erythropoiesis or be transported to ferritin and the ferrum storage pool of bone marrow, spleen regulating liver-QI.
The physiology of ferrum and metabolism: human body is with ferritin and hemosiderin form storage ferric iron.Ferritin comprises the protein coat that contains storage chamber, and described storage chamber is used for holding composition and is about [(FeOOH)
8(Fe) OPO
3h
2] the multinuclear hydrated ferric oxide. iron phosphate core of n.The protein coat of ferritin, apoferritin comprises 24 polypeptide subunits, and it is approximately 440000 apoferritin molecule that described polypeptide subunit forms mean molecule quantity.Diameter 13 nanometers of apoferritin shell, inner chamber approximately 7 nanometers.
The protein shell of ferritin, apoferritin plays a role as ferrous oxidase in combination and oxidation ferrous iron, and then described ferrous iron is stored in the cavity of protein shell as multinuclear hydrated ferric oxide. iron phosphate core.Ferritin can contain the nearly iron ion of 4500 polymerizations, and the molecular weight of whole molecule is 700000 to 800000.Weight in ferritin molecule more than 30% can be ferrum.
In the time that the amount of available ferrum exceedes the ion storage mechanism of ferritin, can form the ferritin of the gathering that is called hemosiderin, it is the normal composition of Monocyte-macrophages system.Hemosiderin comprises the ferritin molecule that loses its Partial Protein mass shell and assemble.Hemosiderin forms approximately 1/3rd of normal ferrum storage capacity, and as insoluble granule, it gathers in the cell of reticuloendothelial system.
Ferritin is water miscible, and can enter blood flow by osmosis.The normal serum level of ferritin depends on sex/age, is 40 to 160ng/mL.It is believed that, in blood flow, ferritin slowly releases ferrous iron and reducing agent as the ascorbic acid of reproducibility flavin mononucleotide (FMN) and small amount.Ferrous iron is oxidized to ferric iron by ceruloplasmin, then with the haemproteins apotransferrin formation transferrin of combining closely.The molecular weight of transferrin is approximately 76000, and each molecule contains two iron ion binding sites.
In the time being applied to patient, iron sucrose complex (or other ferric iron colloid of for example preparing with gluconate, dextran, sorbitol or dextrin) is removed and metabolism by the macrophage of reticuloendothelial system as granule from blood flow, to supplement the ferrum storage of hemosiderin, ferritin and transferrin of body.The speed of removing from blood flow depends on particle diameter and the composition of colloid hydrated ferric oxide..
Ferrum carbohydrate complex synthetic: ferrum carbohydrate complex comprises and the colloid iron hydroxide particle (being core) of sucrose complexation as iron sucrose.These ferrum cores 2 make by iron chloride is neutralized to pH with alkali.Under this pH, saturated hydroxide ion makes to form colloid hydrated ferric oxide., its after formation with suitable carbohydrate as the complexation of sucrose original position.The structure of ferrum core is followed classical Coordinative Chemistry.Carbohydrate replace the hydrone of being combined with ferrum core outer surface by its hydroxyl and with the complexation of ferrum core.
Combination between ferrum core and carbohydrate is non-covalent molecular separating force, for example the captivation of the dipole moment negative terminal of the part positive charge of ferrum core Surface Fe atom to carbohydrate hydroxyl.
For example, the molecular weight of iron sucrose (Mw) is approximately 34000 to 60000 dalton, and its molecular formula is as follows:
[Na
2Fe
5O
8(OH)·3(H
2O)]
n·m(C
12H
22O
11)
Wherein n is the ferrum degree of polymerization, and m is and multinuclear polymerization ferrum core [Na
2fe
5o
8(OH) 3 (H
2o)]
nsucrose molecule (the C of complexation
12h
22o
11) number.
In solution, between multinuclear polymerization ferrum core (Pn) and its solubilising part (L), there is balance:
In order to ensure obtaining stable water-soluble iron complex, need excessive solubilising part, this balance is as follows:
[Pn]+(x)[L]→[Pn]·m[L]+(x-m)[L]。
The method for optimizing of synthetic this ferrum carbohydrate complex is for example described in the PCT application WO97/11711 (1997) announcing by people such as Lawrence.
Be deep brown solution for clinical iron sucrose injection, it is bad and need the patient of Intravenous Iron in Maintenance treatment that it is applicable to Oral Iron Preparations effect conventionally, as: the not tolerant patient of Oral Iron Preparations; Oral Iron Preparations absorbs bad patient.Regular size is 5ml:100mg ferrum and 1.6g sucrose
Typically, iron sucrose injection can only mix with 0.9%w/v normal saline use, conventionally can not mix use with other treatment medicine.Whether the front macroscopy of use once ampoule has precipitation and damaged.Only have those medicinal liquids that do not precipitate just can use.Typically, iron sucrose injection should be to instil or the slow mode intravenously administrable of injection, or be injected directly into the vein end of dialyser, and this medicine is not suitable for intramuscular injection or according to once full dosed administration of the total amount of client need ferrum.Before new patient treats for the first time, should first give a low dose according to the method for recommending tests, adult uses 1-2.5ml (20-50mg) ferrum, the child that body weight > is 14 kilograms uses the half (1.5mg/kg) of daily dose with 1ml (20mg ferrum), the child that body weight < is 14 kilograms.Should have cardio-pulmonary resuscitation equipment.If there is not untoward reaction in administration after 15 minutes, continue to give remaining medicinal liquid.
