CN102367229B - Ethylenediamine diaceturate compound and pharmaceutical composition thereof - Google Patents
Ethylenediamine diaceturate compound and pharmaceutical composition thereof Download PDFInfo
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- CN102367229B CN102367229B CN201110240167A CN201110240167A CN102367229B CN 102367229 B CN102367229 B CN 102367229B CN 201110240167 A CN201110240167 A CN 201110240167A CN 201110240167 A CN201110240167 A CN 201110240167A CN 102367229 B CN102367229 B CN 102367229B
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Abstract
The invention relates to a novel ethylenediamine diaceturate crystalline compound and a pharmaceutical composition thereof. The X-ray powder diffraction obtained by measuring the ethylenediamine diaceturate crystals with Cu-K alfa ray has characteristic peaks when a 2 theta angle is 8.0 degrees, 10.0 degrees, 17.8 degrees, 18.2 degrees, 24.0 degrees, 26.0 degrees and 26.5 degrees. The invention also relates to the pharmaceutical composition containing the ethylenediamine diaceturate crystals, comprising a freeze-drying powder injection or a liquid injection, wherein, the freeze-drying powder injection comprises 10 weight portions of ethylenediamine diaceturate crystals and 0-1 weight portions of excipient which is selected from mannitol, sorbitol, glucose or dextran, and the liquid injection comprises 10 weight portions of ethylenediamine diaceturate crystals and 0.1-1 weight portions of auxiliary materials which are selected from mannitol, sorbitol, glucose, dextran or sodium chloride.
Description
Technical field
The present invention relates to a kind of crystalline compounds of new diacetyl nitrilo acetic acid quadrol, also relate to its pharmaceutical composition.
Background technology
Diacetyl nitrilo acetic acid quadrol is the novel styptic that China develops voluntarily, can impel Fibrinogen to become scleroproein, and can impel thrombocyte to discharge the blood coagulation activity material, and accelerate blood is solidified.It is hemorrhage etc. to be mainly used in digestive tract hemorrhage, eye nasal bleeding, gynecological and hemorrhage, bleeding hemorrhoids, surgery, and better curative effect is all arranged, and has been widely used in clinical.
About diacetyl nitrilo acetic acid quadrol, have a lot of document and patent reports at present.
Patented claim 03111213.7 discloses lyophilized injectable powder, bulk capacity injection of a kind of diacetyl nitrilo acetic acid quadrol and preparation method thereof.Its lyophilized injectable powder is formed and is comprised diacetyl nitrilo acetic acid quadrol, frozen-dried supporting agent, pH regulator agent, and parts by weight are: 0.05～10 part of diacetyl nitrilo acetic acid quadrol, 0～100 part of lyophilized powder balustrade, 0～10 part of pH regulator agent; Bulk capacity injection is formed and is comprised diacetyl nitrilo acetic acid quadrol, osmotic pressure regulator, pH regulator agent, and parts by weight are: 0.05～10 part of diacetyl nitrilo acetic acid quadrol, 0～100 part of osmotic pressure regulator, 0～10 part of pH regulator agent.
Patented claim 200310111341.8 discloses a kind of diacetyl nitrilo acetic acid quadrol powder injection and preparation method thereof; Wherein contain the diacetyl nitrilo acetic acid quadrol 0.2～1.2g of unitary dose, and contain a kind of pharmaceutically acceptable vehicle, pH regulator agent, oxidation inhibitor, stablizer etc. at least; And in container, to provide with unit dosage form.The diacetyl nitrilo acetic acid quadrol 0.2～1.2g that perhaps only contains unitary dose, and in container, to provide with unit dosage form.Thereby overcome the deficiency of diacetyl nitrilo acetic acid quadrol liquid drugs injection, be used to prevent and treat the hemorrhage treatment of a variety of causes.
Patent ZL 200510039248.X discloses a kind of freeze-dried powder of injection diacetyl nitrilo acetic acid quadrol, and preparation is prepared into lyophilisate by diacetyl nitrilo acetic acid quadrol, water for injection through freeze-drying.
Because the liquid drugs injection stability of diacetyl nitrilo acetic acid quadrol is poor slightly; The freeze-dried powder formulation that has occurred a lot of diacetyl nitrilo acetic acid quadrols on the market; Because diacetyl nitrilo acetic acid quadrol is difficult in freeze-drying in the short time, and forms dry, loose lyophilized powder, the contriver starts with from the raw material of diacetyl nitrilo acetic acid quadrol; Prepared a kind of new crystal of diacetyl nitrilo acetic acid quadrol; Thereby solved this difficult problem, and the stability of the diacetyl nitrilo acetic acid quadrol for preparing of this crystal is better, the preparation that is used for liquid drugs injection and powder pin preferably.
Summary of the invention
Primary goal of the invention of the present invention is to provide a kind of new diacetyl ammonia ethylene diamine compound.
Second goal of the invention of the present invention is to provide the pharmaceutical composition of this diacetyl ammonia ethylene diamine compound.
