CN103340827A - Iron sucrose injection and preparation method thereof - Google Patents
Iron sucrose injection and preparation method thereof Download PDFInfo
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- CN103340827A CN103340827A CN2013102984231A CN201310298423A CN103340827A CN 103340827 A CN103340827 A CN 103340827A CN 2013102984231 A CN2013102984231 A CN 2013102984231A CN 201310298423 A CN201310298423 A CN 201310298423A CN 103340827 A CN103340827 A CN 103340827A
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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 sucrose ferrum, relate more particularly to a kind of injection that contains sucrose ferrum.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 by instiling or the mode intravenously administrable of slowly injection be applicable to the bad patient who needs the treatment of vein chalybeate of oral chalybeate effect, and for example oral chalybeate patient and the oral chalybeate that can not tolerate absorbs bad patient.
Background technology
As everyone knows, ferrum is the necessary trace element of human body, because Deficiency of Intake utilizes iron deficiency limited or that other reasons causes quite general, iron deficiency anemia is the widest Deficiency disease that distributes in the world today.Therefore, except actively carrying out the 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 chalybeate commonly used exists the raw meat astringent taste of iron ion as ferrous sulfate, and it is not good to cause mouthfeel, and GI irritation is arranged again, easily causes shortcoming nauseating, vomiting, is difficult to adhere to use; And the ferrous high ferro that is oxidized to easily, cause declined bioavailability of oral administration; And utilize haemachrome that animal proteinum extracts as the iron supplement agent, good absorbing effect, but raw material sources are few, the cost height.The injection that uses sucrose to make does not have the shortcoming of above-mentioned oral ferrum, and rapidly and efficiently, accurate positioning, dangerous low.Sucrose ferrum is a kind of water miscible hydrated ferric oxide. sucrose complex by ferric hydroxide colloid and sucrose complexation preparation, and its ferrum that comprises is in the nonionic state.Ferric hydroxide colloid is formed multinuclear ferrum parent nucleus in molecule, and sucrose passes through the hydrone combination with it that its active hydroxyl replaces ferrum parent nucleus surface, and the adhesion of the two is non-covalent bond molecular separating force.In sucrose ferrum, sucrose exists as the solubilizing agent of ferric hydroxide colloid, and there are a dynamic balance in sucrose and ferric hydroxide colloid.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 form the macromolecular complex (particularly the molecular weight of sucrose ferrum (Mw) is usually in about 34000 to 60000 dalton's scopes) of an about 43Kda, be similar to naturally occurring ferritin on the iron complexes structure of this multinuclear heart.This material has good stability, and can guarantee not have under physiological status ionic iron to discharge, and this stability can well adapt to absorbing of physiological ferrum, and therefore, local organization reaction and other untoward reaction almost do not take place.Control to the sucrose iron stability mainly realizes by controlling its cloud point.
Having suitable molecular weight ranges and having suitable stability is that sucrose ferrum discharges physiological ferrum and the very important precondition of avoiding untoward reaction in order under physiological status.It also is the condition that guarantees the injection safety to the general regulation of injection that the injection that guarantee to obtain simultaneously meets pharmacopeia in indexs such as particulate matter, thermal source, microbial limits.But as mentioned above, sucrose is the relative less non-covalent bond of bond energy with the combination of ferrum nuclear in the sucrose iron molecule, so how to guarantee in the preparation process of sucrose rail injection liquid, it is very important that the molecular weight of crude drug active component sucrose iron molecule and stability do not change.
Sucrose ferrum has had long service time as the vein chalybeate, for example the commodity of using clinically in China that have are called the sucrose rail injection liquid (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.Though sucrose rail injection liquid chemically totally is being stable, but known sucrose rail injection liquid occurs the phenomenon of physical instability, sedimentary phenomenon for example appears, particularly occur under the situation of fluctuation at reserve temperature, for example, clearly putting down in writing its holding conditions in the Wei Lefu commercially available product description is: " be stored in the original-pack carton box under 4 ℃～25 ℃ temperature.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 put down in writing its more strict holding conditions: " preserve under 20 ° of C～25 ° C, permission is fluctuateed between 15 °～30 ° C, must not be freezing ".In addition, the inventor has been found that more existing products hang down the precipitation that has big probability when preserving under the situation in temperature and find.
Therefore, this area still needs to have a kind of new method to prepare sucrose rail injection liquid, expects that this sucrose rail injection liquid has good performance for example physical stability and/or chemical stability.
Summary of the invention
The object of the present invention is to provide a kind of new method to prepare sucrose rail injection liquid, expect that this sucrose rail injection liquid has good performance for example physical property and/or chemical property.The inventor is surprisingly found out that and uses the sucrose rail injection liquid of specific treatment process preparation to demonstrate at least a 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 sucrose rail injection liquid, wherein comprises the sucrose ferrum as active component, optional acid-base modifier (also can be described as the pH regulator agent in the present invention), and water for injection.
According to the sucrose rail injection liquid of the arbitrary embodiment of first aspect present invention, its pH value is 10.0～11.5, for example is 10.5～11.1, for example is 10.5～11.0, for example is 10.7～10.9.
According to the sucrose rail injection liquid of the arbitrary embodiment of first aspect present invention, its osmotic pressure is 1100～1400mOsmol/L, for example is 1150～1350mOsmol/L, for example is 1200～1300mOsmol/L, for example is about 1250mOsmol/L.
Sucrose rail injection liquid according to the arbitrary embodiment of first aspect present invention contains 15～25mg ferrum among its every 1ml, for example contains 18～22mg ferrum among every 1ml, for example contains 19～21mg ferrum among every 1ml, for example contains the 20mg ferrum of having an appointment among every 1ml.
Sucrose rail injection liquid according to the arbitrary embodiment of first aspect present invention, contain 240～400mg sucrose among its every 1ml, for example contain 260～380mg sucrose among every 1ml, for example contain 270～330mg sucrose among every 1ml, for example contain 300～330mg sucrose among every 1ml, for example contain the 320mg sucrose of having an appointment among every 1ml.
According to the sucrose rail injection liquid of the arbitrary embodiment of first aspect present invention, contain sucrose ferrum among its every 1ml and count 15～25mg (for example 18～22mg, for example 19～21mg, for example about 20mg) with ferrum.
According to the sucrose rail injection liquid of the arbitrary embodiment of first aspect present invention, contain sucrose ferrum among its every 1ml and count 240～400mg (for example 260～380mg, for example 270～330mg, for example 300～330mg, for example about 320mg) with sucrose.