Transfusion: the first-selected administering mode of iron sucrose injection is instil (in order to reduce the injection danger outside hypotension generation and vein).1ml this product can only be diluted at most in 20ml0.9%w/v normal saline, after preparing, diluent should use immediately (as: 5ml this product is diluted at most in 100ml0.9% normal saline, and 25ml this product is diluted at most in 500ml0.9%w/v normal saline).The drip velocity of medicinal liquid should be: 100ml ferrum at least instils 15 minutes; 200ml at least instils 30 minutes; 300ml at least drips 1.5 hours; 400ml at least drips 2.5 hours; 500ml at least instils 3.5 hours.If clinical needs, the diluent volume of 0.9% normal saline of this product can be less than specific quantity, is made into this product medicinal liquid of higher concentration.But the speed of instillation must determine that according to the dosage that gives ferrum per minute (as: 10ml this product=200mg ferrum should drip off at least 30 minutes; 25ml this product=500mg ferrum should drip off at least 3.5 hours).For ensureing the stable of medicinal liquid, do not allow medicinal liquid to be made into rarer solution.
Intravenous injection: iron sucrose injection can be without the slow intravenous injection of dilution, and advisory speed is 1ml this product per minute (at least injecting 5 minutes 5ml this product), and each maximum injection dosage is 10ml this product (200mg ferrum).After intravenous injection, should stretch patient's arm.
In dialyser, inject: this product can be injected directly into the vein end of dialyser same " intravenous injection " above of situation.
Adult and old people's common dose are: according to hemoglobin level medication two to three times weekly, 5-10ml (100-200mg ferrum) at every turn.
Child's common dose is: according to hemoglobin level medication two to three times weekly, and each per kilogram of body weight 0.15ml this product (=3mg ferrum/kg body weight).
The iron sucrose injection the present invention relates to, multinuclear hydrated ferric oxide. (111) core surfaces is wherein surrounded by the sucrose molecule of a large amount of non-covalent combinations, thereby forms a complex that mean molecule quantity is 43kDa.This macromolecular structure can be avoided being eliminated from kidney.This composite structure is stable, can not discharge iron ion under physiological condition.The ferrum of multinuclear core by around structure and physiological status under ferritin structural similarity.Use this product can cause the change of Human Physiology, comprising the absorption to ferrum.This product toxicity is very low.White mouse vein gives the ferrum/kg body weight of the LD50>200 milligram after this product, and therefore therapeutic index is about 30 (200/7).
Iron sucrose injection pharmacokinetics: give healthy volunteer's single dose intravenous injection this product containing 100mg ferrum, the level after 10 minutes reaches the highest, average out to 538 μ mol/L.Central compartment's distribution volume equates (approximately 3L) with blood plasma volume.The ferrum of injection is got rid of fast in blood plasma, and the half-life is about 6 hours.Vdss is about 8L, illustrates that ferrum distributes in human body few.Because this product is lower than transferrins stability, can see the competitiveness exchange of ferrum to transferrins.The transport velocity of result ferrum is 31mg ferrum/24 hour.First 4 hours ferrum clearing amounts after injection this product are less than 5% of whole clearing amounts.After 24 hours, in blood plasma, the level of ferrum drops to the level of the front ferrum of injection, and approximately 75% sucrose is drained.
Detailed description of the invention
Following examples further illustrate the present invention, instead of restriction the present invention.In example below.The below object of preparation process in order to give an example, and comparability based on respectively giving an example and making some specific description, those skilled in the art can therefrom summarize according to existing knowledge the method that the present invention prepares compositions that obtains completely.
Prepare below in the example of for example injection of various compositionss, the preparative-scale of every batch of sample is 5000ml, and the amount of the iron sucrose comprising in every bottle is counted 100mg (in each example, listed formula is as the amount of 1 bottle of content) taking ferrum; Although there is the product of multiple packing specification in existing product, for example there are 5ml (ferrum 100mg)/bottle, 10ml (ferrum 200mg)/bottle, those skilled in the art easily obtain the product of above-mentioned multiple loading amount specification by the formula of above-mentioned 100mg/ bottle, for example medicinal liquid is divided install to vial in time, every bottle doubles subpackage medicinal liquid, can easily obtain the product of the loading amount specification of 200mg/ bottle.Prepare below in the example of various compositionss, in dosing process, the pH adjusting agent using is if desired 1M sodium hydroxide solution and 1M hydrochloric acid solution.
