CN104688678A - Preparation method of insulin glargine injection and insulin glargine injection prepared by using preparation method - Google Patents
Preparation method of insulin glargine injection and insulin glargine injection prepared by using preparation method Download PDFInfo
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Abstract
The invention provides a preparation method of an insulin glargine injection and the insulin glargine injection prepared by using the preparation method. The preparation method comprises the following steps: dissolving glycerol into part of water for injection to prepare a glycerol solution, then dividing the glycerol solution into three parts, and respectively adding insulin glargine, metacresol and zinc chloride; firstly uniformly mixing an insulin glargine-glycerol solution and a metacresol-glycerol solution to obtain a mixed solution I; then adding a hydrochloric acid solution into the mixed solution I until the pH value is equal to 3.0 to 3.5, then adding a zinc chloride-glycerol solution, uniformly stirring, and then adding a sodium hydroxide solution until the pH value is equal to 3.5 to 4.5; and finally stabilizing the volume to reach a final volume by using the water for injection. By adopting the preparation method provided by the invention, insulin glargine and other auxiliary materials can be rapidly dissolved, the preparation cycle time can be significantly shortened, process impurities produced in a preparation process can be reduced, the quality of the insulin glargine injection can be improved, the process energy consumption can also be reduced, and the production efficiency can be improved; and the preparation method can be more suitable for the requirements of large-scale production.
Description
Technical field
The invention belongs to pharmaceutics field, be specifically related to a kind of preparation method of insulin glargine injecta and the insulin glargine injecta of preparation thereof.
Background technology
Insulin Glargine is long-acting human insulin analogue, for adult 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 the time of dissolving and absorbing, a small amount of insulin Glargine of sustained release, thus have foreseeable, have long-acting, steadily, without the blood drug level/time response of peak value.Insulin Glargine is because of its long-lasting nature, and patient only needs once a day subcutaneous administrations at a fixed time.But the type ii diabetes needs of patients that type i diabetes patient and oral antidiabetic drug lost efficacy uses insulin type control of product blood glucose all the life, therefore under effective prerequisite, ensure that the safety of medication seems particularly important.
Insulin Glargine dissolubility under the physiological condition close to neutrality is low, and solution occurs precipitation and is muddy shape, and can dissolve completely in sour environment, and solution is water white transparency shape.Therefore, existing insulin glargine injecta all uses with the injection of acid, homogeneous, clear and bright solution form.Such as, US Patent No. 5656722 discloses a kind of preparation method of insulin glargine injecta, is first to be dissolved in sterile vehicle by the adjuvant of recipe quantity, under the condition of pH4, then adds insulin Glargine.Chinese patent CN201110056210.9 discloses the method preparing stability-enhanced acid insulin preparation by adding the surfactants such as tween, the preparation method of wherein said acid insulin preparation is first suspended in a part of water for injection by insulin or insulin analog, dissolving is made under pH3-4, add other adjuvants such as tween again, with hydrochloric acid or sodium hydroxide, pH is adjusted to 4.0, and mixture is settled to final volume.Chinese patent CN201110009384.X discloses by adding PEG and carrying out the method for the insulin glargine injecta that preparation quality is stablized, safety is good with citron acid for adjusting pH.Concrete grammar is as follows: step 1. insulin Glargine adds in water for injection, makes it to dissolve, add PEG with citron acid for adjusting pH to 3.5-4.5, and 0-5 DEG C is stirred placement 12-24h; Other adjuvants of step 2. add in water for injection, with citron acid for adjusting pH to 3.5-4.5; Step 3. the former add under agitation in the latter, mixing, regulate pH to 3.8-4.2.
Cross stability in alkali environment due to insulin Glargine at peracid all can greatly reduce, the trend that cohesion occurs because of heat and physical mechanical stress increases, and in injection preparation process, inevitably use the physical means such as stirring, thus bring undesirable impurity to preparation.
