CN104688678B - A kind of preparation method of insulin glargine injecta and its insulin glargine injecta of preparation - Google Patents
A kind of preparation method of insulin glargine injecta and its insulin glargine injecta of preparation Download PDFInfo
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Abstract
The insulin glargine injecta that the present invention provides a kind of preparation method of insulin glargine injecta and its is prepared.The preparation method includes:Glycerine is dissolved with partial syringe with water, is configured to glycerite, is then divided into three parts, is separately added into insulin glargine, metacresol and zinc chloride;First insulin glargine glycerite is well mixed with metacresol glycerite, obtains mixed solution I;Hydrochloric acid solution is added into the mixed solution I again to pH=3.0~3.5, zinc chloride glycerite is then added, stirs, add sodium hydroxide solution to pH=3.5~4.5;Finally final volume is settled to water for injection.Preparation method of the present invention can be such that insulin glargine and other auxiliary materials dissolves rapidly; significantly shorten the manufacturing cycle time; reduce caused process contaminants in preparation process; improve the quality of insulin glargine injecta; reduce process energy consumption simultaneously; production efficiency is improved, more adapts to large-scale production demand.
Description
Technical field
The invention belongs to pharmaceutics field, and in particular to the preparation method and its system of a kind of insulin glargine injecta
Standby insulin glargine injecta.
Background technology
Insulin glargine is long-acting human insulin analogue, for being grown up and type I diabetes of children and Adult type II
Diabetes.Six stable aggressiveness can be formed after its subcutaneous injection, increase intermolecular adhesion, delay to dissolve and absorb when
Between, a small amount of insulin glargine of sustained release, so as to have, foreseeable, having long-acting, steady, the blood medicine without peak value is dense
Degree/time response.Insulin glargine because of its long-lasting nature, patient only need to be subcutaneously injected at a fixed time once a day to
Medicine.But type i diabetes patient and the type 2 diabetes patient of OHA failure need to use insulin type product all the life
Blood glucose is controlled, therefore under the premise of effective, ensures that the safety of medication is particularly important.
Insulin glargine solubility under the physiological condition close to neutrality is low, and solution occurs precipitating and is in muddy shape, and
It can be completely dissolved in sour environment, solution is in colorless and transparent.Therefore, existing insulin glargine injecta with it is acid,
Homogeneous, clear and bright solution form injection uses.For example, United States Patent (USP) US5656722 discloses a kind of insulin glargine injecta
Preparation method, be that first the auxiliary material of recipe quantity is dissolved in sterile vehicle, under conditions of pH4, add insulin glargine.In
State patent CN201110056210.9 discloses prepares stability-enhanced acid pancreas islet by adding the surfactants such as tween
The method of plain preparation, wherein the preparation method of the acid insulin preparation is first to be suspended in insulin or insulin analog
In a part of water for injection, make dissolving under pH3-4, add other auxiliary materials such as tween, adjusted pH with hydrochloric acid or sodium hydroxide
Final volume is settled to 4.0, and by mixture.Chinese patent CN201110009384.X is disclosed by adding PEG and using Chinese holly
Rafter acid for adjusting pH prepares the method for the good insulin glargine injecta of steady quality, security.Specific method is as follows:Step 1.
Insulin glargine is added in water for injection, is allowed to dissolve to 3.5-4.5 with citron acid for adjusting pH, adds PEG, and 0-5 DEG C of stirring is put
Put 12-24h;Other auxiliary materials of step 2. are added in water for injection, with citron acid for adjusting pH to 3.5-4.5;Step 3. the former stirring
Add in the latter, mix under the conditions of mixing, adjust pH to 3.8-4.2.
Crossing stability in alkali environment in peracid due to insulin glargine can substantially reduce, Yin Re and physical mechanical stress hair
The trend increase of raw cohesion, and inevitably using physical means such as stirrings in injection preparation process, so as to give preparation
Bring undesirable impurity.
The improvement of medicine preparation method is to lift the effective means of its quality.Therefore, it is necessary to develop a kind of new sweet
The preparation method of smart regular iletin, reach the purpose for reducing process contaminants, improving insulin glargine injecta quality.