a, test method example part
test example 1: measure the remaining rate that each injection liquor high-temperature sample keeps sample after test
In this test example method, measure the injection of each embodiment gained and place after 6 months under 40 ° of C, wherein the content of ferrum or the content of sucrose [40 ° of C, June, can be described as high temperature average content, mg/ml, measures the meansigma methods of 10 bottles] under 20 ° of C, process content [20 ° of C of corresponding time up-to-date style I compound with respect to this sample, June, can be described as room temperature average content, mg/ml, measures the meansigma methods of 10 bottles] percent, it can be regarded as remaining percent (%), and available following formula calculates:
Wherein, high temperature average content (mg/ml) and room temperature average content (mg/ml) are that sample is through [the HPLC method A] ferrum of measuring and calculating or the content of sucrose (averages of 10 bottles), the situation of change of active component in the size reflection injection of this remnants percent (%), particularly can reflect the stability of active component, remaining percent (%) larger (more leveling off to 100%) injection after high-temperature process, wherein active component maintenance is more, stability is better.In the present invention, if not otherwise indicated, the content of ferrum or sucrose is all measured (for example can referring to http://www.drugfuture.com/Pharmacopoeia/BP2012/data/5794.html) with reference to the method for 2012 editions records of British Pharmacopoeia, be that iron content titrimetry is measured, and cane sugar content liquid chromatography for measuring.
test example 2: the physical parameter of measuring each injection liquid samples
For various samples, comprise through high temperature accelerate to keep sample process and accelerate the injection that keeps sample and process without high temperature, measure their pH value, cloud point (pH value), weight average molecular weight (Mw), number-average molecular weight (Mn), molecular weight distribution (in Mw/Mn) etc.Method in the iron sucrose injection kind that assay method is recorded with reference to American Pharmacopeia USP35-NF30 version is measured (for example can referring to http://www.drugfuture.com/Pharmacopoeia/usp35/data/v35300/USP35-NF30s0_m42475.html).The iron sucrose injection that American Pharmacopeia records specifies that its pH value is 10.5～11.1, and cloud point (pH value) is 4.4～5.3, MW=34000～60000Da, and MN is not less than 24000Da, and MW/MN is no more than 1.7.
test example 3: cold cycling is disposed test and visible foreign matters inspection
Visible foreign matters checks: carry out according to the first method (lamp test) (referred to as " lamp test ") in two annex IX H visible foreign matters inspection techniques of version Pharmacopoeia of People's Republic of China in 2010.
The cold cycling of injection is disposed: make through lamp test detect visible foreign matters all do not detected at least 100 bottles of injection (if not otherwise indicated, in test, every batch sample is all got and is not detected that 150 bottles of the injection of visible foreign matters carry out cold cycling disposal below), at the temperature of 25 ± 1 ° of C, place 3 days, then transfer at the temperature of 4 ± 1 ° of C and place 3 days, complete cold cycling one time; So repeat in 30 days, to have amounted to five cold cycling (these tests are all carried out under lucifuge condition, because injection is encapsulated in vial, therefore can get rid of the interference of other factors).
The calculating of visible foreign matters recall rate: after five times cold cycling is disposed, every bottle of injection uses through lamp test to detect wherein whether contain visible foreign matters again, calculates the bottle number that the injection that contains visible foreign matters detected in every Lot sample; Dispose the total bottle of number (150 bottles) of sample with this numerical value divided by carrying out cold cycling, then be multiplied by 100%, obtain visible foreign matters recall rate.For example, for certain Lot sample, get 150 bottles of injection that visible foreign matters do not detected and carry out cold cycling disposal, cold cycling is carried out the inspection of visible foreign matters after disposing again, if detected that 5 bottles occur visible foreign matters, visible foreign matters recall rate is: 5/150*100%=3.3%.Cold cycling is disposed and can be reflected that injection is in storage and the variations in temperature contacting in the process of circulation.This visible foreign matters recall rate is larger, and aspect physical stability, to show as stability poorer for sample.
b, embodiment part: the injecta composition that preparation comprises iron sucrose
It can be following commercially available crude drug preparing below the iron sucrose bulk drug using in the example of injection: the crude drug 1 (approval number of the drug: the accurate word H20051241 of traditional Chinese medicines, sub-precious Pharmaceutical pharmacy is produced), the crude drug 2 (approval number of the drug: the accurate word H20103700 of traditional Chinese medicines, Chongqing Inst. of Pharmaceutical Industry produce), the crude drug 3 (approval number of the drug: the accurate word H20051944 of traditional Chinese medicines, the general moral Pharmaceutical in Shanxi is produced), as do not specialize, raw materials used medicine is crude drug 1.These crude drug are all go on the market and can be used for preparing the crude drug of iron sucrose injection through State Food and Drug Administration approval, meet general technical requirement.
embodiment 1, prepare iron sucrose injection (with every bottle of 5ml injection fluid volume meter, preparating liquid 5000ml, lower with)
Prescription: iron sucrose appropriate (iron content 100mg after measured, sucrose amount is within the scope of 315～330mg), water for injection are in right amount to total amount 5ml, and acid-base modifier 1M hydrochloric acid solution and 1M sodium hydroxide solution are for subsequent use.