The improvement of medicine preparation method is the effective means promoting its quality.Therefore, be necessary the preparation method developing a kind of new insulin glargine injecta, reach the object reducing process contaminants, improve insulin glargine injecta quality.
Summary of the invention
For the problems referred to above, one object of the present invention is the preparation method providing a kind of insulin glargine injecta.Based on the security consideration of clinical application, follow the basic principle of " under the prerequisite of satisfying the demand; kind and the consumption of injection adjuvant used should be the least possible ", the present invention, by optimizing the preparation technology of insulin glargine injecta, reaches the object shortening preparation cycle, reduce process energy consumption, improve insulin glargine injecta quality.
In order to realize above-mentioned technique effect, the present invention adopts following technical scheme:
A preparation method for insulin glargine injecta, described insulin glargine injecta is made up of insulin Glargine, glycerol, metacresol, zinc chloride, hydrochloric acid, sodium hydroxide and water for injection; Comprise the steps:
(1) glycerol partial syringe water dissolution, is mixed with glycerite;
(2) described glycerite is divided into three parts, adds insulin Glargine, metacresol and zinc chloride respectively, mix homogeneously, obtains insulin Glargine-glycerite, metacresol-glycerite and zinc chloride-glycerite;
(3) described insulin Glargine-glycerite mixes with metacresol-glycerite, stirs, obtains mixed solution I;
(4) stir under, add in described mixed solution I hydrochloric acid solution to pH=3.0 ~ 3.5 and solution clarification;
(5) add described zinc chloride-glycerite in the solution obtained in step 4, stir;
(6), under stirring, sodium hydroxide solution is added in the solution obtained in step 5 to pH=3.5 ~ 4.5;
(7) final volume is settled to water for injection.
Preferably, in described step 1, the consumption of water for injection accounts for 60% ~ 80% of described insulin glargine injecta cumulative volume.
Preferably, in described step 2, the glycerite for the preparation of described insulin Glargine-glycerite is no less than 30% of described glycerite cumulative volume; Glycerite for the preparation of described metacresol-glycerite is no less than 50% of described glycerite cumulative volume; Remaining glycerite is for the preparation of described zinc chloride-glycerite.
Preferred, in described step 2, the glycerite for the preparation of described insulin Glargine-glycerite accounts for 30% ~ 40% of described glycerite cumulative volume.
Preferred, in described step 2, the glycerite for the preparation of described metacresol-glycerite accounts for 50% ~ 60% of described glycerite cumulative volume.
Preferred further, in described step 2, described glycerite is divided into three parts (the percent by volume sum of three parts of glycerites is 100%) according to volume ratio 3 ~ 4:5 ~ 6:2 ~ 1, add insulin Glargine, metacresol and zinc chloride respectively, mix homogeneously, obtains insulin Glargine-glycerite, metacresol-glycerite and zinc chloride-glycerite.
Preferably, in described step 4, the concentration of described hydrochloric acid solution is 0.1mol/L.
Also preferred, in described step 4, regulate pH=3.1 ~ 3.2.
Preferably, in described step 6, the concentration of described sodium hydroxide solution is 0.1mol/L.
Also preferred, in described step 6, regulate pH=4.0.
As one preferred embodiment, the invention provides a kind of preparation method of insulin glargine injecta, described insulin glargine injecta is made up of insulin Glargine, glycerol, metacresol, zinc chloride, hydrochloric acid, sodium hydroxide and water for injection; Concrete operating procedure comprises:
(1) the glycerol water for injection accounting for described insulin glargine injecta cumulative volume 60% ~ 80% dissolves, and is mixed with glycerite;
(2) described glycerite is divided into three parts (the percent by volume sum of three parts of glycerites is 100%) according to volume ratio 3 ~ 4:5 ~ 6:2 ~ 1, add insulin Glargine, metacresol and zinc chloride respectively, mix homogeneously, obtains insulin Glargine-glycerite, metacresol-glycerite and zinc chloride-glycerite;
(3) described insulin Glargine-glycerite mixes with metacresol-glycerite, stirs, obtains mixed solution I;
(4) stir under, add in described mixed solution I 0.1mol/L hydrochloric acid solution to pH=3.1 ~ 3.2 and solution clarification;
(5) add described zinc chloride-glycerite in the solution obtained in step 4, stir;
(6), under stirring, 0.1mol/L sodium hydroxide solution is added in the solution obtained in step 5 to pH=4.0;
(7) final volume is settled to water for injection.