Sucrose rail injection liquid according to the arbitrary embodiment of first aspect present invention, contain sucrose ferrum among its every 1ml and count 15～25mg (18～22mg for example with ferrum, 19～21mg for example, about 20mg for example), count 240～400mg (260～380mg for example with sucrose, for example 270～330mg, for example 300～330mg, for example about 320mg).
According to the sucrose rail injection liquid 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 the 1M sodium hydroxide solution.
Sucrose rail injection liquid according to the arbitrary embodiment of first aspect present invention, it is after disposing through cold cycling, check according to first method (lamp test) (this method also can abbreviate " lamp test " or similar abbreviation in the present invention as) in two (can be called for short " 2010 editions two ones of Chinese Pharmacopoeias " or similar abbreviation in the present invention) appendix IX H visible foreign matters inspection techniques of version Pharmacopoeia of People's Republic of China in 2010, the visible foreign matters recall rate is less than 8%, particularly less than 5%, more especially less than 3%.
In the present invention, above-mentioned " cold cycling disposal " refer to, makes through above-mentioned lamp test and detect at least 100 bottles of injection that all do not detect visible foreign matters, placed 3 days under the temperature of 25 ± 1 ° of C, then transfer under the temperature of 4 ± 1 ° of C and placed 3 days, finish cold cycling one time; So repeat to finish freeze cycle five times in 30 days, to amount to.
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 all not detecting visible foreign matters through lamp test, after the described cold cycling of five freeze cycle of experience is disposed, check visible foreign matters in each bottle injection through lamp test again, the injection bottle number that detects visible foreign matters accounts for the percent of overall test bottle number.
Unexpectedly find, the sucrose rail injection liquid for preparing through the inventive method have than the remarkable lower visible foreign matters recall rate of the sucrose rail injection liquid that obtains in prior art.
According to the sucrose rail injection liquid of the arbitrary embodiment of first aspect present invention, it is that the method for shining following steps prepares basically:
(a) will write out a prescription the sucrose ferrum of amount of calculation with being dissolved in an amount of water for injection;
(b) in step (a) gained medicinal liquid, add 0.05～0.2% (w/v) active carbon, under agitation use pH value to 5.5～6.5 of 1M hydrochloric acid solution regulator solution again, then make medicinal liquid under 60-70 ℃ of temperature, be incubated absorption 20～30 minutes; Use 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9 again, continue to make medicinal liquid under 60-70 ℃ of temperature, to be incubated absorption 10～15 minutes, filtering decarbonization;
(c) add water for injection to the full dose of writing out a prescription, check the pH value of solution, use in case of necessity in pH value to 10.7～10.9 scopes of acid-base modifier regulator solution; Make medicinal liquid use 0.4 μ m and 0.22 μ m filtering with microporous membrane successively, the medicinal liquid branch is installed in the vial, sealing, 115 ° of C pressure sterilizing 30min, namely.
Sucrose rail injection liquid according to the arbitrary embodiment of first aspect present invention, wherein an amount of water for injection can be 30～60% water for injection of prescription full dose in the step (a), for example can be 45～55% water for injection of prescription full dose, for example can be about 50% water for injection of prescription full dose.
According to the sucrose rail injection liquid of the arbitrary embodiment of first aspect present invention, wherein use pH value to 5.8～6.2 of 1M hydrochloric acid solution regulator solution in the step (b).
Further, second aspect present invention provides the method for preparing sucrose rail injection liquid (for example described sucrose rail injection of the arbitrary embodiment of first aspect present invention liquid), and it consists essentially of following steps:
(a) will write out a prescription the sucrose ferrum of amount of calculation with being dissolved in an amount of water for injection;
(b) in step (a) gained medicinal liquid, add 0.05～0.2% (w/v) active carbon, under agitation use pH value to 5.5～6.5 of 1M hydrochloric acid solution regulator solution again, then make medicinal liquid under 60-70 ℃ of temperature, be incubated absorption 20～30 minutes; Use 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9 again, continue to make medicinal liquid under 60-70 ℃ of temperature, to be incubated absorption 10～15 minutes, filtering decarbonization;
(c) add water for injection to the full dose of writing out a prescription, check the pH value of solution, use in case of necessity in pH value to 10.7～10.9 scopes of acid-base modifier regulator solution; Make medicinal liquid use 0.4 μ m and 0.22 μ m filtering with microporous membrane successively, the medicinal liquid branch is installed in the vial, sealing, 115 ° of C pressure sterilizing 30min, namely.
Method according to the arbitrary embodiment of second aspect present invention, wherein an amount of water for injection can be 30～60% water for injection of prescription full dose in the step (a), for example can be 45～55% water for injection of prescription full dose, for example can be about 50% water for injection of prescription full dose.
According to the method for the arbitrary embodiment of second aspect present invention, wherein use pH value to 5.8～6.2 of 1M hydrochloric acid solution regulator solution in the step (b).
According to the method for the arbitrary embodiment of second aspect present invention, wherein said sucrose rail injection liquid comprises the sucrose ferrum as active component, optional acid-base modifier (also can be described as the pH regulator agent in the present invention), and water for injection.
According to the method for the arbitrary embodiment of second aspect present invention, the pH value of wherein said sucrose rail injection liquid is 10.0～11.5, for example is 10.5～11.1, for example is 10.5～11.0, for example is 10.7～10.9.
According to the method for the arbitrary embodiment of second aspect present invention, the osmotic pressure of wherein said sucrose rail injection liquid is 1100～1400mOsmol/L, for example is 1150～1350mOsmol/L, for example is 1200～1300mOsmol/L, for example is about 1250mOsmol/L.
According to the method for the arbitrary embodiment of second aspect present invention, contain 15～25mg ferrum among wherein said its every 1ml of sucrose rail injection liquid, for example contain 18～22mg ferrum among every 1ml, for example contain 19～21mg ferrum among every 1ml, for example contain the 20mg ferrum of having an appointment among every 1ml.
Method according to the arbitrary embodiment of second aspect present invention, contain 240～400mg sucrose among wherein said its every 1ml of sucrose rail injection liquid, for example contain 260～380mg sucrose among every 1ml, for example contain 270～330mg sucrose among every 1ml, for example contain 300～330mg sucrose among every 1ml, for example contain the 320mg sucrose of having an appointment among every 1ml.