The content of the invention
In view of the above-mentioned problems, it is an object of the present invention to provide a kind of preparation method of insulin glargine injecta.
Security consideration based on clinical application, it then follows " on the premise of needs are met, the species and dosage of auxiliary material used in injection should
It is as few as possible " basic principle, the present invention reaches shortening and prepares week by optimizing the preparation technology of insulin glargine injecta
Phase, the purpose for reducing process energy consumption, improving insulin glargine injecta quality.
In order to realize above-mentioned technique effect, the present invention adopts the following technical scheme that:
A kind of preparation method of insulin glargine injecta, the insulin glargine injecta by insulin glargine, glycerine,
Metacresol, zinc chloride, hydrochloric acid, sodium hydroxide and water for injection composition;Comprise the following steps:
(1) glycerine is dissolved with partial syringe with water, is configured to glycerite;
(2) glycerite is divided into three parts, is separately added into insulin glargine, metacresol and zinc chloride, is well mixed, obtains
To insulin glargine-glycerite, metacresol-glycerite and zinc chloride-glycerite;
(3) insulin glargine-glycerite mixes with metacresol-glycerite, stirs, obtains mixed solution
I;
(4) under stirring, hydrochloric acid solution to pH=3.0~3.5 and solution is added into the mixed solution I and are clarified;
(5) zinc chloride-glycerite is added in the solution obtained into step 4, is stirred;
(6) sodium hydroxide solution is added under stirring, in the solution obtained into step 5 to pH=3.5~4.5;
(7) it is settled to final volume with water for injection.
Preferably, in the step 1, the dosage of water for injection account for the insulin glargine injecta cumulative volume 60%~
80%.
Preferably, in the step 2, the glycerite for preparing the insulin glargine-glycerite is no less than institute
State the 30% of glycerite cumulative volume;Glycerite for preparing the metacresol-glycerite is molten no less than the glycerine
The 50% of liquid cumulative volume;Remaining glycerite is used to prepare the zinc chloride-glycerite.
It is furthermore preferred that in the step 2, the glycerite for preparing the insulin glargine-glycerite accounts for described
The 30%~40% of glycerite cumulative volume.
It is furthermore preferred that in the step 2, the glycerite for preparing the metacresol-glycerite accounts for the glycerine
The 50%~60% of overall solution volume.
It is further preferred that in the step 2, the glycerite is according to volume ratio 3~4:5~6:2~1 points are three parts
(the percent by volume sum of three parts of glycerites is 100%), is separately added into insulin glargine, metacresol and zinc chloride, mixes
Uniformly, insulin glargine-glycerite, metacresol-glycerite and zinc chloride-glycerite are obtained.
Preferably, in the step 4, the concentration of the hydrochloric acid solution is 0.1mol/L.
It is also preferred that in the step 4, pH=3.1~3.2 are adjusted.
Preferably, in the step 6, the concentration of the sodium hydroxide solution is 0.1mol/L.
It is also preferred that in the step 6, pH=4.0 is adjusted.
As a preferred embodiment, the present invention provides a kind of preparation method of insulin glargine injecta, described
Insulin glargine injecta is made up of insulin glargine, glycerine, metacresol, zinc chloride, hydrochloric acid, sodium hydroxide and water for injection;
Specific operating procedure includes:
(1) the glycerine water for injection for accounting for the insulin glargine injecta cumulative volume 60%~80% dissolves, and is configured to
Glycerite;
(2) glycerite is according to volume ratio 3~4:5~6:2~1 points are three parts of (volumes hundred of three parts of glycerites
Point than sum for 100%), insulin glargine, metacresol and zinc chloride are separately added into, is well mixed, obtain insulin glargine-sweet
Oil solution, metacresol-glycerite and zinc chloride-glycerite;
(3) insulin glargine-glycerite mixes with metacresol-glycerite, stirs, obtains mixed solution
I;
(4) stir under, into the mixed solution I add 0.1mol/L hydrochloric acid solutions to pH=3.1~3.2 and solution it is clear
Clearly;
(5) zinc chloride-glycerite is added in the solution obtained into step 4, is stirred;
(6) 0.1mol/L sodium hydroxide solutions are added under stirring, in the solution obtained into step 5 to pH=4.0;
(7) it is settled to final volume with water for injection.