In order to realize the object of the invention, the technical scheme of employing is:
The present invention relates to a kind of diacetyl nitrilo acetic acid ethylene diamine compound; The X-ray powder diffraction that said diacetyl nitrilo acetic acid ethylene diamine compound crystal uses the Cu-K alpha-ray to measure is 8.0 °, 10.0 °, 17.8 °, 18.2 °, 24.0 °, 26.0 ° and 26.5 ° at 2 θ and shows characteristic peak that its chemical formula is suc as formula shown in the I:
First optimal technical scheme of the present invention is: described diacetyl nitrilo acetic acid ethylene diamine compound crystalline preparation method does; Diacetyl nitrilo acetic acid quadrol solid is dissolved in the zero(ppm) water; At 25 ℃～45 ℃, add the mixed solvent of absolute ethyl alcohol and anhydrous propanone under preferred 30 ℃～40 ℃ conditions, after adding, mixed solvent is cooled to 5 ℃～15 ℃; Preferred 10 ℃～15 ℃, obtain leaving standstill behind the crystal; Filter, filter cake is used absolute ethanol washing, after the vacuum-drying 2～5 hours, obtains diacetyl nitrilo acetic acid quadrol crystal.
Second optimal technical scheme of the present invention is: the volume of the volume of the mixed solvent of described absolute ethyl alcohol and anhydrous propanone and diacetyl nitrilo acetic acid quadrol solid aqueous solution is 2～5: 1, preferred 2.5～3.5: 1.
The 3rd optimal technical scheme of the present invention is: the volume ratio of described absolute ethyl alcohol, anhydrous propanone is 1: 0.2～0.8, preferred 1: 0.25～0.75, more preferably 1: 0.25～0.5.
The 4th optimal technical scheme of the present invention is: the speed of the dropping of absolute ethyl alcohol and anhydrous propanone is 2～5ml/ minute, preferred 2.5～4.5ml/ minute.
The 5th optimal technical scheme of the present invention is: stirring velocity is 30～60 rev/mins when dripping absolute ethyl alcohol and anhydrous propanone, preferred 45～60 rev/mins.
The 6th optimal technical scheme of the present invention is: the speed that mixed solvent adds the back cooling is 2～6 ℃/min, preferred 2.5～3.5 ℃/min.
The invention still further relates to a kind of pharmaceutical composition of diacetyl nitrilo acetic acid ethylene diamine compound, described compsn comprises diacetyl nitrilo acetic acid quadrol crystal and pharmaceutical excipient.
Described pharmaceutical composition is lyophilized injectable powder or aqueous injection.
Consisting of of described lyophilized injectable powder: diacetyl nitrilo acetic acid quadrol crystal 10 weight parts, vehicle 0～1 weight part, vehicle is selected from N.F,USP MANNITOL, sorbyl alcohol, glucose, Expex, is not limited to this;
Consisting of of described liquid drugs injection: diacetyl nitrilo acetic acid quadrol crystal 10 weight parts, auxiliary material 0.1～1 weight part, auxiliary material is not limited to this from N.F,USP MANNITOL, sorbyl alcohol, glucose, Expex, sodium-chlor.
Wherein, can also add stablizer, pH regulator agent, sanitas, inhibitor etc. in the preparation of the present invention, and can do further optimization process to prescription through the formulation optimization experiment.
The preparation method of lyophilized injectable powder may further comprise the steps:
(1) used container of dosing and pipeline washing and sterilizing are handled, and control antibiotic glass bottle, plug, aluminium lid clean, dry, sterilization;
Taking by weighing diacetyl nitrilo acetic acid quadrol crystal in proportion joins in the water for injection; In above-mentioned solution, add sorbyl alcohol then in proportion, add to the full amount of water for injection 80%, stirring and dissolving; The adding mass percent is 0.01～0.04% medicinal carbon; Adsorbed 15～30 minutes, and took off charcoal, add sterilized water for injection to full dose with φ 0.45 μ m millipore filtration;
(2) with the smart filter of φ 0.22 μ m millipore filtration, packing;
(3) the filtrating lyophilize that step (2) is obtained in aseptic condition lower cover, aluminium envelope, promptly gets;
Described freeze-drying method is: earlier the freeze drying box temperature is reduced to-40～-45 ℃, put into filtrating pre-freeze 2～3 hours, be cooled to-45～-55 ℃ rapidly, kept 1 hour; Vacuumize, in 3～6 hours, be warming up to-5～-10 ℃, in 1～3 hour, be warming up to 40 ℃ at last and kept 2～3 hours.
Wherein the mass percent of the consumption of medicinal carbon is 0.03%.
Do further explanation and explanation in the face of content of the present invention down.
The present invention relates to a kind of diacetyl nitrilo acetic acid ethylene diamine compound; The X-ray powder diffraction that said diacetyl nitrilo acetic acid ethylene diamine compound crystal uses the Cu-K alpha-ray to measure is 8.0 °, 10.0 °, 17.8 °, 18.2 °, 24.0 °, 26.0 ° and 26.5 ° at 2 θ and shows characteristic peak that its fusing point is 199.5～202.5.
Described diacetyl nitrilo acetic acid ethylene diamine compound crystalline preparation method does; Diacetyl nitrilo acetic acid quadrol solid is dissolved in the zero(ppm) water; At 25 ℃～45 ℃, add the mixed solvent of absolute ethyl alcohol and anhydrous propanone under preferred 30 ℃～40 ℃ conditions, the volume ratio of described absolute ethyl alcohol, anhydrous propanone is 1: 0.2～0.8; Preferred 1: 0.25～0.75, more preferably 1: 0.25～0.5; The volume of the volume of the mixed solvent of absolute ethyl alcohol and anhydrous propanone and diacetyl nitrilo acetic acid ethylenediamine solution is 2～5: 1, preferred 2.5～3.5: 1; Stirring velocity is 30～60 rev/mins when dripping absolute ethyl alcohol and anhydrous propanone, preferred 45～60 rev/mins; The speed of the dropping of absolute ethyl alcohol and anhydrous propanone is 2～5ml/ minute, preferred 2.5～4.5ml/ minute; Be cooled to 5 ℃～15 ℃ after mixed solvent adds, preferred 10 ℃～15 ℃, the speed that mixed solvent adds the back cooling is 2～6 ℃/min, preferred 2.5～3.5 ℃/min; Obtain leaving standstill behind the crystal, filter, filter cake is used absolute ethanol washing, after the vacuum-drying 2～5 hours, obtains diacetyl nitrilo acetic acid quadrol crystal.