Method for making: (a) under agitation make it be dissolved in 2.5ml water for injection the iron sucrose of prescription amount of calculation;
(b) in step (a) gained medicinal liquid, add 0.1% (w/v) active carbon, under agitation use again pH value to 6.0 ± 0.1 of 1M hydrochloric acid solution regulator solution, then make medicinal liquid at 60-70 DEG C of temperature, be incubated absorption 25 minutes (can be described as in the present invention absorption for the first time or the absorption of neutral charcoal); Use 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9 again, continue to make medicinal liquid at 60-70 DEG C of temperature, to be incubated absorption 12 minutes, 0.8 μ m filtering with microporous membrane takes off charcoal (can be described as in the present invention absorption for the second time or the absorption of alkaline charcoal);
(c) mend and inject water to prescription full dose, check the pH value of solution, use if desired in pH value to 10.7～10.9 scope of acid-base modifier regulator solution; Make medicinal liquid use successively 0.4 μ m and 0.22 μ m filtering with microporous membrane, medicinal liquid is divided and installed in vial, sealing, 115 ° of C pressure sterilizing 30min, to obtain final product.
embodiment 2, prepare iron sucrose injection
Prescription: with embodiment 1.
Method for making: (a) under agitation make it be dissolved in 2.25ml water for injection the iron sucrose of prescription amount of calculation;
(b) in step (a) gained medicinal liquid, add 0.2% (w/v) active carbon, more under agitation use pH value to 5.6 ± 0.1 of 1M hydrochloric acid solution regulator solution, then make medicinal liquid at 60-70 DEG C of temperature, be incubated absorption 20 minutes; Use 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9 again, continue to make medicinal liquid at 60-70 DEG C of temperature, to be incubated absorption 15 minutes, 0.8 μ m filtering with microporous membrane takes off charcoal;
(c) mend and inject water to prescription full dose, check the pH value of solution, use if desired in pH value to 10.7～10.9 scope of acid-base modifier regulator solution; Make medicinal liquid use successively 0.4 μ m and 0.22 μ m microporous filter membrane (this example is poly (ether sulfone) film) to filter, medicinal liquid is divided and installed in vial, sealing, 115 ° of C pressure sterilizing 30min, to obtain final product.
embodiment 3, prepare iron sucrose injection
Prescription: with embodiment 1.
Method for making: (a) under agitation make it be dissolved in 2.75ml water for injection the iron sucrose of prescription amount of calculation;
(b) in step (a) gained medicinal liquid, add 0.05% (w/v) active carbon, more under agitation use pH value to 6.4 ± 0.1 of 1M hydrochloric acid solution regulator solution, then make medicinal liquid at 60-70 DEG C of temperature, be incubated absorption 30 minutes; Use 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9 again, continue to make medicinal liquid at 60-70 DEG C of temperature, to be incubated absorption 10 minutes, 0.8 μ m filtering with microporous membrane takes off charcoal;
(c) mend and inject water to prescription full dose, check the pH value of solution, use if desired in pH value to 10.7～10.9 scope of acid-base modifier regulator solution; Make medicinal liquid use successively 0.4 μ m and 0.22 μ m microporous filter membrane (this example is nitrocellulose membrane) to filter, medicinal liquid is divided and installed in vial, sealing, 115 ° of C pressure sterilizing 30min, to obtain final product.
embodiment 4, prepare iron sucrose injection
Prescription: iron sucrose appropriate (sucrose amount is within the scope of 310～330mg for crude drug 2, iron content 110mg after measured), water for injection are in right amount to total amount 5ml, and acid-base modifier 1M hydrochloric acid solution and 1M sodium hydroxide solution are for subsequent use.
Method for making: (a) under agitation make it be dissolved in 2.4ml water for injection the iron sucrose of prescription amount of calculation;
(b) in step (a) gained medicinal liquid, add 0.1% (w/v) active carbon, more under agitation use pH value to 6.2 ± 0.1 of 1M hydrochloric acid solution regulator solution, then make medicinal liquid at 60-70 DEG C of temperature, be incubated absorption 25 minutes; Use 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9 again, continue to make medicinal liquid at 60-70 DEG C of temperature, to be incubated absorption 12 minutes, 0.8 μ m filtering with microporous membrane takes off charcoal;
(c) mend and inject water to prescription full dose, check the pH value of solution, use if desired in pH value to 10.7～10.9 scope of acid-base modifier regulator solution; Make medicinal liquid use successively 0.4 μ m and 0.22 μ m microporous filter membrane (this example is nylon membrane) to filter, medicinal liquid is divided and installed in vial, sealing, 115 ° of C pressure sterilizing 30min, to obtain final product.
embodiment 5, prepare iron sucrose injection
Prescription: iron sucrose appropriate (sucrose amount is within the scope of 300～330mg for crude drug 3, iron content 95mg after measured), water for injection are in right amount to total amount 5ml, and acid-base modifier 1M hydrochloric acid solution and 1M sodium hydroxide solution are for subsequent use.
Method for making: (a) under agitation make it be dissolved in 2.6ml water for injection the iron sucrose of prescription amount of calculation;
(b) in step (a) gained medicinal liquid, add 0.1% (w/v) active carbon, more under agitation use pH value to 5.8 ± 0.1 of 1M hydrochloric acid solution regulator solution, then make medicinal liquid at 60-70 DEG C of temperature, be incubated absorption 25 minutes; Use 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9 again, continue to make medicinal liquid at 60-70 DEG C of temperature, to be incubated absorption 12 minutes, 0.8 μ m filtering with microporous membrane takes off charcoal;
(c) mend and inject water to prescription full dose, check the pH value of solution, use if desired in pH value to 10.7～10.9 scope of acid-base modifier regulator solution; Make medicinal liquid use successively 0.4 μ m and 0.22 μ m filtering with microporous membrane, medicinal liquid is divided and installed in vial, sealing, 115 ° of C pressure sterilizing 30min, to obtain final product.
reference examples 1, prepare iron sucrose injection
Prescription: with embodiment 1.