Preparation method of the present invention, also comprises filtration sterilization.
Another object of the present invention, is to provide the insulin glargine injecta obtained by above-mentioned preparation method.
Preferably, in described insulin glargine injecta, containing insulin Glargine 40-500IU/mL, glycerol 9.2-23mg/mL, metacresol 1.7-5.0mg/mL, zinc 5 μ g-200 μ g/mL.
Preferred, described insulin glargine injecta contains insulin Glargine 100IU/mL, glycerol 17mg/mL, metacresol 2.7mg/mL, zinc 30 μ g/mL.
Also preferred, described insulin glargine injecta contains insulin Glargine 100IU/mL, glycerol 16mg/mL, metacresol 3.2mg/mL, zinc 27 μ g/mL.
The present invention, by optimizing the preparation technology of insulin glargine injecta, makes manufacturing cycle within more than 90 minutes, shorten to about 30 minutes by prior art, at least saves the time of nearly 2/3rds.Due to the shortening of preparation time, the process contaminants of finished product is significantly reduced, improve the quality of injection, ensure patient medication safety.Insulin glargine injecta prepared by the inventive method, not containing surfactants such as high polymer adjuvant and tween such as PEG, reduces the probability that untoward reaction occurs, therefore safer, is more suitable for patient's life-time service.
Detailed description of the invention
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiments are only for illustration of the present invention, its scope do not limited the present invention in any way.Every do not deviate from the present invention's design change or equivalent substituting include within protection scope of the present invention.
Experimental technique in following embodiment, if no special instructions, is conventional method.Medicinal raw material used in following embodiment, reagent material etc., if no special instructions, be commercially available purchase product.
Preparation method 1 (preparation method provided by the invention): (1) gets 1L beaker, adds rotor, is placed on magnetic stirring apparatus, adds glycerol and 600mL water for injection, under stirring, glycerol is dissolved, obtain glycerite; (2) insulin Glargine, metacresol, zinc chloride use glycerite described in 180mL, 300mL, 120mL molten in advance respectively, obtain insulin Glargine-glycerite, metacresol-glycerite and zinc chloride-glycerite; (3) described insulin Glargine-glycerite mixes with metacresol-glycerite, stirs, obtains mixed solution I; (4) under stirring, in described mixed solution I, add the hydrochloric acid solution of 0.1mol/L to pH=3.0 ~ 3.5, insulin Glargine dissolves rapidly, and solution is clarified; (5) add zinc chloride-glycerite, stir; (6) be settled to 900mL with water for injection, the sodium hydroxide solution adding 0.1mol/L regulates pH=4.0; (7) 1L is settled to water for injection, filtration sterilization and get final product.
Preparation method 2 (preparation method provided by the invention): (1) gets 1L beaker, adds rotor, is placed on magnetic stirring apparatus, adds glycerol and 800mL water for injection, under stirring, glycerol is dissolved, obtain glycerite; (2) insulin Glargine, metacresol, zinc chloride use 320mL, 400mL, 80mL glycerite molten in advance respectively, obtain insulin Glargine-glycerite, metacresol-glycerite and zinc chloride-glycerite; (3) described insulin Glargine-glycerite and metacresol-glycerite mixing, stir, obtain mixed solution I; (4) under stirring, add the hydrochloric acid solution of 0.1mol/L to pH=3.1 ~ 3.2, insulin Glargine is dissolved rapidly in described mixed solution I, solution is clarified; (5) add zinc chloride-glycerite, stir; (6) 900mL is settled to water for injection; The sodium hydroxide solution adding 0.1mol/L regulates pH=4.0; (7) 1L is settled to water for injection, filtration sterilization and get final product.