According to the method for the arbitrary embodiment of second aspect present invention, contain sucrose ferrum among wherein said its every 1ml of sucrose rail injection liquid 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, contain sucrose ferrum among wherein said its every 1ml of sucrose rail injection liquid and count 240～400mg (for example 260～380mg, for example 270～330mg, for example 300～330mg, for example about 320mg) with sucrose.
Method according to the arbitrary embodiment of second aspect present invention, contain sucrose ferrum among wherein said its every 1ml of sucrose rail injection liquid and count 15～25mg (18～22mg for example with ferrum, 19～21mg for example, about 20mg for example), count 240～400mg (260～380mg for example 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 the 1M sodium hydroxide solution.
Method according to the arbitrary embodiment of second aspect present invention, its prepared sucrose rail injection liquid is after disposing through cold cycling, check according to first method (lamp test) (this method also can abbreviate " lamp test " or similar abbreviation in the present invention as) in two (can be called for short " 2010 editions two ones of Chinese Pharmacopoeias " or similar abbreviation in the present invention) appendix IX H visible foreign matters inspection techniques of version Pharmacopoeia of People's Republic of China in 2010, the visible foreign matters recall rate is less than 8%, particularly less than 5%, more especially less than 3%.In the present invention, above-mentioned " cold cycling disposal " refer to, makes through above-mentioned lamp test and detect at least 100 bottles of injection that all do not detect visible foreign matters, placed 3 days under the temperature of 25 ± 1 ° of C, then transfer under the temperature of 4 ± 1 ° of C and placed 3 days, finish cold cycling one time; So repeat to finish freeze cycle five times in 30 days, to amount to.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 all not detecting visible foreign matters through lamp test, after the described cold cycling of five freeze cycle of experience is disposed, check visible foreign matters in each bottle 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, though the concrete steps of its description on some details or the step described in the preparation example of language description up and down stationery body embodiment part distinguish to some extent, yet the open in detail of those skilled in the art's full text according to the present invention can summarize the above method step fully.
Arbitrary embodiment of either side of the present invention can make up with other embodiment, as long as they contradiction can not occur.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 contradiction can not occur.Below the invention will be further described.
All documents that the present invention quotes from, their full content is incorporated this paper by reference into, and if the expressed implication of these documents and the present invention when 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 more detailed description and interpretation to be made in these terms and phrase, the term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.
In the present invention, symbol % according to its employed linguistic context, can have the implication that those skilled in the art understand easily.
When preparation medicinal liquid of the present invention, as well known to those skilled in the art, for example can use the microporous filter membrane of about 0.45um to carry out coarse filtration and filter, with before liquid medicine filling is in the vial, for example can use the microporous filter membrane of about 0.22um to carry out fine straining and filter with degerming, can filter repeatedly in case of necessity.
The invention provides a kind of sucrose rail injection liquid for vein iron supplement treatment iron deficiency anemia.The pH value of sucrose rail injection liquid of the present invention for example is 10.5～11.1 usually 10.0～11.5, for example is 10.5～11.0, for example is 10.7～10.9.
The cloud point of sucrose rail injection liquid of the present invention (for example can with reference to American Pharmacopeia USP35-NF30 sucrose rail injection liquid cloud point (Turbidity) definition and detection method mensuration down) with pH meter in 4.4～5.3 scopes.
The weight average molecular weight (Mw) of sucrose rail injection liquid of the present invention is in 34000 – 60000Da scopes, for example in 34000 – 54000Da scopes.
The number-average molecular weight (Mn) of sucrose rail injection liquid of the present invention is not less than 24000Da.
The molecular weight distribution (in Mw/Mn) of sucrose rail injection liquid of the present invention is less than 1.7.
In the process of preparation sucrose rail injection liquid of the present invention, when medicinal liquid is filtered, used microporous filter membrane is hydrophilic film, this class hydrophilic film is such as but not limited to cellulose acetate film (hereinafter all being to use cellulose acetate film as not specifying in the present invention), nitrocellulose membrane, polypropylene film, poly (ether sulfone) film or nylon membrane, and the different choice of these several films does not have harmful effect to the preparation of injection usually.
The sucrose rail injection liquid that the inventive method prepares has good performance, particularly its many physical and chemical parameter for example the parameter such as pH value, cloud point, weight average molecular weight, number-average molecular weight, molecular weight distribution of injection all meet the regulation of American Pharmacopeia and/or British Pharmacopoeia.
Find unexpectedly that the sucrose rail injection liquid that uses the inventive method to prepare is disposed the back in cold cycling and shown extremely low visible foreign matters recall rate; Find unexpectedly that also these sucrose rail injection liquid show lower cloud point rate of change after disposing through cold cycling.This is that prior art was not instructed fully.
According to sucrose rail injection liquid of the present invention, it is injection for the injection of solution-type.In one embodiment, this injection is single-dose preparations (for example injection of glass bottle), the sucrose ferrum that comprises in the per unit dosage can be in 10～500mg scope, 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).
Iron deficiency for example iron deficiency anemia is clinical common diseases.Previously, iron dextran is developed and is used for the treatment of the 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﹠amp; Technology52 (5): 190-197 (1998).Afterwards, iron dextran was also used through intravenous, and found to produce similar beneficial effect.
Developed the multiple iron preparation that contains.Intravenous injection colloid hydrated ferric oxide. preparation, particularly sucrose ferrum are applicable to the additional epo treatment for the treatment of acceptance clinically, carry out the patient's of chronic hemodialysis iron deficiency anemia.
Sucrose ferrum is prepared to colloidal suspension and uses as prodrug, and it is discharged iron ion by the cellular uptake of reticuloendothelial system.Iron ion is combined with transferrin, transferrin and then it is transported to bone marrow is used for erythropoiesis or is transported to ferritin and the ferrum storage pool of bone marrow, spleen regulating liver-QI.
The physiology of ferrum and metabolism: human body is stored ferric iron with ferritin and hemosiderin form.Ferritin comprises the protein coat that contains storage chamber, and described storage chamber is used for holding forming and is about [(FeOOH)
8(Fe) OPO
3H
2] the multinuclear hydrated ferric oxide. iron phosphate nuclear of n.The protein coat of ferritin, be that apoferritin comprises 24 polypeptide subunits, it is about 440000 apoferritin molecule that described polypeptide subunit forms mean molecule quantity.About 13 nanometers of the diameter of apoferritin shell, about 7 nanometers of inner chamber.