Method for making: the water using in step (a) is 3.5ml or 4.5ml, and all the other obtain respectively reference examples 1a, two samples of reference examples 1b with method for making described in embodiment 1.When water consumption is 2ml or when lower, can not dissolve crude drug completely, only in the time that being more than or equal to 2.25ml, water consumption could dissolve the crude drug of recipe quantity completely.
reference examples 2, prepare iron sucrose injection
Prescription: with embodiment 1.
Method for making: in step (b) in the time of the absorption of charcoal for the first time, under agitation use pH value to 4.5 ± 0.1,5.0 ± 0.1,7.0 ± 0.1,7.5 ± 0.1,8.0 ± 0.1 or 9.0 ± 0.1 of 1M hydrochloric acid solution regulator solution, then make medicinal liquid at 60-70 DEG C of temperature, be incubated absorption 25 minutes.All the other obtain respectively reference examples 2a, reference examples 2b, reference examples 2c, reference examples 2d, reference examples 2e, six samples of reference examples 2f with method for making described in embodiment 1.
reference examples 3, prepare iron sucrose injection
Prescription: with embodiment 1.
Method for making: step (b) is not carried out the charcoal absorption under the neutrallty condition of pH5.0～6.5, concrete grammar is: (b) in step (a) gained medicinal liquid, add 0.1% (w/v) active carbon, with 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9, make medicinal liquid at 60-70 DEG C of temperature, be incubated absorption 30 minutes, 0.8 μ m filtering with microporous membrane takes off charcoal; Other operates with embodiment 1.
reference examples 4, prepare iron sucrose injection
Use crude drug 2, according to the method preparation of above-mentioned reference examples 2b, reference examples 2d, reference examples 3, obtain reference examples 4a, reference examples 4b, tri-samples of reference examples 4c respectively.
reference examples 5, prepare iron sucrose injection
Use crude drug 3, according to the method preparation of above-mentioned reference examples 2a, reference examples 2c, reference examples 2f, reference examples 3, obtain reference examples 5a, reference examples 5b, reference examples 5c, tetra-samples of reference examples 5d respectively.
reference examples 6,5 batches of iron sucrose injection of preparation (200510094323.2)
Reference examples 61: iron sucrose bulk drug dry product dissolves by fresh water for injection, is mixed with every milliliter of solution containing ferrum element 20mg; At 40 ° of C temperature, add 0.1% active carbon, stir after 15min the titanium rod carbon removal in 1um aperture; It is every milliliter of 20mg that filtered solution regulates iron content, and regulating pH is that 10.2,0.22um hydrophilic micro-filtration membrane (nitrocellulose filter) is filtered, and degerming, except insoluble granule; Fill 2.5ml/ ampoule; Obtain iron sucrose injection.
Reference examples 62: iron sucrose bulk drug dry product dissolves by fresh water for injection, is mixed with every milliliter of solution that closes ferrum element 22mg; At 55 DEG C of temperature, add 0.01% active carbon, stir after 45min the titanium rod carbon removal in 1um aperture; It is every milliliter of 20mg that filtered solution regulates iron content, and regulating pH is that 10.5,0.22um hydrophilic micro-filtration membrane (polypropylene film) is filtered, and degerming, except insoluble granule; Fill 5ml/ ampoule; 100 DEG C of decocting in water 30min, obtain iron sucrose injection.
Reference examples 63: iron sucrose bulk drug dry product dissolves by fresh water for injection, is mixed with every milliliter of solution containing ferrum element 21mg; Regulating pH is 10.8, at 65 DEG C of temperature, adds 0.05% active carbon, stirs after 45min plate and frame type filter-press; It is every milliliter of 20mg that filtered solution regulates iron content, and 0.22um hydrophilic micro-filtration membrane (poly (ether sulfone) film) is filtered, and degerming, except insoluble granule; Fill 2ml/ ampoule; Flowing steam sterilization 20min, obtains iron sucrose injection.
Reference examples 64: iron sucrose bulk drug dry product dissolves by fresh water for injection, is mixed with every milliliter of solution containing ferrum element 24mg; At 80 DEG C of temperature, add 0.15% active carbon, stir after 50min the titanium rod carbon removal in 1um aperture; It is every milliliter of 20mg that filtered solution regulates iron content, and regulating pH is that 11.2,0.22um hydrophilic micro-filtration membrane (cellulose acetate membrane) is filtered, and degerming, except insoluble granule; Fill 5ml/ ampoule; Flowing steam sterilization 20min, obtains iron sucrose injection.