Preparation method of the present invention, in addition to filtration sterilization.
Another object of the present invention, it is to provide the insulin glargine injecta obtained by above-mentioned preparation method.
Preferably, in the insulin glargine injecta, insulin glargine 40-500IU/mL, glycerine 9.2-23mg/ are contained
ML, metacresol 1.7-5.0mg/mL, the μ g-200 μ g/mL of zinc 5.
It is furthermore preferred that the insulin glargine injecta contains insulin glargine 100IU/mL, glycerine 17mg/mL, a first
Phenol 2.7mg/mL, the μ g/mL of zinc 30.
It is also preferred that the insulin glargine injecta contains insulin glargine 100IU/mL, glycerine 16mg/mL, a first
Phenol 3.2mg/mL, the μ g/mL of zinc 27.
Preparation technology of the invention by optimizing insulin glargine injecta, make manufacturing cycle by 90 minutes of prior art
Shorten to above 30 minutes or so, at least save for nearly 2/3rds time.Due to the shortening of preparation time, the technique for making finished product
Impurity is greatly decreased, and improves the quality of parenteral solution, ensures patient medication safety.Insulin glargine injection prepared by the inventive method
Liquid, without the surfactant such as the high polymer adjuvants such as PEG and tween, the probability that adverse reaction occurs is reduced, thus it is safer, more
It is long-term use of suitable for patient.
Embodiment
Illustrate the present invention referring to specific embodiment.It will be appreciated by those skilled in the art that these embodiments are only
For illustrating the present invention, its scope not limiting the invention in any way.Every change without departing substantially from present inventive concept waits
It is included in substituting within protection scope of the present invention.
Experimental method in following embodiments, it is conventional method unless otherwise specified.Medicine used in following embodiments
Material raw material, reagent material etc., unless otherwise specified, it is commercially available products.
Preparation method 1 (preparation method provided by the invention):(1) 1L beakers are taken, rotor is added, is placed in magnetic stirring apparatus
On, glycerine and 600mL waters for injection are added, glycerine is dissolved under stirring, obtains glycerite;(2) insulin glargine, a first
Glycerite is pre-dissolved described in 180mL, 300mL, 120mL respectively for phenol, zinc chloride, obtains insulin glargine-glycerite, a first
Phenol-glycerite and zinc chloride-glycerite;(3) insulin glargine-glycerite mixes with metacresol-glycerite,
Stir, obtain mixed solution I;(4) under stirring, 0.1mol/L hydrochloric acid solution is added into the mixed solution I to pH
=3.0~3.5, insulin glargine dissolves rapidly, solution clarification;(5) zinc chloride-glycerite is added, is stirred;(6) use
Water for injection is settled to 900mL, adds 0.1mol/L sodium hydroxide solution regulation pH=4.0;(7) it is settled to water for injection
1L, filtration sterilization produce.
Preparation method 2 (preparation method provided by the invention):(1) 1L beakers are taken, rotor is added, is placed in magnetic stirring apparatus
On, glycerine and 800mL waters for injection are added, glycerine is dissolved under stirring, obtains glycerite;(2) insulin glargine, a first
Phenol, zinc chloride are pre-dissolved with 320mL, 400mL, 80mL glycerite respectively, obtain insulin glargine-glycerite, metacresol-sweet
Oil solution and zinc chloride-glycerite;(3) insulin glargine-glycerite and metacresol-glycerite mixing, stirring
Uniformly, mixed solution I is obtained;(4) under stirring, 0.1mol/L hydrochloric acid solution is added into the mixed solution I to pH=3.1
~3.2, insulin glargine is dissolved rapidly, solution clarification;(5) zinc chloride-glycerite is added, is stirred;(6) with injection
900mL is settled to water;Add 0.1mol/L sodium hydroxide solution regulation pH=4.0;(7) 1L is settled to water for injection,
Filtration sterilization produces.