The protein shell of ferritin, be that apoferritin plays a role as ferrous oxidase in combination and oxidation ferrous iron, described ferrous iron is stored in the cavity of protein shell as multinuclear hydrated ferric oxide. iron phosphate nuclear then.Ferritin can contain the nearly iron ion of 4500 polymerizations, and the molecular weight of whole molecule is 700000 to 800000.Weight in the ferritin molecule more than 30% can be ferrum.
When the amount of available ferrum surpasses the ion storage mechanism of ferritin, can form the ferritin of the gathering that is called hemosiderin, it is the normal composition of mononuclear cell-macrophage system.Hemosiderin comprises the ferritin molecule that loses its Partial Protein mass shell and assemble.Hemosiderin constitutes the about 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 ferritin slowly releases ferrous iron and Reducing agent such as reproducibility flavin mononucleotide (FMN) and more a spot of ascorbic acid in blood flow.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 about 76000, and each molecule contains two iron ion binding sites.
When being applied to the patient, sucrose iron complex (or other is for example with ferric iron colloid of gluconate, dextran, sorbitol or dextrin preparation) is removed from blood flow and metabolism by the macrophage of reticuloendothelial system as granule, stores with the ferrum of the hemosiderin, ferritin and the transferrin that replenish body.The speed of removing from blood flow depends on particle diameter and the composition of colloid hydrated ferric oxide..
Synthesizing of ferrum carbohydrate complex: ferrum carbohydrate complex such as sucrose ferrum comprise the colloid iron hydroxide particle (i.e. nuclear) with the sucrose complexation.These ferrum nuclear 2 makes by iron chloride is neutralized to pH with alkali.Under this pH, saturated hydroxide ion make to form the colloid hydrated ferric oxide., its after formation with suitable carbohydrate such as the complexation of sucrose original position.The structure of ferrum nuclear is followed classical Coordinative Chemistry.Carbohydrate is replaced the hydrone of being combined with ferrum nuclear outer surface and is examined complexation with ferrum by its hydroxyl.
Combination between ferrum nuclear and the carbohydrate is non-covalent molecular separating force, and for example ferrum is examined the part positive charge of surperficial iron atom to the captivation of the dipole moment negative terminal of carbohydrate hydroxyl.
For example, the molecular weight of sucrose ferrum (Mw) is about 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 nuclear [Na
2Fe
5O
8(OH) 3 (H
2O)]
nSucrose molecule (the C of complexation
12H
22O
11) number.
In solution, between multinuclear polymerization ferrum nuclear (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 for example is described in the PCT application WO97/11711 (1997) that announces by people such as Lawrence.
Being used for clinical sucrose rail injection liquid is deep brown solution, and it is applicable to the patient that oral chalybeate effect is bad and need the vein chalybeate to treat usually, as: the patient that oral chalybeate can not tolerate; Oral chalybeate absorbs bad patient.Regular size is 5ml:100mg ferrum and 1.6g sucrose
Usually, sucrose rail injection liquid can only mix use with the 0.9%w/v normal saline, can not mix use with other treatment medicine usually.Whether the preceding macroscopy of use once ampoule has precipitation and damaged.Have only those not have the medicinal liquid of precipitation just can use.Usually, sucrose rail injection liquid should be instiling or the slow mode intravenously administrable of injection, or be injected directly into the vein end of dialyser, and the total amount that this medicine is not suitable for intramuscular injection or needs ferrum according to patient is full dosed administration once.Before the new patient treats for the first time, should give a low dose earlier according to the method for recommending tests, the adult is with 1-2.5ml (20-50mg) ferrum, and the child of body weight＞14 kilogram is with 1ml (20mg ferrum), and the child of body weight＜14 kilogram is with daily dose half (1.5mg/kg).Should have cardio-pulmonary resuscitation equipment.If do not occur untoward reaction in administration after 15 minutes, continue to give remaining medicinal liquid.
Transfusion: the first-selected administering mode of sucrose rail injection liquid is instil (in order to reduce the injection danger that hypotension takes place and vein is outer).1ml this product can only be diluted in the 20ml0.9%w/v normal saline at most, should use (as: 5ml this product is diluted at most in the 100ml0.9% normal saline, and 25ml this product is diluted at most in the 500ml0.9%w/v normal saline) after diluent prepares immediately.The drip velocity of medicinal liquid should be: 100ml ferrum instiled 15 minutes at least; 200ml instiled 30 minutes at least; 300ml dripped 1.5 hours at least; 400ml dripped 2.5 hours at least; 500ml instiled 3.5 hours at least.If clinical needs, the diluent volume of 0.9% normal saline of this product can be made into this product medicinal liquid of higher concentration less than specific quantity.Yet the speed of instillation must determine that (as: 10ml this product=200mg ferrum should drip off at least in 30 minutes according to the dosage that per minute gives ferrum; 25ml this product=500mg ferrum should drip off at least in 3.5 hours).For guaranteeing the stable of medicinal liquid, do not allow medicinal liquid is made into rarer solution.
Intravenous injection: sucrose rail injection liquid can be without the slow intravenous injection of dilution, and advisory speed is per minute 1ml this product (injecting 5 minutes 5ml this product at least), and each maximum injection dosage is 10ml this product (200mg ferrum).After the intravenous injection, should stretch patient's arm.
Inject in dialyser: this product can be injected directly into the vein end of dialyser, and situation is with " intravenous injection " of front.
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 sucrose rail injection liquid that 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, thus the complex that to form a mean molecule quantity be 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 the ferritin structural similarity under the physiological status.Use this product can cause the change of Human Physiology, comprising the absorption to ferrum.This product toxicity is very low.The white mouse vein gives the LD50 after this product〉200 milligrams of ferrum/kg body weight, so therapeutic index is about 30 (200/7).
Sucrose rail injection liquid pharmacokinetics: contain this product of 100mg ferrum for the intravenous injection of healthy volunteer's single dose, the level after 10 minutes reaches the highest, average out to 538 μ mol/L.Central compartment's distribution volume equates (approximately 3L) with the blood plasma volume.The ferrum of injection is got rid of in blood plasma fast, and the half-life is about 6 hours.Vdss is about 8L, and it is few to illustrate that ferrum distributes in human body.Because this product is lower than transferrins stability, can see that ferrum is to the competitiveness exchange of transferrins.The transport velocity of ferrum is 31mg ferrum/24 hour as a result.Preceding 4 hours ferrum removing amounts after injection this product are less than 5% of whole removing amounts.After 24 hours, the level of ferrum drops to the level of the preceding ferrum of injection in the blood plasma, and about 75% sucrose is drained.