The present invention passes through the speed that temperature, pH value, solvent are added, the control of stirring velocity, thereby refined control is carried out in the crystallization of diacetyl nitrilo acetic acid quadrol.In the crystallisation process of diacetyl nitrilo acetic acid quadrol; Three kinds of mixed solvents that solvent forms have been adopted; Thereby make solution form the system of diacetyl nitrilo acetic acid quadrol-ethanol-acetone-water, this system has the long steady district of crystallization Jie, and the adding of organic solvent slowly descends the saturation solubility of diacetyl nitrilo acetic acid quadrol; Thereby the system degree of supersaturation of making slowly rises; Thereby can be through control to solvent speed and solvent load, the speed of growth and the crystalline speed of growth of control nucleus, thereby control crystalline granularity.Simultaneously the crystalline temperature is controlled, cooling after organic solvent adds is left standstill, thereby has obtained a kind of new crystal of diacetyl nitrilo acetic acid quadrol.
The contriver finds when the freeze-dried powder of preparation diacetyl nitrilo acetic acid quadrol; Existing diacetyl nitrilo acetic acid quadrol is difficult to by freeze-drying; Even if through TE adjustment freeze-drying curve, need about 24 hours better freeze-dried powders of ability formation state at least.The freeze-drying time of diacetyl nitrilo acetic acid quadrol lyophilized injectable powder is at least more than 24 hours in the prior art.The diacetyl nitrilo acetic acid quadrol crystal that the present invention prepares can form lyophilized powder fluffy, in good condition in the relatively shorter time.This possibly be because, the diacetyl nitrilo acetic acid quadrol crystal of the present invention preparation is a kind of metastable polymorphic, its polar surfaces free energy is greater than stable state; Thereby total per surface free energy is bigger, be dissolved in water after because the metastable particle surface is easy to aquation; The deflocculation effect of thicker hydration shell is superior to stable state crystal formation thing; Thereby metastable crystal particles more disperses, in freeze-drying process, along with the continuous evaporation of water molecules; Metastable crystal particles keeps dispersion state, thereby makes the in good condition of lyophilized powder that freeze-drying obtains.Therefore, adopt the diacetyl nitrilo acetic acid quadrol crystal of the present invention's preparation to prepare in the process of freeze-dried powder, adopt short time and simple freeze-dry process just can be prepared into full, the loose lyophilized powder of outward appearance.Adopt the compound of commercially available diacetyl nitrilo acetic acid quadrol then can not in the same short time, prepare the full lyophilized powder of outward appearance.
Confirm the having good stability of the lyophilized injectable powder of diacetyl nitrilo acetic acid quadrol crystal preparation of the present invention and aqueous injection through stability test.
Description of drawings:
Fig. 1 is embodiment 1 preparation crystalline X-ray powder diffraction figure.
Embodiment of the present invention only limits to further explain and explain content of the present invention, content of the present invention is not constituted restriction.
Embodiment
The preparation of embodiment 1 diacetyl nitrilo acetic acid quadrol crystalline
Diacetyl nitrilo acetic acid ethylene diamine compound crystalline preparation method does; Diacetyl nitrilo acetic acid quadrol solid is dissolved in the zero(ppm) water; The mixed solvent that under 40 ℃ of conditions, adds absolute ethyl alcohol and anhydrous propanone; The volume ratio of described absolute ethyl alcohol, anhydrous propanone is 1: 0.25, and the volume of the volume of the mixed solvent of absolute ethyl alcohol and anhydrous propanone and diacetyl nitrilo acetic acid ethylenediamine solution is 2: 1, and stirring velocity is 60 rev/mins when dripping absolute ethyl alcohol and anhydrous propanone; The speed of the dropping of absolute ethyl alcohol and anhydrous propanone is 5ml/ minute; Be cooled to 15 ℃ after mixed solvent adds, the speed of cooling is 2.5 ℃/min; Obtain leaving standstill behind the crystal, filter, filter cake is used absolute ethanol washing, after the vacuum-drying 2 hours, obtains diacetyl nitrilo acetic acid quadrol crystal.
The X-ray powder diffraction that this diacetyl nitrilo acetic acid ethylene diamine compound crystal uses the Cu-K alpha-ray to measure is 8.0 °, 10.0 °, 17.8 °, 18.2 °, 24.0 °, 26.0 ° and 26.5 ° at 2 θ and shows characteristic peak that its fusing point is 199.5～202.5.
Embodiment 2
Diacetyl nitrilo acetic acid ethylene diamine compound crystalline preparation method does; Diacetyl nitrilo acetic acid quadrol solid is dissolved in the zero(ppm) water; The mixed solvent that under 30 ℃ of conditions, adds absolute ethyl alcohol and anhydrous propanone; The volume ratio of described absolute ethyl alcohol, anhydrous propanone is 1: 0.8, and the volume of mixed solvent and the volume of the aqueous solution are 5: 1; Stirring velocity is 30 rev/mins when dripping absolute ethyl alcohol and anhydrous propanone, and the speed of dropping is 2ml/ minute; Be cooled to 10 ℃ after mixed solvent adds, the speed of cooling is 3.5 ℃/min; Obtain leaving standstill behind the crystal, filter, filter cake is used absolute ethanol washing, after the vacuum-drying 2 hours, obtains diacetyl nitrilo acetic acid quadrol crystal.