Preparation method 3 (United States Patent (USP) US5656722 preparation method):1L beakers are taken, rotor is added, is placed in magnetic agitation
On device, glycerine, metacresol, zinc chloride and 900mL waters for injection are added, stirring clarifies solution;Adjusted with 0.1mol/L hydrochloric acid
Save pH=4;Insulin glargine is added, stirring clarifies solution;PH=4 is adjusted with 0.1mol/L sodium hydroxide, uses injection
Water is settled to 1L, and filtration sterilization produces.
Preparation method 4:Preparation method 4:1L beakers are taken, rotor is added, is placed on magnetic stirring apparatus, add insulin glargine
With 900mL waters for injection, clarify solution with 0.1mol/L salt acid for adjusting pH to 3-4, stirring;Add glycerine, metacresol, chlorine
Change zinc, stirring clarifies solution;1L is settled to water for injection, filtration sterilization produces.
In above-mentioned preparation method, when each step stirs, the rotating speed of rotor adjusts rotating speed in the range of 200~400 revs/min,
Can not only stir, caused foam but can receive for degree.
Embodiment 1Insulin glargine injecta prepared by distinct methods
This implementation insulin glargine injecta contains insulin glargine 100IU/mL, glycerine 17mg/mL, metacresol
2.7mg/mL, μ g/mL of zinc 30, hydrochloric acid, sodium hydroxide and water for injection, pH=4;According to above-mentioned preparation method 1, preparation method
2nd, preparation method 3 and preparation method 4 prepare insulin glargine injecta respectively, and record manufacturing cycle required time, as a result see
Table 1.
Embodiment 2Insulin glargine injecta prepared by distinct methods
This implementation insulin glargine injecta contains insulin glargine 100IU/mL, glycerine 16mg/mL, metacresol
3.2mg/mL, μ g/mL of zinc 27, hydrochloric acid, sodium hydroxide and water for injection, pH=4.According to above-mentioned preparation method 1, preparation method
2nd, preparation method 3 and preparation method 4 prepare insulin glargine injecta respectively, and record manufacturing cycle required time, as a result see
Table 1.
Embodiment 3Insulin glargine injecta prepared by distinct methods
This implementation insulin glargine injecta contains insulin glargine 200IU/mL, glycerine 23mg/mL, metacresol
4.0mg/mL, μ g/mL of zinc 60, hydrochloric acid, sodium hydroxide and water for injection, pH=4.According to above-mentioned preparation method 1, preparation method
2nd, preparation method 3 and preparation method 4 prepare insulin glargine injecta respectively, and record manufacturing cycle required time, as a result see
Table 1.
Embodiment 4Insulin glargine injecta prepared by distinct methods
This implementation insulin glargine injecta contains insulin glargine 50IU/mL, glycerine 10mg/mL, metacresol
1.7mg/mL, μ g/mL of zinc 20, hydrochloric acid, sodium hydroxide and water for injection, pH=4.According to above-mentioned preparation method 1, preparation method
2nd, preparation method 3 and preparation method 4 prepare insulin glargine injecta respectively, and record manufacturing cycle required time, as a result see
Table 1.
Embodiment 5Insulin glargine injecta prepared by distinct methods
This implementation insulin glargine injecta contains insulin glargine 300IU/mL, glycerine 23mg/mL, metacresol
4.9mg/mL, μ g/mL of zinc 100, hydrochloric acid, sodium hydroxide and water for injection, pH=4.According to above-mentioned preparation method 1, preparation side
Method 2, preparation method 3 and preparation method 4 prepare insulin glargine injecta respectively, and record manufacturing cycle required time, as a result
It is shown in Table 1.
Embodiment 6Insulin glargine injecta prepared by distinct methods
This implementation insulin glargine injecta contains insulin glargine 150IU/mL, glycerine 20mg/mL, metacresol
2.5mg/mL, μ g/mL of zinc 45, hydrochloric acid, sodium hydroxide and water for injection, pH=4.According to above-mentioned preparation method 1, preparation method
2nd, preparation method 3 and preparation method 4 prepare insulin glargine injecta respectively, and record manufacturing cycle required time, as a result see
Table 1.