The specific embodiment
Following examples further specify the present invention, rather than restriction the present invention.In the example below.Preparation process purpose for example hereinafter, and made some specific descriptions based on the comparability of respectively giving an example, those skilled in the art can therefrom summarize fully according to existing knowledge and obtain the present invention and prepare method for compositions.
Prepare various compositionss below for example in the example of injection, the preparative-scale of every batch of sample is 5000ml, and the amount of the sucrose ferrum that comprises in every bottle is counted 100mg (listed prescription is the amount of 1 bottle of content in each example) with ferrum; Although the product of multiple packing specification is arranged in the existing product, 5ml (ferrum 100mg)/bottle, 10ml (ferrum 200mg)/bottle are for example arranged, those skilled in the art obtain the product of above-mentioned multiple loading amount specification easily by the prescription of above-mentioned 100mg/ bottle, for example when installing to the medicinal liquid branch in the vial, every bottle doubles the packing medicinal liquid, can obtain the product of the loading amount specification of 200mg/ bottle easily.Prepare below in the example of various compositionss, in the dosing process, the pH regulator agent of using in case of necessity is 1M sodium hydroxide solution and 1M hydrochloric acid solution.
A, test method example part
Test example 1: measure and respectively to inject keep sample remaining rate after the test of liquor high-temperature sample
This is tested in the routine method, measures the injection of each embodiment gained after placing 6 months under 40 ° of C, wherein the content of the content of ferrum or sucrose [40 ° of C, June, can be described as the high temperature average content, mg/ml measures 10 bottles meansigma methods] under 20 ° of C, handle content [20 ° of C of corresponding time up-to-date style I chemical compound with respect to this sample, June, can be described as the room temperature average content, mg/ml measures 10 bottles meansigma methods] percent, it can be regarded as remaining percent (%), and namely 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 (10 bottles averages), the situation of change of active component in the size reflection injection of this remnants percent (%), the stability that particularly can reflect active component, remaining percent (%) more big (more leveling off to 100%) then injection after high-temperature process wherein active component keep more, stability is better.In the present invention, as not explanation in addition, 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 is measured with titrimetry, and the 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 handle and accelerate the injection that keeps sample and handle 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.Assay method is measured with reference to the method in the sucrose rail injection liquid kind of American Pharmacopeia USP35-NF30 version record (for example can be referring to http://www.drugfuture.com/Pharmacopoeia/usp35/data/v35300/USP35-NF30s0_m42475.html).The sucrose rail injection liquid that American Pharmacopeia records stipulates 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 first method (lamp test) (abbreviating " lamp test " as) in two appendix IX of version Pharmacopoeia of People's Republic of China in 2010 H visible foreign matters inspection technique.
The cold cycling of injection is disposed: make through lamp test detect all do not detect visible foreign matters at least 100 bottles of injection (as not explanation in addition, every batch sample is all got 150 bottles of injection that do not detect visible foreign matters and is carried out cold cycling and dispose in the test below), under the temperature of 25 ± 1 ° of C, placed 3 days, then transfer under the temperature of 4 ± 1 ° of C and placed 3 days, finish cold cycling one time; So repeat to finish five cold cycling (these tests are all carried out, because injection is encapsulated in the vial, therefore can get rid of the interference of other factors) in 30 days, to amount under the lucifuge condition.
The calculating of visible foreign matters recall rate: after five cold cycling were disposed and finished, every bottle of injection used through lamp test to detect wherein whether contain visible foreign matters again, calculated the bottle number that detects the injection that contains visible foreign matters in every Lot sample; Dispose the total bottle of number (namely 150 bottles) of sample with this numerical value divided by carrying out cold cycling, multiply by 100% again, obtain the visible foreign matters recall rate.For example for certain Lot sample, get 150 bottles of injection that do not detect visible foreign matters and carry out the cold cycling disposal, cold cycling is carried out the inspection of visible foreign matters after disposing and finishing again, visible foreign matters occurs if detected 5 bottles, and then the visible foreign matters recall rate is: 5/150*100%=3.3%.Cold cycling is disposed the variations in temperature can reflect that injection contacts in storage and the process of circulation.This visible foreign matters recall rate is more big, and it is more poor that then sample shows as stability aspect physical stability.
B, embodiment part: preparation comprises the injecta composition of sucrose ferrum
The iron sucrose bulk drug that uses in the example of following preparation injection can be following commercially available crude drug: the crude drug 1 (approval number of the drug: the accurate word H20051241 of traditional Chinese medicines, inferior precious Pharmaceutical pharmacy product), the crude drug 2 (approval number of the drug: the accurate word H20103700 of traditional Chinese medicines, Chongqing Inst. of Pharmaceutical Industry's product), 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 all are through State Food and Drug Administration's approval listing and can be used for preparing the crude drug of sucrose rail injection liquid, meet general specification requirement.
Embodiment 1, preparation sucrose rail injection liquid (with every bottle of 5ml injection fluid volume meter, preparating liquid 5000ml, down with)
Prescription: sucrose ferrum an amount of (iron content 100mg, the sucrose amount is in 315～330mg scope) 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 standby.
Method for making: (a) will the write out a prescription sucrose ferrum of amount of calculation under agitation makes it be dissolved in the 2.5ml water for injection;
(b) in step (a) gained medicinal liquid, add 0.1% (w/v) active carbon, under agitation use pH value to 6.0 ± 0.1 of 1M hydrochloric acid solution regulator solution again, then make medicinal liquid under 60-70 ℃ of temperature, be incubated absorption 25 minutes (can be described as absorption for the first time or the absorption of neutral charcoal in the present invention); Use 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9 again, continue to make medicinal liquid to be incubated absorption 12 minutes under 60-70 ℃ of temperature, 0.8 μ m filtering with microporous membrane takes off charcoal (can be described as absorption for the second time or the absorption of alkaline charcoal in the present invention);
(c) add water for injection to the full dose of writing out a prescription, check the pH value of solution, use in case of necessity in pH value to 10.7～10.9 scopes of acid-base modifier regulator solution; Make medicinal liquid use 0.4 μ m and 0.22 μ m filtering with microporous membrane successively, the medicinal liquid branch is installed in the vial, sealing, 115 ° of C pressure sterilizing 30min, namely.