Preparation method 3 (preparation method of US Patent No. 5656722): get 1L beaker, add rotor, be placed on magnetic stirring apparatus, adds glycerol, metacresol, zinc chloride and 900mL water for injection, stirs and solution is clarified; PH=4 is regulated with the hydrochloric acid of 0.1mol/L; Add insulin Glargine, stir and solution is clarified; Regulate pH=4 with the sodium hydroxide of 0.1mol/L, be settled to 1L with water for injection, filtration sterilization and get final product.Preparation method 4: get 1L beaker, add rotor, is placed on magnetic stirring apparatus, adds insulin Glargine and 900mL water for injection, with the salt acid for adjusting pH of 0.1mol/L to 3-4; Stirring makes solution clarify; Add glycerol, metacresol, zinc chloride, stir and solution is clarified; 1L is settled to, filtration sterilization and get final product with water for injection.
Preparation method 4: preparation method 4: get 1L beaker, add rotor, is placed on magnetic stirring apparatus, adds insulin Glargine and 900mL water for injection, with the salt acid for adjusting pH of 0.1mol/L to 3-4, stirs and solution is clarified; Add glycerol, metacresol, zinc chloride, stir and solution is clarified; 1L is settled to, filtration sterilization and get final product with water for injection.
In above-mentioned preparation method, when each step stirs, rotating speed adjusting rotary speed within the scope of 200 ~ 400 revs/min of rotor, with the foam that not only can stir, produce but also can degree of being accepted as.
embodiment 1insulin glargine injecta prepared by distinct methods
This is implemented described insulin glargine injecta and contains insulin Glargine 100IU/mL, glycerol 17mg/mL, metacresol 2.7mg/mL, zinc 30 μ g/mL, hydrochloric acid, sodium hydroxide and water for injection, pH=4; Prepare insulin glargine injecta respectively according to above-mentioned preparation method 1, preparation method 2, preparation method 3 and preparation method 4, and record manufacturing cycle required time, the results are shown in Table 1.
embodiment 2insulin glargine injecta prepared by distinct methods
This is implemented described insulin glargine injecta and contains insulin Glargine 100IU/mL, glycerol 16mg/mL, metacresol 3.2mg/mL, zinc 27 μ g/mL, hydrochloric acid, sodium hydroxide and water for injection, pH=4.Prepare insulin glargine injecta respectively according to above-mentioned preparation method 1, preparation method 2, preparation method 3 and preparation method 4, and record manufacturing cycle required time, the results are shown in Table 1.
embodiment 3insulin glargine injecta prepared by distinct methods
This is implemented described insulin glargine injecta and contains insulin Glargine 200IU/mL, glycerol 23mg/mL, metacresol 4.0mg/mL, zinc 60 μ g/mL, hydrochloric acid, sodium hydroxide and water for injection, pH=4.Prepare insulin glargine injecta respectively according to above-mentioned preparation method 1, preparation method 2, preparation method 3 and preparation method 4, and record manufacturing cycle required time, the results are shown in Table 1.
embodiment 4insulin glargine injecta prepared by distinct methods
This is implemented described insulin glargine injecta and contains insulin Glargine 50IU/mL, glycerol 10mg/mL, metacresol 1.7mg/mL, zinc 20 μ g/mL, hydrochloric acid, sodium hydroxide and water for injection, pH=4.Prepare insulin glargine injecta respectively according to above-mentioned preparation method 1, preparation method 2, preparation method 3 and preparation method 4, and record manufacturing cycle required time, the results are shown in Table 1.