The manufacturing cycle time of insulin glargine injecta described in the embodiment 1-6 of table 1
The raw material of different prescriptions is respectively adopted preparation method provided by the invention and is prepared into insulin glargine with prior art
Parenteral solution.The data of table 1 show that the manufacturing cycle time of preparation method provided by the invention is only 30 minutes or so, method 3 and 4
90 minutes or so are then needed, for up to 101 minutes (preparation method 3 in embodiment 5).Examined using t to the data in table 1
Statistical analysis is carried out, manufacturing cycle time of preparation method 1 and 2 of the invention, there was no significant difference (P>0.05);And prepare
The manufacturing cycle time of method 1 is respectively provided with significant difference (P compared with prior art preparation method 3 and 4 respectively<0.05);System
The manufacturing cycle time of Preparation Method 2 compared with prior art preparation method 3 and 4, is also respectively provided with significant difference (P<0.05).Cause
This, compares prior art, and method of the invention can significantly shorten the manufacturing cycle of insulin glargine injecta;With preparation method
3 and 4 be benchmark, and the manufacturing cycle time can be reduced nearly 2/3rds by method of the invention.
Test example 1Insulin glargine injecta correlated quality is investigated
Investigate the quality of insulin glargine injecta made from embodiment 1-2, detection pH, potency, total correlation material, maximum
Related substances, macromolecule protein and freeze point depression.
Wherein pH is detected using pH meter;Potency, total correlation material and maximal correlation material are examined using high performance liquid chromatography
Survey;Macromolecule protein is detected using molecular exclusion chromatography;Freeze point depression is detected using cryoscopic method;Specific detection method referring to
2010 editions《Chinese Pharmacopoeia》Annex.
High performance liquid chromatography detects total correlation material and the concrete operations of maximal correlation material are as follows:
Chromatographic condition:Waters high performance liquid chromatographs, Kromasil C4 posts (column length=150mm, diameter 4.6mm;
100A-3.5um), mobile phase is mixture of acetonitrile-phosphate buffer system, flow velocity 1.0ml/min per minute, 35 DEG C of column temperature, detects ripple
Long 214nm.
The specific compound method of mobile phase is as follows:
Phosphate buffer:Sodium dihydrogen phosphate 20.7g is taken, adds water 800ml to dissolve, then with 85% phosphorus acid for adjusting pH value extremely
2.5,1L is added water to, is filtered.
Mobile phase A (25% acetonitrile):Sodium chloride 18.4g is taken, plus phosphate buffer 250ml dissolvings are stated, adds acetonitrile
250ml, after mixing, it is diluted with water to 1000mL, 0.45 μm of membrane filtration;
Mobile phase B (65% acetonitrile):Sodium chloride 3.2g is taken, plus phosphate buffer 250ml dissolvings are stated, adds acetonitrile
650ml, after mixing, it is diluted with water to 1000mL, 0.45 μm of membrane filtration.
According to the form below carries out gradient elution:
The preparation of test sample:Precision measures the Lantus sample as made from preparation method 1,2,3,4 respectively
5ml, add the μ l of 9.6mol/L hydrochloric acid solutions 3 by every 1ml, as need testing solution.
Determination method:Precision measures 10 μ l, injects liquid chromatograph, records chromatogram, deducts metacresol peak, returns by peak area
One, which changes method, calculates, and produces total correlation material and maximal correlation content of material.
4 kinds of insulin glargine injectas prepared by embodiment 1, are detected including sweet smart pancreas islet altogether under above-mentioned chromatographic condition
More than ten of absworption peak (deducting the absworption peak of metacresol, chromatogram omits) including element, the areas of peak normalization method at each peak calculates knot
Fruit is shown in Table 2- tables 5.