Embodiment 2, preparation sucrose rail injection liquid
Prescription: with embodiment 1.
Method for making: (a) will the write out a prescription sucrose ferrum of amount of calculation under agitation makes it be dissolved in the 2.25ml water for injection;
(b) in step (a) gained medicinal liquid, add 0.2% (w/v) active carbon, under agitation use pH value to 5.6 ± 0.1 of 1M hydrochloric acid solution regulator solution again, then make medicinal liquid under 60-70 ℃ 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 to be incubated absorption 15 minutes under 60-70 ℃ of temperature, 0.8 μ m filtering with microporous membrane takes off charcoal;
(c) add water for injection to the full dose of writing out a prescription, check the pH value of solution, use in case of necessity in pH value to 10.7～10.9 scopes of acid-base modifier regulator solution; Make medicinal liquid use 0.4 μ m and 0.22 μ m microporous filter membrane (this example is poly (ether sulfone) film) to filter successively, the medicinal liquid branch is installed in the vial, sealing, 115 ° of C pressure sterilizing 30min, namely.
Embodiment 3, preparation sucrose rail injection liquid
Prescription: with embodiment 1.
Method for making: (a) will the write out a prescription sucrose ferrum of amount of calculation under agitation makes it be dissolved in the 2.75ml water for injection;
(b) in step (a) gained medicinal liquid, add 0.05% (w/v) active carbon, under agitation use pH value to 6.4 ± 0.1 of 1M hydrochloric acid solution regulator solution again, then make medicinal liquid under 60-70 ℃ 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 to be incubated absorption 10 minutes under 60-70 ℃ of temperature, 0.8 μ m filtering with microporous membrane takes off charcoal;
(c) add water for injection to the full dose of writing out a prescription, check the pH value of solution, use in case of necessity in pH value to 10.7～10.9 scopes of acid-base modifier regulator solution; Make medicinal liquid use 0.4 μ m and 0.22 μ m microporous filter membrane (this example is nitrocellulose membrane) to filter successively, the medicinal liquid branch is installed in the vial, sealing, 115 ° of C pressure sterilizing 30min, namely.
Embodiment 4, preparation sucrose rail injection liquid
Prescription: sucrose ferrum an amount of (the sucrose amount is in 310～330mg scope 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 standby.
Method for making: (a) will the write out a prescription sucrose ferrum of amount of calculation under agitation makes it be dissolved in the 2.4ml water for injection;
(b) in step (a) gained medicinal liquid, add 0.1% (w/v) active carbon, under agitation use pH value to 6.2 ± 0.1 of 1M hydrochloric acid solution regulator solution again, then make medicinal liquid under 60-70 ℃ 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 to be incubated absorption 12 minutes under 60-70 ℃ of temperature, 0.8 μ m filtering with microporous membrane takes off charcoal;
(c) add water for injection to the full dose of writing out a prescription, check the pH value of solution, use in case of necessity in pH value to 10.7～10.9 scopes of acid-base modifier regulator solution; Make medicinal liquid use 0.4 μ m and 0.22 μ m microporous filter membrane (this example is nylon membrane) to filter successively, the medicinal liquid branch is installed in the vial, sealing, 115 ° of C pressure sterilizing 30min, namely.
Embodiment 5, preparation sucrose rail injection liquid
Prescription: sucrose ferrum an amount of (the sucrose amount is in 300～330mg scope 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 standby.
Method for making: (a) will the write out a prescription sucrose ferrum of amount of calculation under agitation makes it be dissolved in the 2.6ml water for injection;
(b) in step (a) gained medicinal liquid, add 0.1% (w/v) active carbon, under agitation use pH value to 5.8 ± 0.1 of 1M hydrochloric acid solution regulator solution again, then make medicinal liquid under 60-70 ℃ 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 to be incubated absorption 12 minutes under 60-70 ℃ of temperature, 0.8 μ m filtering with microporous membrane takes off charcoal;
(c) add water for injection to the full dose of writing out a prescription, check the pH value of solution, use in case of necessity in pH value to 10.7～10.9 scopes of acid-base modifier regulator solution; Make medicinal liquid use 0.4 μ m and 0.22 μ m filtering with microporous membrane successively, the medicinal liquid branch is installed in the vial, sealing, 115 ° of C pressure sterilizing 30min, namely.
Reference examples 1, preparation sucrose rail injection liquid
Prescription: with embodiment 1.
Method for making: the water that uses in the step (a) is 3.5ml or 4.5ml, and all the other obtain two samples of reference examples 1a, reference examples 1b respectively with embodiment 1 described method for making.When water consumption is 2ml or when lower, can not dissolve crude drug fully, only could dissolve the crude drug of recipe quantity during more than or equal to 2.25ml fully in water consumption.
Reference examples 2, preparation sucrose rail injection liquid
Prescription: with embodiment 1.
Method for making: in the step (b) in charcoal when absorption 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 under 60-70 ℃ of temperature, be incubated absorption 25 minutes.All the other obtain reference examples 2a, reference examples 2b, reference examples 2c, reference examples 2d, six samples of reference examples 2e, reference examples 2f respectively with embodiment 1 described method for making.
Reference examples 3, preparation sucrose rail injection liquid
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) add 0.1% (w/v) active carbon in step (a) gained medicinal liquid, with 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9, make medicinal liquid be incubated absorption 30 minutes under 60-70 ℃ of temperature, 0.8 μ m filtering with microporous membrane takes off charcoal; Other operation is with embodiment 1.
Reference examples 4, preparation sucrose rail injection liquid
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, three samples of reference examples 4c respectively.
Reference examples 5, preparation sucrose rail injection liquid
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, four samples of reference examples 5c, reference examples 5d respectively.
Reference examples 6, preparation 5 batches of sucrose rail injection liquid (200510094323.2)
Reference examples 61: the iron sucrose bulk drug dry product dissolves with fresh water for injection, is mixed with every milliliter of solution that contains ferrum element 20mg; Under 40 ° of C temperature, add 0.1% active carbon, behind the stirring 15min, the titanium rod carbon removal in 1um aperture; It is every milliliter of 20mg that filtered solution is regulated iron content, and regulating pH is that 10.2,0.22um hydrophilic micro-filtration membrane (nitrocellulose filter) is filtered, and degerming is except insoluble granule; Fill 2.5ml/ ampoule; Namely get sucrose rail injection liquid.