The X-ray powder diffraction pattern that uses the Cu-K alpha-ray to measure to crystalline has identical characteristic peak with embodiment 1.
Embodiment 3
Diacetyl nitrilo acetic acid ethylene diamine compound crystalline preparation method does; Diacetyl nitrilo acetic acid quadrol solid is dissolved in the zero(ppm) water; The mixed solvent that under 45 ℃ of conditions, adds absolute ethyl alcohol and anhydrous propanone; The volume ratio of described absolute ethyl alcohol, anhydrous propanone is 1: 0.5, and the volume of mixed solvent and the volume of the aqueous solution are 2.5: 1; Stirring velocity is 45 rev/mins when dripping absolute ethyl alcohol and anhydrous propanone, and the speed of dropping is 3ml/ minute; Be cooled to 12 ℃ after mixed solvent adds, the speed that mixed solvent adds the back cooling is 3 ℃/min; Obtain leaving standstill behind the crystal, filter, filter cake is used absolute ethanol washing, after the vacuum-drying 2 hours, obtains diacetyl nitrilo acetic acid quadrol crystal.
The X-ray powder diffraction pattern that uses the Cu-K alpha-ray to measure to crystalline has identical characteristic peak with embodiment 1.
Described diacetyl nitrilo acetic acid ethylene diamine compound crystalline preparation method does; Diacetyl nitrilo acetic acid quadrol solid is dissolved in the zero(ppm) water; Under 35 ℃ of conditions, add the mixed solvent of absolute ethyl alcohol and anhydrous propanone, the volume ratio of described absolute ethyl alcohol, anhydrous propanone is 1: 0.75; The volume of mixed solvent and the volume of the aqueous solution are 3.5: 1; Stirring velocity is 40 rev/mins when dripping absolute ethyl alcohol and anhydrous propanone, and the speed of dropping is 3ml/ minute; Be cooled to 5 ℃ after mixed solvent adds, the speed that mixed solvent adds the back cooling is 5 ℃/min; Obtain leaving standstill behind the crystal, filter, filter cake is used absolute ethanol washing, after the vacuum-drying 5 hours, obtains diacetyl nitrilo acetic acid quadrol crystal.
The X-ray powder diffraction pattern that uses the Cu-K alpha-ray to measure to crystalline has identical characteristic peak with embodiment 1.
Embodiment 5
Described diacetyl nitrilo acetic acid ethylene diamine compound crystalline preparation method does; Diacetyl nitrilo acetic acid quadrol solid is dissolved in the zero(ppm) water; The mixed solvent that under 30 ℃ of conditions, adds absolute ethyl alcohol and anhydrous propanone; The volume ratio of described absolute ethyl alcohol, anhydrous propanone is 1: 0.4, and the volume of mixed solvent and the volume of the aqueous solution are 3.5: 1; Stirring velocity is 60 rev/mins when dripping absolute ethyl alcohol and anhydrous propanone, and the speed of dropping is 4ml/ minute; Be cooled to 8 ℃ after mixed solvent adds, the speed that mixed solvent adds the back cooling is 2.5 ℃/min; Obtain leaving standstill behind the crystal, filter, filter cake is used absolute ethanol washing, after the vacuum-drying 3 hours, obtains diacetyl nitrilo acetic acid quadrol crystal.
The X-ray powder diffraction pattern that uses the Cu-K alpha-ray to measure to crystalline has identical characteristic peak with embodiment 1.
The preparation of embodiment 6 freeze-dried powders
Consist of: diacetyl nitrilo acetic acid quadrol crystal 2 00g, sorbyl alcohol 20g.
The preparation method may further comprise the steps:
(1) used container of dosing and pipeline washing and sterilizing are handled, and control antibiotic glass bottle, plug, aluminium lid clean, dry, sterilization;
Taking by weighing diacetyl nitrilo acetic acid quadrol crystal in proportion joins in the water for injection; In above-mentioned solution, add sorbyl alcohol then in proportion, add to the full amount of water for injection 80%, stirring and dissolving; The adding mass percent is 0.03% medicinal carbon; Adsorbed 15 minutes, and took off charcoal, add sterilized water for injection to 1000ml with φ 0.45 μ m millipore filtration;
(2) with the smart filter of φ 0.22 μ m millipore filtration, be packed as 1000;
(3) lyophilize in aseptic condition lower cover, aluminium envelope, promptly gets;
Described freeze-drying method is: earlier the freeze drying box temperature is reduced to-40～-45 ℃, put into filtrating pre-freeze 2.5 hours, be cooled to-55 ℃ rapidly, kept 1 hour; Vacuumize, in 6 hours, be warming up to-5～-10 ℃, in 3 hours, be warming up to 40 ℃ at last and kept 3 hours.
The preparation of embodiment 7 freeze-dried powders
Consist of: diacetyl nitrilo acetic acid quadrol crystal 2 00g.