The insulin glargine injecta HPLC collection of illustrative plates integral result (preparation method 1 of embodiment 1) of table 2
The insulin glargine injecta HPLC collection of illustrative plates integral result (preparation method 2 of embodiment 1) of table 3
The insulin glargine injecta HPLC collection of illustrative plates integral result (preparation method 3 of embodiment 1) of table 4
The insulin glargine injecta HPLC collection of illustrative plates integral result (preparation method 4 of embodiment 1) of table 5
The concrete operations of molecular exclusion chromatography detection macromolecule protein are as follows:
Chromatographic condition:Warters high performance liquid chromatographs, Waters Insulin HMWP posts, mobile phase be glacial acetic acid-
Acetonitrile-water mixed solution (takes glacial acetic acid 200ml, adds acetonitrile 300ml, add water 400ml, after mixing, pH is adjusted with 25% ammonia solution
Value adds water to 1000ml to 3.0), flow velocity 0.5ml/min per minute;Detection wavelength 276nm.
The preparation of test sample:Precision measures the Lantus sample as made from preparation method 1,2,3,4 respectively
2ml, 5ml is diluted to 0.01mol/L hydrochloric acid solutions.
Determination method:The μ l of need testing solution 100 are taken, inject liquid chromatograph, record chromatogram, retention time is less than sweet smart pancreas
All peak area sums of island element main peak are calculated by areas of peak normalization method, produce macromolecule protein content.
Investigate result:
Every quality investigation testing result of insulin glargine injecta sample made from embodiment 1 and embodiment 2 is shown in Table 6
With table 7.
The preparation technology quality investigation result of the embodiment 1 of table 6
The preparation technology quality investigation result of the embodiment 2 of table 7
Use insulin glargine injecta made from preparation method provided by the invention in embodiment 1 and embodiment 2, pH,
Potency and freeze point depression and insulin glargine injecta no significant difference made from prior art;But total correlation material, maximum phase
Closing material substantially reduces, and macromolecule protein does not also detect.
In addition, insulin glargine injecta prepared by embodiment 3-6, by quality testing, as a result with Examples 1 and 2
Unanimously:Compared with the insulin glargine injecta that method 3 and 4 obtains, using preparation method provided by the invention (method 1 and 2)
The total correlation material and maximal correlation content of material of obtained parenteral solution substantially reduce, and macromolecule protein does not detect (concrete outcome
And chromatogram omits).
Therefore, preparation method provided by the invention can reduce the process contaminants of insulin glargine injecta, so as to improve
Drug safety.
In a word, preparation method of the invention makes the manufacturing cycle time of insulin glargine injecta be shorten to by about 90 minutes
About 30 minutes, nearly 2/3rds are shortened, improves preparation efficiency, reduce technique power consumption.Importantly, green
While, preparation method of the invention reduces the generation of the process contaminants such as related substances and macromolecule protein, improves sweet essence
The quality of regular iletin.In addition, operation is simple for this method, it is adapted to the big production of scale.
Specific description of embodiments of the present invention above is not intended to limit the present invention, and those skilled in the art can be according to this
Various changes or deformation are made in invention, without departing from the spirit of the present invention, all should belong to the models of appended claims of the present invention
Enclose.
Claims (12)
1. a kind of preparation method of insulin glargine injecta, the insulin glargine injecta by insulin glargine, glycerine,
Cresols, zinc chloride, hydrochloric acid, sodium hydroxide and water for injection composition, wherein, insulin glargine 40-500IU/mL, glycerine 9.2-
23mg/mL, metacresol 1.7-5.0mg/mL, the μ g-200 μ g/mL of zinc 5;Comprise the following steps:
(1) glycerine is dissolved with partial syringe with water, is configured to glycerite;The dosage of water for injection accounts for the insulin glargine note
Penetrate the 60%~80% of liquid cumulative volume;
(2) glycerite is divided into three parts, is separately added into insulin glargine, metacresol and zinc chloride, is well mixed, obtains sweet
Smart insulin-glycerite, metacresol-glycerite and zinc chloride-glycerite;For preparing the insulin glargine-sweet
The glycerite of oil solution is no less than the 30% of the glycerite cumulative volume;For preparing the metacresol-glycerite
Glycerite is no less than the 50% of the glycerite cumulative volume;Remaining glycerite is used to prepare the zinc chloride-glycerine
Solution;
(3) insulin glargine-glycerite mixes with metacresol-glycerite, stirs, obtains mixed solution I;
(4) under stirring, hydrochloric acid solution to pH=3.0~3.5 and solution is added into the mixed solution I and are clarified;
(5) to step( 4)In add the zinc chloride-glycerite in obtained solution, stir;
(6) under stirring, to step( 5)In add sodium hydroxide solution to pH=3.5~4.5 in obtained solution;
(7) it is settled to final volume with water for injection.