Reference examples 65: iron sucrose bulk drug dry product dissolves by fresh water for injection, is mixed with every milliliter of solution containing ferrum element 25mg; At 70 DEG C of temperature, add 0.2% active carbon, stir after 50min the titanium rod carbon removal in 1um aperture; The filtered solution joint iron content that withers is every milliliter of 20mg, and regulating pH is that 11.5,0.22um hydrophilic micro-filtration membrane (cellulose acetate membrane) is filtered, and degerming, except insoluble granule; Fill 5ml/ ampoule; Flowing steam sterilization 40min, obtains iron sucrose injection.
reference examples 7,with reference to the method for CN1685227A (Chinese Patent Application No. 02829664, Wei Fu) description embodiment 1 and embodiment 2, obtain described in embodiment 2 the heat treated iron sucrose injection of 35 minutes at 100 DEG C.
reference examples 8,the method of recording to [0030] section with reference to CN103040730A (Chinese Patent Application No. 201110309357.4, Ao in Tianjin) description embodiment 1 [0024] prepares iron sucrose injection.
c, injection Performance
To the injection of above-described embodiment 1, embodiment 2, embodiment 3, embodiment 4, embodiment 5; And following each reference examples injection is investigated:
Reference examples 1a (step a water 3.5ml), reference examples 1b (step a water 4.5ml),
Reference examples 2a (pH4.5), reference examples 2b (pH5.0), reference examples 2c (pH7.0), reference examples 2d (pH7.5), reference examples 2e (pH8.0), reference examples 2f (pH9.0),
Reference examples 3 (not doing neutral charcoal absorption),
Reference examples 4a (pH5.0, with crude drug 2), reference examples 4b (pH7.5), reference examples 4c (not doing neutral charcoal absorption),
Reference examples 5a (pH4.5, with crude drug 3), reference examples 5b (pH7.0), reference examples 5c (pH9.0), reference examples 5d (not doing neutral charcoal absorption),
Reference examples 61, reference examples 62, reference examples 63, reference examples 64, reference examples 65, reference examples 7, reference examples 8.
investigate example 1: measure the remaining rate that each injection liquor high-temperature sample keeps sample after test
The sample of each embodiment and reference examples above is all placed 6 months under 40 ° of C, all under 20 ° of C, places 6 months side by side.
After measured, the remaining percent of sucrose (%) of embodiment 1～5 each injection is all in 97.6%～99.8% scope, the remaining percents of the ferrum of embodiment 1～5 each injection (%) all in 98.1%～99.6% scope, show that injection of the present invention need to do to have good chemical stability aspect the sucrose of quality monitoring and two indexs of ferrum;
All the remaining percent of the sucrose of reference examples injection (%), all in 97.4%～99.9% scope, shows that they are being good aspect sucrochemistry stability;
The remaining percents of ferrum (%) of the higher or injection that do not adsorb for the first time of reference examples 2c, reference examples 2d, reference examples 2e, reference examples 2f, reference examples 3, reference examples 4b, reference examples 4c, reference examples 5b, reference examples 5c, reference examples 5d, reference examples 61, reference examples 62, reference examples 63, reference examples 64, reference examples 65, reference examples 7, reference examples 8 these pH value in the time adsorbing for the first time all, in 97.3%～99.5% scope, show that they are being good aspect ferrum chemical stability; The reference examples that the remaining percent of these ferrum is good above and the ferrous iron of embodiment 1～5 each injection are that the amount of ferrum (II) is monthly lower than 0.26% (measure according to USP35-NF30, and ferrous amount should be less than 0.4% in USP35-NF30 regulation injection) in 40 ° of C-6 months and 20 ° of C-6;
But surprisingly, these use the injection of more water reference examples 1a, reference examples 1b in step (a), and the remaining percents of the ferrum of reference examples 2a, reference examples 2b, these injection that pH value is lower in the time adsorbing for the first time of reference examples 4a, reference examples 5a (%) are all in 83.5%～89.1% scope, show that they accept can not make us aspect ferrum chemical stability; Although 20 ° of amounts of processing rear ferrum (II) the C-6 month of the unsafty reference examples injection of the remaining percent of these ferrum are all lower than 0.23% in addition, but the amount of these reference examples injection ferrum (II) after processing 40 ° of C-6 months all reaches 0.71～1.26% scope, far can not meet general pharmacopeia regulation;
Visible, aspect the chemical stability of ferrum, be can not make us accepting completely for use more water and pH value is lower in the time adsorbing for the first time injection in step (a).
investigate example 2: the physical parameter of measuring each injection liquid samples
For various samples, comprise through high temperature accelerate to keep sample process and accelerate the injection that keeps sample and process without high temperature, measure their pH value, cloud point (pH value), weight average molecular weight (Mw), number-average molecular weight (Mn), molecular weight distribution (in Mw/Mn) etc.The method that assay method is recorded with reference to American Pharmacopeia USP35-NF30 version is measured (for example can referring to http://www.drugfuture.com/Pharmacopoeia/usp35/data/v35300/USP35-NF30s0_m42475.html).The iron sucrose injection that American Pharmacopeia records specifies that its pH value is 10.5～11.1, and cloud point (pH value) is 4.4～5.3, MW=34000～60000Da, and MN is not less than 24000Da, and MW/MN is no more than 1.7.