The preparation method may further comprise the steps:
(1) used container of dosing and pipeline washing and sterilizing are handled, and control antibiotic glass bottle, plug, aluminium lid clean, dry, sterilization;
Take by weighing diacetyl nitrilo acetic acid quadrol crystal in proportion and join in the water for injection, add to the full amount of water for injection 80%, stirring and dissolving; The adding mass percent is 0.03% medicinal carbon; Adsorbed 15 minutes, and took off charcoal, add sterilized water for injection to 1000ml with φ 0.45 μ m millipore filtration;
(2) with the smart filter of φ 0.22 μ m millipore filtration, be packed as 1000;
(3) lyophilize in aseptic condition lower cover, aluminium envelope, promptly gets;
Described freeze-drying method is: earlier the freeze drying box temperature is reduced to-45 ℃, put into filtrating pre-freeze 2 hours, be cooled to-45 ℃ rapidly, kept 1 hour; Vacuumize, in 3 hours, be warming up to-5 ℃, in 1 hour, be warming up to 40 ℃ at last and kept 3 hours.
The preparation of embodiment 8 freeze-dried powders
Consist of: diacetyl nitrilo acetic acid quadrol crystal 2 00g, Dextran 10 0g.
The preparation method may further comprise the steps:
(1) used container of dosing and pipeline washing and sterilizing are handled, and control antibiotic glass bottle, plug, aluminium lid clean, dry, sterilization;
Taking by weighing diacetyl nitrilo acetic acid quadrol crystal in proportion joins in the water for injection; In above-mentioned solution, add Expex then in proportion, add to the full amount of water for injection 80%, stirring and dissolving; The adding mass percent is 0.03% medicinal carbon; Adsorbed 15 minutes, and took off charcoal, add sterilized water for injection to 1000ml with φ 0.45 μ m millipore filtration;
(2) with the smart filter of φ 0.22 μ m millipore filtration, be packed as 1000;
(3) lyophilize in aseptic condition lower cover, aluminium envelope, promptly gets;
Described freeze-drying method is: earlier the freeze drying box temperature is reduced to-40 ℃, put into filtrating pre-freeze 3 hours, be cooled to-55 ℃ rapidly, kept 1 hour; Vacuumize, in 6 hours, be warming up to-10 ℃, in 3 hours, be warming up to 40 ℃ at last and kept 3 hours.
The preparation of embodiment 9 liquid drugs injections
Consist of: diacetyl nitrilo acetic acid quadrol crystal 2 00g, glucose 10g.
The preparation method may further comprise the steps:
(1) used container of dosing and pipeline washing and sterilizing are handled, and control antibiotic glass bottle, plug, aluminium lid clean, dry, sterilization;
Taking by weighing diacetyl nitrilo acetic acid quadrol crystal in proportion joins in the water for injection; In above-mentioned solution, add glucose then in proportion, add to the full amount of water for injection 80%, stirring and dissolving; The adding mass percent is 0.03% medicinal carbon; Adsorbed 15 minutes, and took off charcoal, add sterilized water for injection to 1000ml with φ 0.45 μ m millipore filtration;
(2) with the smart filter of φ 0.22 μ m millipore filtration, be packed as 1000;
(3) sterilization is sealed, and packing promptly gets;
Experimental example 1 diacetyl nitrilo acetic acid quadrol crystalline stability test
1. high temperature test
Get two batches 01 of the diacetyl nitrilo acetic acid quadrol crystalline, 02 of embodiment 1 gained, simulation listing packing is put in the sealing clean container; In 45 ℃ of temperature held 10 days; In the 5th day and sampling in the 10th day, detect test-results and comparison in 0 day by stable high spot reviews project.
2. high humidity test
Get the diacetyl nitrilo acetic acid quadrol crystal of embodiment 6 gained, simulation listing packing is put in the constant humidity encloses container; The condition held of 25 ℃ of relative humidity 90% ± 5% 10 days; In the 5th day and sampling in the 10th day, detect test-results and comparison in 0 day by stable high spot reviews project.
3. strong illumination test
Get the diacetyl nitrilo acetic acid quadrol crystal of embodiment 6 gained, simulation listing packing is put in the sealing clean container; Placing illumination is the condition held 10 days of 4500lx; In the 5th day and sampling in the 10th day, detect result and comparison in 0 day by stable high spot reviews project.
The influence factor test-results see the following form 1 with table 2.
Table 1: diacetyl nitrilo acetic acid quadrol crystal influence factor test-results (batch: 0101)
Table 2: diacetyl nitrilo acetic acid quadrol crystal influence factor test-results (batch: 0102)
The result shows: these article are under the condition of simulation listing packing, and high temperature, high humidity, illumination condition held 10 days, removing related substance slightly increased, and outside content slightly reduced, other each item indexs did not have considerable change.Each item index has no significant change under illumination and super-humid conditions.
This has also carried out identical test to the prepared crystallization diacetyl nitrilo acetic acid quadrol of other embodiment of the present invention, and the result of its acquisition is similar.
Experimental example 2: diacetyl nitrilo acetic acid quadrol crystalline accelerated stability test
Get six batches of the diacetyl nitrilo acetic acid quadrol crystalline of embodiment 2; Simulation listing packing was put in the sealing clean container, in 40 ℃ of temperature held 6 months; At duration of test once, each stable high spot reviews project is tested respectively at 1,2,3,6 sampling at the end of month.And check that in quickening June, pyrogen aseptic test-results is seen table 4～5 to sample.
Table 3: injection diacetyl nitrilo acetic acid quadrol accelerated test is investigated the result
Can be known that by the accelerated test result these article were investigated through accelerated test in 6 months, related substance slightly increases, and content slightly reduces, and considerable change does not take place all the other each item indexs, all in specialized range, proves that diacetyl nitrilo acetic acid quadrol crystalline has good stability.