embodiment 5insulin glargine injecta prepared by distinct methods
This is implemented described insulin glargine injecta and contains insulin Glargine 300IU/mL, glycerol 23mg/mL, metacresol 4.9mg/mL, zinc 100 μ g/mL, hydrochloric acid, sodium hydroxide and water for injection, pH=4.Prepare insulin glargine injecta respectively according to above-mentioned preparation method 1, preparation method 2, preparation method 3 and preparation method 4, and record manufacturing cycle required time, the results are shown in Table 1.
embodiment 6insulin glargine injecta prepared by distinct methods
This is implemented described insulin glargine injecta and contains insulin Glargine 150IU/mL, glycerol 20mg/mL, metacresol 2.5mg/mL, zinc 45 μ g/mL, hydrochloric acid, sodium hydroxide and water for injection, pH=4.Prepare insulin glargine injecta respectively according to above-mentioned preparation method 1, preparation method 2, preparation method 3 and preparation method 4, and record manufacturing cycle required time, the results are shown in Table 1.
The manufacturing cycle time of insulin glargine injecta described in table 1 embodiment 1-6
The raw material of different prescription adopts preparation method provided by the invention and prior art to be prepared into insulin glargine injecta respectively.Table 1 data show, and the manufacturing cycle time of preparation method provided by the invention is only about 30 minutes, and method 3 and 4 needs about 90 minutes, reach 101 minutes most (preparation method 3 in embodiment 5).T is adopted to check the data in his-and-hers watches 1 to carry out statistical analysis, manufacturing cycle time there was no significant difference (P>0.05) of preparation method 1 and 2 of the present invention; And the manufacturing cycle time of preparation method 1 is compared with 4 with prior art preparation method 3 respectively, all there is significant difference (P<0.05); The manufacturing cycle time of preparation method 2 is compared with 4 with prior art preparation method 3, also all has significant difference (P<0.05).Therefore, compare prior art, method of the present invention significantly can shorten the manufacturing cycle of insulin glargine injecta; With preparation method 3 and 4 for benchmark, method of the present invention can by nearly for manufacturing cycle time decreased 2/3rds.
test example 1insulin glargine injecta correlated quality is investigated
Investigate the quality of insulin glargine injecta that embodiment 1-2 obtains, detect pH, tire, total correlation material, maximal correlation material, macromolecule protein and freeze point depression.
Wherein pH adopts pH meter to detect; Tire, total correlation material and maximal correlation material adopt high performance liquid chromatography to detect; Macromolecule protein adopts molecular exclusion chromatography to detect; Freeze point depression adopts cryoscopic method to detect; Concrete detection method is see 2010 editions " Chinese Pharmacopoeia " annex.
The concrete operations that high performance liquid chromatography detects total correlation material and maximal correlation material are as follows:
Chromatographic condition: Waters high performance liquid chromatograph, Kromasil C4 post (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, column temperature 35 DEG C, determined wavelength 214nm.
The concrete compound method of mobile phase is as follows:
Phosphate buffer: get sodium dihydrogen phosphate 20.7g, the 800ml that adds water dissolves, then uses 85% phosphoric acid adjust ph to 2.5, adds water to 1L, filters.
Mobile phase A (25% acetonitrile): get sodium chloride 18.4g, adds above-mentioned phosphate buffer 250ml and dissolves, add acetonitrile 250ml, after mixing, be diluted with water to 1000mL, 0.45 μm of membrane filtration;
Mobile phase B (65% acetonitrile): get sodium chloride 3.2g, adds above-mentioned phosphate buffer 250ml and dissolves, add acetonitrile 650ml, after mixing, be 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 by the obtained Lantus sample 5ml of preparation method 1,2,3,4 respectively, adds 9.6mol/L hydrochloric acid solution 3 μ l, as need testing solution by every 1ml.