As a result, under experience two kinds for the treatment of conditions of 4 months:
The pH value of embodiment 1～5 each injection all in 10.5～11.1 scopes, cloud point (pH value) all in 4.4～5.3 scopes, weight average molecular weight (Mw) all within the scope of 34000 – 54000Da, number-average molecular weight (Mn) is all greater than 24000Da, molecular weight distribution (in Mw/Mn) all in 1.22～1.46 scopes;
Reference examples 2c, reference examples 2d, reference examples 2e, reference examples 2f, reference examples 3, reference examples 4b, reference examples 4c, reference examples 5b, reference examples 5c, reference examples 5d, reference examples 61, reference examples 62, reference examples 63, reference examples 64, reference examples 65, reference examples 7, higher or the injection that do not adsorb for the first time of reference examples 8 these pH value in the time adsorbing for the first time, and reference examples 1a, these use the injection of more water and reference examples 2a reference examples 1b in step (a), reference examples 2b, reference examples 4a, these lower injection of pH value in the time adsorbing for the first time of reference examples 5a, their pH value is all in 10.3～11.6 scopes, cloud point (pH value) is all in 4.2～5.7 scopes, weight average molecular weight (Mw) is all within the scope of 34000 – 60000Da, number-average molecular weight (Mn) is all greater than 24000Da, molecular weight distribution (in Mw/Mn) all, in 1.08～1.57 scopes, shows that these reference examples are all meeting general standards of pharmacopoeia regulation aspect each canonical parameter.
In addition, the injection that above-mentioned whole embodiment and reference examples prepare, their osmotic pressure is all within the scope of 1150～1350mOsmol/L, in every 1ml, contain 18～22mg ferrum (III, ferrum in iron sucrose injection of the present invention is III valency, and if not otherwise indicated, the ferrum of mentioning is III valency), in every 1ml, contain 300～330mg sucrose
investigate example 3: cold cycling is disposed test and visible foreign matters inspection
Carry out according to test example 3 methods above, visible foreign matters recall rate result is as follows:
The visible foreign matters recall rate of 1～5 each batch of injection of embodiment, all lower than 3%, all, in 0～2.8% scope, shows that injection of the present invention has good physical stability;
These use the injection of more water reference examples 1a, reference examples 1b in step (a), and reference examples 2a, reference examples 2b, these lower injection of pH value in the time adsorbing for the first time of reference examples 4a, reference examples 5a, visible foreign matters recall rate is all lower than 5%, all, in 0.75～4.76% scope, show that these injection have good physical stability;
But surprisingly, higher or the injection that do not adsorb for the first time of reference examples 2c, reference examples 2d, reference examples 2e, reference examples 2f, reference examples 3, reference examples 4b, reference examples 4c, reference examples 5b, reference examples 5c, reference examples 5d, reference examples 61, reference examples 62, reference examples 63, reference examples 64, reference examples 65, reference examples 7, reference examples 8 these pH value in the time adsorbing for the first time, visible foreign matters recall rate is all greater than 16%, all, in 16.5～24.3% scopes, show that the physical stability that these injection have can not be satisfactory;
Visible, there is feature of the present invention or the injection physical stability that prepared by the inventive method has gratifying result.
industrial applicability
It can be used for treating iron deficiency anemia especially the injection that contains iron sucrose the present invention relates to, particularly it can be applicable to the bad patient who needs Intravenous Iron in Maintenance treatment of Oral Iron Preparations effect by the mode intravenously administrable instiling or slowly inject, and the not tolerant patient of for example Oral Iron Preparations and Oral Iron Preparations absorb bad patient.
Claims (1)
1. an iron sucrose injection, wherein comprises as the iron sucrose of active component, optional acid-base modifier and water for injection, and the pH value of this injection is 10.0 ~ 11.5, and the iron sucrose comprising in the every 1ml of this injection is counted 15 ~ 25mg with Fe; This injection is to prepare according to the method for following steps:
(a) iron sucrose of prescription amount of calculation is dissolved in 45 ~ 55% water for injection of prescription full dose;
(b) in step (a) gained medicinal liquid, add 0.05 ~ 0.2% (w/v) active carbon, under agitation use again pH value to 5.5 ~ 6.5 of 1M hydrochloric acid solution regulator solution, then make medicinal liquid at 60-70 DEG C of temperature, be incubated absorption 20 ~ 30 minutes; Use again 1M sodium hydroxide solution regulator solution pH value to 10.7 ~ 10.9, continue to make medicinal liquid at 60-70 DEG C of temperature, to be incubated absorption 10 ~ 15 minutes, filtering decarbonization;
(c) mend and inject water to prescription full dose, check the pH value of solution, use if desired in pH value to 10.7 ~ 10.9 scope of acid-base modifier regulator solution; Make medicinal liquid use successively 0.4 μ m and 0.22 μ m filtering with microporous membrane, medicinal liquid is divided and installed in vial, sealing, 115 DEG C of pressure sterilizing 30min, to obtain final product.
2. according to the iron sucrose injection of claim 1, its osmotic pressure is 1100 ~ 1400 mOsmol/L.
3. according to the iron sucrose injection of claim 1, the iron sucrose containing in its every 1ml is counted 18 ~ 22mg with Fe.