Crystallization diacetyl nitrilo acetic acid quadrol to other embodiment preparation of the present invention has carried out identical test, and the result of its acquisition is similar.
Experimental example 3: diacetyl nitrilo acetic acid quadrol crystalline stability test of long duration
Get six batches of the diacetyl nitrilo acetic acid quadrol crystalline of embodiment 3 gained; Simulation listing packing; Put in the sealing clean container; 6 ℃ ± 2 ℃ condition held of temperature 36 months, at duration of test once, each Interventions Requested is tested respectively at the 3rd, 6,9,12,18,24,36 sampling at the end of month.Test-results sees the following form
Table 4: injection diacetyl nitrilo acetic acid quadrol test of long duration is investigated the result
Can be known that by long-term test results these article were investigated through test of long duration in 24 months, considerable change does not all take place in each item index, explains that the crystalline of the present invention's preparation is stable very high, is suitable for preparing various preparations.
Product among other embodiment among the present invention has been done same experiment, and the experimental data that obtains is similar.
The stability test of the freeze-dried powder of embodiment 4 diacetyl nitrilo acetic acid quadrols
One, sample: the freeze-dried powder of diacetyl nitrilo acetic acid quadrol
Trial target: embodiment 6,7,8 preparation samples, lot number 601,602,701,702,801,802;
Reference substance: adopt diacetyl nitrilo acetic acid quadrol bulk drug (commercially available), prepare drugs compared, use as reference substance according to embodiment 6,7,8 preparing methods.
Two, test apparatus
Electronic balance, acidometer, climatic chamber, high performance liquid chromatograph etc.
Three, TP and condition
Influence factor test, accelerated test and test of long duration have been carried out respectively.
3.1 high temperature test
Sample thief is put in the sealing clean container, and 60 ℃ of temperature held 20 days in sampling in the 5th day, the 10th, the 20th day, detect by stable high spot reviews project.Test-results and comparison in 0 day.Experimental result is as shown in table 5:
Show stable comparison test result under the 5:60 ℃ of temperature condition
Can know by above-mentioned experimental result; Stability by the freeze-dried powder of diacetyl nitrilo acetic acid quadrol of the present invention is higher than the powder pin that adopts common diacetyl nitrilo acetic acid quadrol preparation; 60 ℃ of condition held 10 days, adopt its related substance showed increased of powder pin of common diacetyl nitrilo acetic acid ethylene diamine compound preparation; 60 ℃ of condition held 20 days, its related substance of powder pin of common diacetyl nitrilo acetic acid ethylene diamine compound preparation further increased, and medicament contg further reduces.And the powder pin that adopts diacetyl nitrilo acetic acid quadrol crystal to prepare, wherein related substance and medicament contg have no significant change.Confirmed that the stability of powder pin under hot conditions that crystal of the present invention prepares is good.
3.2 high humidity test
Sample thief; Put in the constant humidity encloses container, at 25 ℃ respectively at the condition held of relative humidity 90% ± 5% 20 days, in sampling in the 5th day, the 10th day, the 20th day; Detect by stable high spot reviews project; Test-results and comparison in 0 day, the weight of trial-product before and after accurately weighing is tested simultaneously is with the moisture absorption deliquescence performance of investigation trial-product.Its experimental result is as shown in table 6:
Table 6: stable comparison test result under the super-humid conditions
Shown in experimental result; Under super-humid conditions; Stability by the powder pin of diacetyl nitrilo acetic acid quadrol crystal of the present invention preparation is higher than the powder pin that adopts common diacetyl nitrilo acetic acid quadrol preparation; Super-humid conditions held 10 days, adopt the related substance showed increased of the powder pin of common diacetyl nitrilo acetic acid ethylene diamine compound preparation, medicament contg reduces; Be placed to 20 days, the related substance of the powder pin of common diacetyl nitrilo acetic acid ethylene diamine compound preparation further increases, and medicament contg further reduces.And the powder pin that adopts diacetyl nitrilo acetic acid quadrol crystal to prepare, wherein related substance and medicament contg have no significant change.Confirmed that powder pin stability under super-humid conditions that crystal of the present invention prepares is good.
3.3 strong illumination test
Sample thief, placing illumination is the condition held 20 days of 4500lx,, detects result and comparison in 0 day in sampling in the 5th day, the 10th day, the 20th day by stable high spot reviews project.Experimental result is as shown in table 7.
Table 7: comparative test result under the intense light irradiation condition
Shown in experimental result; Under the intense light irradiation condition; Stability by the powder pin of diacetyl nitrilo acetic acid quadrol crystal of the present invention preparation is higher than the powder pin that adopts common diacetyl nitrilo acetic acid quadrol preparation; Intense light irradiation condition held 10 days, adopt related substance showed increased in the powder pin of common diacetyl nitrilo acetic acid ethylene diamine compound preparation, medicament contg reduces; Be placed to 20 days, related substance further increases in the powder pin of common diacetyl nitrilo acetic acid ethylene diamine compound preparation, and medicament contg further reduces.And the powder pin that adopts diacetyl nitrilo acetic acid quadrol crystal to prepare, wherein related substance and medicament contg have no significant change.Confirmed that powder pin stability under the high light condition that crystal of the present invention prepares is good.