Reference examples 62: the iron sucrose bulk drug dry product dissolves with fresh water for injection, is mixed with every milliliter of solution that closes ferrum element 22mg; Under 55 ℃ of temperature, add 0.01% active carbon, behind the stirring 45min, the titanium rod carbon removal in 1um aperture; It is every milliliter of 20mg that filtered solution is regulated iron content, and regulating pH is that 10.5,0.22um hydrophilic micro-filtration membrane (polypropylene film) is filtered, and degerming is except insoluble granule; Fill 5ml/ ampoule; 100 ℃ of decocting in water 30min namely get sucrose rail injection liquid.
Reference examples 63: the iron sucrose bulk drug dry product dissolves with fresh water for injection, is mixed with every milliliter of solution that contains ferrum element 21mg; Regulating pH is 10.8, under 65 ℃ of temperature, adds 0.05% active carbon, behind the stirring 45min, and plate and frame type filter-press; It is every milliliter of 20mg that filtered solution is regulated iron content, and 0.22um hydrophilic micro-filtration membrane (poly (ether sulfone) film) is filtered, and degerming is except insoluble granule; Fill 2ml/ ampoule; Flowing steam sterilization 20min namely gets sucrose rail injection liquid.
Reference examples 64: the iron sucrose bulk drug dry product dissolves with fresh water for injection, is mixed with every milliliter of solution that contains ferrum element 24mg; Under 80 ℃ of temperature, add 0.15% active carbon, behind the stirring 50min, the titanium rod carbon removal in 1um aperture; It is every milliliter of 20mg that filtered solution is regulated iron content, and regulating pH is that 11.2,0.22um hydrophilic micro-filtration membrane (cellulose acetate membrane) is filtered, and degerming is except insoluble granule; Fill 5ml/ ampoule; Flowing steam sterilization 20min namely gets sucrose rail injection liquid.
Reference examples 65: the iron sucrose bulk drug dry product dissolves with fresh water for injection, is mixed with every milliliter of solution that contains ferrum element 25mg; Under 70 ℃ of temperature, add 0.2% active carbon, behind the stirring 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 is except insoluble granule; Fill 5ml/ ampoule; Flowing steam sterilization 40min namely gets sucrose rail injection liquid.
Reference examples 7,(it is described through 35 minutes sucrose rail injection liquid of 100 ℃ of following heat treated to obtain embodiment 2 for Chinese patent application number 02829664, the Wei Fu) method of description embodiment 1 and embodiment 2 with reference to CN1685227A.
Reference examples 8,Prepare sucrose rail injection liquid with reference to CN103040730A (Chinese patent application number 201110309357.4, Ao in the Tianjin) description embodiment 1 [0024] to method of [0030] section record.
C, injection performance are investigated
Injection to 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 is with crude drug 2), reference examples 4b (pH7.5), reference examples 4c (not doing neutral charcoal absorption),
Reference examples 5a (pH4.5 is 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 and respectively inject keep sample remaining rate after the test of liquor high-temperature sample
More than the sample of each embodiment and reference examples, all under 40 ° of C, placed 6 months, all under 20 ° of C, placed 6 months side by side.
After measured, the remaining percent of the 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 (%) show that injection of the present invention does to have good chemical stability aspect the sucrose of quality monitoring and two indexs of ferrum at needs all in 98.1%～99.6% scope;
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 the sucrochemistry stability;
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 when adsorbing for the first time are higher or the remaining percents of ferrum (%) that do not carry out the injection of absorption for the first time all in 97.3%～99.5% scope, show that they are being good aspect the ferrum chemical stability; More than the good reference examples of the remaining percent of these ferrum and embodiment 1～5 each injection ferrous be that the amount of ferrum (II) is in that 40 ° of C-6 months and 20 ° of C-6 are monthly is lower than 0.26% (measure according to USP35-NF30, and ferrous amount should be less than 0.4% in the USP35-NF30 regulation injection);
But beat allly be, these use the injection of more water reference examples 1a, reference examples 1b in step (a), and the remaining percents of ferrum (%) of these injection that pH value is lower when adsorbing for the first time of reference examples 2a, reference examples 2b, reference examples 4a, reference examples 5a are all in 83.5%～89.1% scope, show that they accept can not making us aspect the ferrum chemical stability; Though 20 ° of amounts of handling back ferrum (II) the C-6 month of the unsafty reference examples injection of the remaining percent of these ferrum all are lower than 0.23% in addition, but these reference examples injection all reach 0.71～1.26% scope in the amount of handling back ferrum (II) 40 ° of C-6 months, far can not meet general pharmacopeia regulation;
As seen, in step (a), using more water and pH value is lower when adsorbing for the first time injection to accept can not making us fully aspect the chemical stability of ferrum.
Investigate example 2: the physical parameter of measuring each injection liquid samples
For various samples, comprise through high temperature accelerate to keep sample handle and accelerate the injection that keeps sample and handle 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.Assay method is measured with reference to the method for American Pharmacopeia USP35-NF30 version record (for example can be referring to http://www.drugfuture.com/Pharmacopoeia/usp35/data/v35300/USP35-NF30s0_m42475.html).The sucrose rail injection liquid that American Pharmacopeia records stipulates 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 two kinds for the treatment of conditions of 4 months of experience:
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 in 34000 – 54000Da scopes, number-average molecular weight (Mn) 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, these pH value when adsorbing for the first time of reference examples 8 are higher or do not carry out the injection of absorption for the first time, and reference examples 1a, these use the injection of more water reference examples 1b in step (a), and reference examples 2a, reference examples 2b, reference examples 4a, these lower injection of pH value when 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 in 34000 – 60000Da scopes, 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 satisfying 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 in 1150～1350mOsmol/L scope, contain 18～22mg ferrum (III among every 1ml, ferrum in the sucrose rail injection liquid of the present invention is the III valency, and as not explanation in addition, the ferrum of mentioning is the III valency), contain 300～330mg sucrose among every 1ml
Investigate example 3: cold cycling is disposed test and visible foreign matters inspection
Carry out according to above testing example 3 methods, the result is as follows for the visible foreign matters recall rate:
The visible foreign matters recall rate of embodiment 1～5 each batch injection all is 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 these lower injection of pH value when adsorbing for the first time of reference examples 2a, reference examples 2b, reference examples 4a, reference examples 5a, the visible foreign matters recall rate all is lower than 5%, all in 0.75～4.76% scope, show that these injection have better physical stability;
But beat allly be, 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 when adsorbing for the first time are higher or do not carry out the injection of absorption for the first time, the 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;
As seen, has feature of the present invention or have gratifying result by the injection physical stability that the inventive method prepares.