2. preparation method according to claim 1, it is characterised in that the step( 2)In, for preparing the sweet essence
The glycerite of insulin-glycerite accounts for the 30%~40% of the glycerite cumulative volume.
3. preparation method according to claim 1, it is characterised in that for preparing the sweet of the metacresol-glycerite
Oil solution accounts for the 50%~60% of the glycerite cumulative volume.
4. preparation method according to claim 1, it is characterised in that the step( 2)In, the glycerite according to
Volume ratio 3~4:5~6:2~1 points are three parts, are separately added into insulin glargine, metacresol and zinc chloride, are well mixed, obtain
Insulin glargine-glycerite, metacresol-glycerite and zinc chloride-glycerite.
5. preparation method according to claim 1, it is characterised in that the step( 4)In, the hydrochloric acid solution it is dense
Spend for 0.1mol/L.
6. preparation method according to claim 1, it is characterised in that the step( 4)In, regulation pH=3.1~
3.2。
7. preparation method according to claim 1, it is characterised in that the step( 6)In, the sodium hydroxide solution
Concentration be 0.1mol/L.
8. preparation method according to claim 1, it is characterised in that the step( 6)In, adjust pH=4.0.
9. a kind of preparation method of insulin glargine injecta, the insulin glargine injecta by insulin glargine, glycerine,
Cresols, zinc chloride, hydrochloric acid, sodium hydroxide and water for injection composition, the concentration of each component are:Insulin glargine 40-500IU/mL,
Glycerine 9.2-23mg/mL, metacresol 1.7-5.0mg/mL, the μ g-200 μ g/mL of zinc 5;Specific operating procedure includes:
(1) the glycerine water for injection for accounting for the insulin glargine injecta cumulative volume 60%~80% dissolves, and is configured to glycerine
Solution;
(2) glycerite is according to volume ratio 3~4:5~6:2~1 points are three parts, are separately added into insulin glargine, metacresol
And zinc chloride, it is well mixed, obtains insulin glargine-glycerite, metacresol-glycerite and zinc chloride-glycerite;
(3) insulin glargine-glycerite mixes with metacresol-glycerite, stirs, obtains mixed solution I;
(4) under stirring, 0.1mol/L hydrochloric acid solutions to pH=3.1~3.2 and solution is added into the mixed solution I and are clarified;
(5) to step( 4)In add the zinc chloride-glycerite in obtained solution, stir;
(6) under stirring, to step( 5)In add 0.1mol/L sodium hydroxide solutions to pH=4.0 in obtained solution;
(7) it is settled to final volume with water for injection.
10. preparation method according to any one of claim 1 to 9, it is characterised in that also including filtration sterilization.
11. preparation method according to any one of claim 1 to 9, it is characterised in that the insulin glargine injecta
In, contain insulin glargine 100IU/mL, glycerine 17mg/mL, metacresol 2.7mg/mL, the μ g/mL of zinc 30.
12. preparation method according to claim 11, it is characterised in that in the insulin glargine injecta, containing sweet
Smart insulin 100IU/mL, glycerine 16mg/mL, metacresol 3.2mg/mL, the μ g/mL of zinc 27.
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CN105527357B (en) * | 2016-02-04 | 2018-02-27 | 广东省医疗器械质量监督检验所 | A kind of method of antioxidant BHT in measure insulin glargine injecta |
CN106729639B (en) * | 2017-01-10 | 2018-02-27 | 鲁南制药集团股份有限公司 | A kind of insulin glargine injecta and preparation method thereof |
CN115702880B (en) * | 2021-08-12 | 2023-11-03 | 山东新时代药业有限公司 | Recombinant insulin glargine injection and preparation process thereof |
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CN102188367A (en) * | 2011-01-05 | 2011-09-21 | 山东新时代药业有限公司 | Insulin glargine injecta and preparation method thereof |
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