The stability test of experimental example 5 diacetyl nitrilo acetic acid quadrol powder pins: accelerated test
Get the diacetyl nitrilo acetic acid quadrol powder injection of embodiment 6,7,8 preparations; Intend commercially available back; Adopt commercially available diacetyl nitrilo acetic acid quadrol to be prepared into powder injection according to the method for embodiment 6,7,8 respectively simultaneously, in 45 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% condition held 6 months, respectively at the 1st, 2,3,6 sampling at the end of month once at duration of test; Each stable high spot reviews project is tested, and the stability later stage increases limit test of microbe.Test-results is seen table 8.
Table 8: diacetyl nitrilo acetic acid quadrol powder injection accelerated test result
Shown in experimental result; At a certain temperature and humidity conditions; Stability by the powder pin of diacetyl nitrilo acetic acid quadrol crystal of the present invention preparation is higher than the powder pin that adopts common diacetyl nitrilo acetic acid quadrol preparation; Acceleration environment held 3 months, adopt its related substance showed increased of powder pin of common diacetyl nitrilo acetic acid ethylene diamine compound preparation, medicament contg reduces; Be placed to 6 months, its related substance of powder pin of common diacetyl nitrilo acetic acid ethylene diamine compound preparation further increases, and medicament contg further reduces.And the powder pin that adopts diacetyl nitrilo acetic acid quadrol crystal to prepare, wherein related substance and medicament contg have no significant change.Confirmed that powder pin stability under the high light condition that crystal of the present invention prepares is good.
The stability test of experimental example 6 diacetyl nitrilo acetic acid quadrol powder pins: test of long duration
Get the diacetyl nitrilo acetic acid quadrol powder injection of embodiment 6,7,8 preparations; Intend commercially available back; Adopt commercially available diacetyl nitrilo acetic acid quadrol to be prepared into powder injection according to the method for embodiment 6,7,8 respectively simultaneously; In 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% condition held 36 months, each stable high spot reviews project to be tested, the stability later stage increases limit test of microbe.Test-results is seen table 9.
Table 9: the long-term test results of diacetyl nitrilo acetic acid quadrol powder pin
Can know by above result; These article were investigated through long-term 36 months; The stability of the powder pin of diacetyl nitrilo acetic acid quadrol crystal preparation of the present invention is higher than the powder pin that adopts common diacetyl nitrilo acetic acid quadrol preparation; And its related substance showed increased of powder pin that adopts common diacetyl nitrilo acetic acid ethylene diamine compound to prepare, medicament contg reduces and the powder pin of employing diacetyl nitrilo acetic acid quadrol crystal preparation, and wherein related substance and medicament contg have no significant change.Confirmed that the powder pin stability that crystal of the present invention prepares is good.
Claims (20)
1. diacetyl nitrilo acetic acid ethylene diamine compound; It is characterized in that; Said diacetyl nitrilo acetic acid ethylene diamine compound is a crystal; The X-ray powder diffraction that said diacetyl nitrilo acetic acid ethylene diamine compound crystal uses the Cu-K alpha-ray to measure is 8.0 °, 10.0 °, 17.8 °, 18.2 °, 24.0 °, 26.0 ° and 26.5 ° at 2 θ and shows characteristic peak that its chemical formula is suc as formula shown in the I:
2. the preparation method of diacetyl nitrilo acetic acid quadrol as claimed in claim 1; It is characterized in that; Diacetyl nitrilo acetic acid quadrol solid is dissolved in the zero(ppm) water; Under 25 ℃～45 ℃ conditions, add the mixed solvent of absolute ethyl alcohol and anhydrous propanone, be cooled to 5 ℃～15 ℃ after mixed solvent adds, obtain leaving standstill behind the crystal; Filter, filter cake is used absolute ethanol washing, after the vacuum-drying 2～5 hours, obtains diacetyl nitrilo acetic acid quadrol crystal.
3. preparation method according to claim 2 is characterized in that, under 30 ℃～40 ℃ conditions, adds the mixed solvent of absolute ethyl alcohol and anhydrous propanone.
4. preparation method according to claim 2 is characterized in that, is cooled to 10 ℃～15 ℃ after mixed solvent adds.
5. preparation method according to claim 2 is characterized in that, the volume of the volume of the mixed solvent of described absolute ethyl alcohol and anhydrous propanone and diacetyl nitrilo acetic acid quadrol solid aqueous solution is 2～5: 1.
6. preparation method according to claim 5 is characterized in that, the volume of the volume of the mixed solvent of described absolute ethyl alcohol and anhydrous propanone and diacetyl nitrilo acetic acid quadrol solid aqueous solution is 2.5～3.5: 1.
7. preparation method according to claim 2 is characterized in that, the volume ratio of described absolute ethyl alcohol, anhydrous propanone is 1: 0.2～0.8.
8. preparation method according to claim 7 is characterized in that, the volume ratio of described absolute ethyl alcohol, anhydrous propanone is 1: 0.25～0.75.
9. preparation method according to claim 7 is characterized in that, the volume ratio of described absolute ethyl alcohol, anhydrous propanone is 1: 0.25～0.5.
10. preparation method according to claim 2 is characterized in that, the speed of the dropping of absolute ethyl alcohol and anhydrous propanone is 2～5ml/ minute.
11. preparation method according to claim 10 is characterized in that, the speed of the dropping of absolute ethyl alcohol and anhydrous propanone is 2.5～4.5ml/ minute.
12. preparation method according to claim 2 is characterized in that, the stirring velocity that drips absolute ethyl alcohol and anhydrous propanone is 30～60 rev/mins.