Industrial applicability
It can be used for treating iron deficiency anemia especially the injection that contains sucrose ferrum that the present invention relates to, particularly it can be by instiling or the mode intravenously administrable of slowly injection be applicable to the bad patient who needs the treatment of vein chalybeate of oral chalybeate effect, and for example oral chalybeate patient and the oral chalybeate that can not tolerate absorbs bad patient.
Claims (10)
1. a sucrose rail injection liquid wherein comprises the sucrose ferrum as active component, optional acid-base modifier and water for injection, and the pH value of this injection is 10.0～11.5.
2. according to the sucrose rail injection liquid of claim 1, it is characterized in that:
Osmotic pressure is 1100～1400mOsmol/L;
Contain 15～25mg (for example 18～22mg, for example 19～21mg, for example about 20mg) ferrum among every 1ml;
Contain 240～400mg (for example 260～380mg, for example 270～330mg, for example 300～330mg, for example about 320mg) sucrose among every 1ml; And/or
Described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution.
3. according to the sucrose rail injection liquid of claim 1-2, it is after disposing through cold cycling, and with the lamp test inspection, the visible foreign matters recall rate is less than 8%, particularly less than 5%, more especially less than 3%.
4. according to the sucrose rail injection liquid of claim 1-3, it is characterized in that:
Its cloud point with pH meter in 4.4～5.3 scopes;
Its weight average molecular weight (Mw) is in 34000 – 60000Da scopes, for example in 34000 – 54000Da scopes;
It is characterized in that: number-average molecular weight (Mn) is not less than 24000Da; And/or
Its molecular weight distribution (in Mw/Mn) is less than 1.7.
5. according to the sucrose rail injection liquid of claim 1-4, it is that the method for shining following steps prepares basically:
(a) will write out a prescription the sucrose ferrum of amount of calculation with being dissolved in an amount of water for injection;
(b) in step (a) gained medicinal liquid, add 0.05～0.2% (w/v) active carbon, under agitation use pH value to 5.5～6.5 of 1M hydrochloric acid solution regulator solution again, then make medicinal liquid under 60-70 ℃ of temperature, be incubated absorption 20～30 minutes; Use 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9 again, continue to make medicinal liquid under 60-70 ℃ of temperature, to be incubated absorption 10～15 minutes, filtering decarbonization;
(c) add water for injection to the full dose of writing out a prescription, check the pH value of solution, use in case of necessity in pH value to 10.7～10.9 scopes of acid-base modifier regulator solution; Make medicinal liquid use 0.4 μ m and 0.22 μ m filtering with microporous membrane successively, the medicinal liquid branch is installed in the vial, sealing, 115 ° of C pressure sterilizing 30min, namely.
6. according to the sucrose rail injection liquid of claim 5, wherein an amount of water for injection can be 30～60% water for injection of prescription full dose in the step (a), for example can be 45～55% water for injection of prescription full dose, for example can be about 50% water for injection of prescription full dose.
7. according to the sucrose rail injection liquid of claim 5, wherein use pH value to 5.8～6.2 of 1M hydrochloric acid solution regulator solution in the step (b).
8. according to the sucrose rail injection liquid of claim 1, it is single-dose preparations, it measures in 10～500mg scope the sucrose ferrum that comprises in the per unit dosage in ferrum (Fe), for example about 10mg, about 20mg, about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 400mg or about 500mg.
9. prepare the method for each described sucrose rail injection liquid of claim 1-8, it consists essentially of following steps:
(a) will write out a prescription the sucrose ferrum of amount of calculation with being dissolved in an amount of water for injection;
(b) in step (a) gained medicinal liquid, add 0.05～0.2% (w/v) active carbon, under agitation use pH value to 5.5～6.5 of 1M hydrochloric acid solution regulator solution again, then make medicinal liquid under 60-70 ℃ of temperature, be incubated absorption 20～30 minutes; Use 1M sodium hydroxide solution regulator solution pH value to 10.7～10.9 again, continue to make medicinal liquid under 60-70 ℃ of temperature, to be incubated absorption 10～15 minutes, filtering decarbonization;
(c) add water for injection to the full dose of writing out a prescription, check the pH value of solution, use in case of necessity in pH value to 10.7～10.9 scopes of acid-base modifier regulator solution; Make medicinal liquid use 0.4 μ m and 0.22 μ m filtering with microporous membrane successively, the medicinal liquid branch is installed in the vial, sealing, 115 ° of C pressure sterilizing 30min, namely.
10. according to the method for claim 9, wherein an amount of water for injection is 45～55% water for injection of prescription full dose in the step (a); And/or, middle pH value to 5.8～6.2 with 1M hydrochloric acid solution regulator solution of step (b).
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Cited By (2)
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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 |
| CN113825496A (en) * | 2019-02-28 | 2021-12-21 | 雷尼布斯治疗公司 | Novel iron compositions and methods of making and using the same |
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| JP2024534172A (en) * | 2021-08-27 | 2024-09-18 | ヴァイフォー（インターナショナル）アーゲー | Iron compositions and methods of making and using them - Patents.com |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN113825496A (en) * | 2019-02-28 | 2021-12-21 | 雷尼布斯治疗公司 | Novel iron compositions and methods of making and using the same |
| JP2022522009A (en) * | 2019-02-28 | 2022-04-13 | レニバス・セラピューティクス・インコーポレイテッド | New iron composition and its manufacturing method and usage method |
| JP7320611B2 (en) | 2019-02-28 | 2023-08-03 | レニバス・セラピューティクス・インコーポレイテッド | Novel iron composition and method of making and using same |
| US11834471B2 (en) | 2019-02-28 | 2023-12-05 | Renibus Therapeutics, Inc. | Iron compositions and methods of making and using the same |
| US11840552B2 (en) | 2019-02-28 | 2023-12-12 | Renibus Therapeutics, Inc. | Iron compositions and methods of making and using the same |
| CN113825496B (en) * | 2019-02-28 | 2024-09-27 | 雷尼布斯治疗公司 | Novel iron compositions and methods of making and using the same |
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