4. according to the iron sucrose injection of claim 1, the iron sucrose containing in its every 1ml is counted 19 ~ 21mg with Fe.
5. according to the iron sucrose injection of claim 1, the iron sucrose containing in its every 1ml is counted 20mg with Fe.
6. according to the iron sucrose injection of claim 1, the iron sucrose containing in its every 1ml is counted 240 ~ 400mg with sucrose.
7. according to the iron sucrose injection of claim 1, the iron sucrose containing in its every 1ml is counted 260 ~ 380mg with sucrose.
8. according to the iron sucrose injection of claim 1, the iron sucrose containing in its every 1ml is counted 270 ~ 330mg with sucrose.
9. according to the iron sucrose injection of claim 1, the iron sucrose containing in its every 1ml is counted 300 ~ 330mg with sucrose.
10. according to the iron sucrose injection of claim 1, the iron sucrose containing in its every 1ml is counted 320mg with sucrose.
11. according to the iron sucrose injection of claim 1, and described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution.
12. according to the iron sucrose injection of claim 1, and it is after cold cycling is disposed, and with lamp test inspection, visible foreign matters recall rate is less than 8%.
13. according to the iron sucrose injection of claim 1, and it is after cold cycling is disposed, and with lamp test inspection, visible foreign matters recall rate is less than 5%.
14. according to the iron sucrose injection of claim 1, and it is after cold cycling is disposed, and with lamp test inspection, visible foreign matters recall rate is less than 3%.
15. according to the iron sucrose injection of claim 1, its cloud point with pH meter in 4.4 ~ 5.3 scopes.
16. according to the iron sucrose injection of claim 1, and its weight average molecular weight is within the scope of 34000 – 60000Da.
17. according to the iron sucrose injection of claim 1, and its weight average molecular weight is within the scope of 34000 – 54000Da.
18. according to the iron sucrose injection of claim 1, and its number-average molecular weight is not less than 24000Da.
19. according to the iron sucrose injection of claim 1, and its molecular weight distribution is less than 1.7 in Mw/Mn.
20. according to the iron sucrose injection of claim 1, wherein in step (a), iron sucrose is dissolved in 50% water for injection of prescription full dose.
21. according to the iron sucrose injection of claim 1, wherein in step (b), uses pH value to 5.8 ~ 6.2 of 1M hydrochloric acid solution regulator solution.
22. according to the iron sucrose injection of claim 1, and it is unit dose formulations, and in Fe, it measures within the scope of 10 ~ 500mg the iron sucrose comprising in per unit dosage.
23. according to the iron sucrose injection of claim 1, and it is unit dose formulations, and the iron sucrose comprising in per unit dosage is taking its amount of Fe as 10mg, 20mg, 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 400mg or 500mg.
24. prepare the method for iron sucrose injection described in claim 1-23 any one, and the iron sucrose comprising in the every 1ml of this injection is counted 15 ~ 25mg with Fe, and the method comprises the following steps:
(a) iron sucrose of prescription amount of calculation is dissolved in 45 ~ 55% water for injection of prescription full dose;
(b) in step (a) gained medicinal liquid, add 0.05 ~ 0.2% (w/v) active carbon, under agitation use again pH value to 5.5 ~ 6.5 of 1M hydrochloric acid solution regulator solution, then make medicinal liquid at 60-70 DEG C of temperature, be incubated absorption 20 ~ 30 minutes; Use again 1M sodium hydroxide solution regulator solution pH value to 10.7 ~ 10.9, continue to make medicinal liquid at 60-70 DEG C of temperature, to be incubated absorption 10 ~ 15 minutes, filtering decarbonization;
(c) mend and inject water to prescription full dose, check the pH value of solution, use if desired in pH value to 10.7 ~ 10.9 scope of acid-base modifier regulator solution; Make medicinal liquid use successively 0.4 μ m and 0.22 μ m filtering with microporous membrane, medicinal liquid is divided and installed in vial, sealing, 115 DEG C of pressure sterilizing 30min, to obtain final product.
25. according to the method for claim 24, wherein in step (b), uses pH value to 5.8 ~ 6.2 of 1M hydrochloric acid solution regulator solution.
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| WO2023028252A1 (en) * | 2021-08-27 | 2023-03-02 | American Regent, Inc. | Iron compositions and methods of making and using them |
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| CN106137953A (en) * | 2016-08-01 | 2016-11-23 | 嘉实（湖南）医药科技有限公司 | Iron sucrose injection and preparation method thereof |
| US11292813B2 (en) * | 2019-02-28 | 2022-04-05 | Renibus Therapeutics, Inc. | Iron compositions and methods of making and using the same |
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| CN1739531A (en) * | 2005-09-12 | 2006-03-01 | 南京生命能科技开发有限公司 | Ferric saccharate injection for treating iron-deficiency anemia and its prepn process |
| JP5597490B2 (en) * | 2010-09-01 | 2014-10-01 | ニプロ株式会社 | Sugar-containing iron oxide preparation for injection |
| CN102362870A (en) * | 2011-11-18 | 2012-02-29 | 陕西盘龙制药集团有限公司 | Injection for treating iron deficiency anemia and preparation method thereof |
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