13. preparation method according to claim 12 is characterized in that, the stirring velocity that drips absolute ethyl alcohol and anhydrous propanone is 45～60 rev/mins.
14. preparation method according to claim 2 is characterized in that, the speed that mixed solvent adds the back cooling is 2～6 ℃/min.
15. preparation method according to claim 14 is characterized in that, the speed that mixed solvent adds the back cooling is 2.5～3.5 ℃/min.
16. a pharmaceutical composition that comprises the described diacetyl nitrilo acetic acid of claim 1 ethylene diamine compound is characterized in that described compsn comprises said diacetyl nitrilo acetic acid ethylene diamine compound and pharmaceutical excipient.
17. pharmaceutical composition according to claim 16 is characterized in that, described pharmaceutical composition is lyophilized injectable powder or aqueous injection.
18. pharmaceutical composition according to claim 17; It is characterized in that; Consisting of of described aqueous injection: said diacetyl nitrilo acetic acid ethylene diamine compound 10 weight parts, auxiliary material 0.1～1 weight part, auxiliary material is selected from N.F,USP MANNITOL, sorbyl alcohol, glucose, Expex, sodium-chlor.
19. pharmaceutical composition according to claim 17; It is characterized in that; Consisting of of described lyophilized injectable powder: said diacetyl nitrilo acetic acid ethylene diamine compound 10 weight parts, vehicle 1 weight part, vehicle is selected from N.F,USP MANNITOL, sorbyl alcohol, glucose, Expex.
20. preparation of drug combination method as claimed in claim 19 is characterized in that, may further comprise the steps:
(1) taking by weighing said diacetyl nitrilo acetic acid ethylene diamine compound in proportion joins in the water for injection; In above-mentioned solution, add sorbyl alcohol then in proportion, add to the full amount of water for injection 80%, stirring and dissolving; The adding mass percent is 0.01～0.04% medicinal carbon; Adsorbed 15～30 minutes, and took off charcoal, add sterilized water for injection to full dose with φ 0.45 μ m millipore filtration;
(2) with the smart filter of φ 0.22 μ m millipore filtration, packing;
(3) the filtrating lyophilize that step (2) is obtained in aseptic condition lower cover, aluminium envelope, promptly gets;
Described freeze-drying method is: earlier the freeze drying box temperature is reduced to-40～-45 ℃, put into filtrating pre-freeze 2～3 hours, be cooled to-45～-55 ℃ rapidly, kept 1 hour; Vacuumize, in 3～6 hours, be warming up to-5～-10 ℃, in 1～3 hour, be warming up to 40 ℃ at last and kept 2～3 hours.
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| CN102973520B (en) * | 2012-07-12 | 2013-12-25 | 姚云 | Diethylamide ethylenediamine compound-containing drug composition |
| CN103012187B (en) * | 2013-01-10 | 2014-08-20 | 黄明芳 | Novel diacetyl acetic acid quadrol compound and drug combination thereof |
| CN104352450A (en) * | 2014-10-09 | 2015-02-18 | 海南通用康力制药有限公司 | Ethylenediamine diaceturate freeze-dried powder for injection and preparation method thereof |
| CN110772487B (en) * | 2019-12-09 | 2021-09-21 | 湖南科伦制药有限公司 | Freeze-drying method of ethylenediamine diaceturate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1422615A (en) * | 2002-12-03 | 2003-06-11 | 陈义忠 | Diacetylamino-acetoxy-ethylenediamine larg-volume injecta and preparation method thereof |
| CN1444933A (en) * | 2003-04-18 | 2003-10-01 | 张嵩 | Ethylenediamine Diaceturate injection |
| CN1454590A (en) * | 2003-05-26 | 2003-11-12 | 王景成 | Ethylenediamine diaceturate lyophilized powder injection and preparing method thereof |
| CN1541647A (en) * | 2003-11-06 | 2004-11-03 | 武汉佑德医药科技有限公司 | Di-acetyl-aminoethyl-ethylenediamine powder injection and its preparation method |
-
2011
- 2011-08-19 CN CN201110240167A patent/CN102367229B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1422615A (en) * | 2002-12-03 | 2003-06-11 | 陈义忠 | Diacetylamino-acetoxy-ethylenediamine larg-volume injecta and preparation method thereof |
| CN1444933A (en) * | 2003-04-18 | 2003-10-01 | 张嵩 | Ethylenediamine Diaceturate injection |
| CN1454590A (en) * | 2003-05-26 | 2003-11-12 | 王景成 | Ethylenediamine diaceturate lyophilized powder injection and preparing method thereof |
| CN1541647A (en) * | 2003-11-06 | 2004-11-03 | 武汉佑德医药科技有限公司 | Di-acetyl-aminoethyl-ethylenediamine powder injection and its preparation method |
Non-Patent Citations (2)
| Title |
|---|
| 刘玉梅等.二乙酰氨乙酸乙二胺的制备.《锦州医学院学报》.2005,第26卷(第4期),44-46. * |
| 谢建军等.注射用二乙酰氨乙酸乙二胺的工艺筛选.《中南药学》.2005,第3卷(第4期),228-230. * |
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Application publication date: 20120307 Assignee: Gannan Haixin pharmaceutical Limited by Share Ltd Assignor: Jiangxi Pioneer Medical Co., Ltd. Contract record no.: 2013360000138 Denomination of invention: Ethylenediamine diaceturate compound and pharmaceutical composition thereof Granted publication date: 20120829 License type: Common License Record date: 20130930 |
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