Algoscopy: precision measures 10 μ l, injection liquid chromatography, record chromatogram, deduction metacresol peak, calculates by areas of peak normalization method, obtains total correlation material and maximal correlation content of material.
4 kinds of insulin glargine injectas prepared by embodiment 1, tens absworption peaks (absworption peak of deduction metacresol comprising insulin Glargine is detected altogether under above-mentioned chromatographic condition, chromatogram is slightly), the areas of peak normalization method result of calculation at each peak is in Table 2-table 5.
Table 2 insulin glargine injecta HPLC collection of illustrative plates integral result (embodiment 1 preparation method 1)
Table 3 insulin glargine injecta HPLC collection of illustrative plates integral result (embodiment 1 preparation method 2)
Table 4 insulin glargine injecta HPLC collection of illustrative plates integral result (embodiment 1 preparation method 3)
Table 5 insulin glargine injecta HPLC collection of illustrative plates integral result (embodiment 1 preparation method 4)
The concrete operations that molecular exclusion chromatography detects macromolecule protein are as follows:
Chromatographic condition: Warters high performance liquid chromatograph, Waters Insulin HMWP post, mobile phase is that glacial acetic acid-acetonitrile-water mixed solution (gets glacial acetic acid 200ml, add acetonitrile 300ml, add water 400ml, after mixing, by 25% ammonia solution adjust ph to 3.0, add water to 1000ml), flow velocity 0.5ml/min per minute; Determined wavelength 276nm.
The preparation of test sample: precision measures by the obtained Lantus sample 2ml of preparation method 1,2,3,4 respectively, is diluted to 5ml with 0.01mol/L hydrochloric acid solution.
Algoscopy: get need testing solution 100 μ l, injection liquid chromatography, record chromatogram, all peak area sums that retention time is less than insulin Glargine main peak calculate by areas of peak normalization method, and namely secure satisfactory grades sub-protein content.
Investigate result:
Every quality investigation testing result of the insulin glargine injecta sample that embodiment 1 and embodiment 2 obtain is in table 6 and table 7.
Preparation technology's quality investigation result of table 6 embodiment 1
Preparation technology's quality investigation result of table 7 embodiment 2
Adopt the insulin glargine injecta that preparation method provided by the invention is obtained in embodiment 1 and embodiment 2, pH, to tire and insulin glargine injecta no significant difference that freeze point depression obtains with prior art; But total correlation material, maximal correlation material all obviously reduce, and macromolecule protein does not also detect.
In addition, insulin glargine injecta prepared by embodiment 3-6, through quality testing, result is consistent with embodiment 1 and 2: the insulin glargine injecta obtained with method 3 and 4 compares, adopt the total correlation material of the obtained injection of preparation method provided by the invention (method 1 and 2) and maximal correlation content of material obviously to reduce, macromolecule protein does not detect (concrete outcome and chromatogram are slightly).
Therefore, preparation method provided by the invention can reduce the process contaminants of insulin glargine injecta, thus improves drug safety.
In a word, preparation method of the present invention makes the manufacturing cycle time of insulin glargine injecta shorten to about 30 minutes by about 90 minutes, shortens nearly 2/3rds, improves preparation efficiency, reduces technique power consumption.The more important thing is, while environmental protection, preparation method of the present invention decreases the generation of the process contaminants such as related substances and macromolecule protein, improves the quality of insulin glargine injecta.In addition, operation is simple for this method, is applicable to the large production of scale.
Specific description of embodiments of the present invention does not above limit the present invention, and those skilled in the art can make various change or distortion according to the present invention, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (10)
1. a preparation method for insulin glargine injecta, described insulin glargine injecta is made up of insulin Glargine, glycerol, metacresol, zinc chloride, hydrochloric acid, sodium hydroxide and water for injection; Comprise the steps:
(1) glycerol partial syringe water dissolution, is mixed with glycerite;
(2) described glycerite is divided into three parts, adds insulin Glargine, metacresol and zinc chloride respectively, mix homogeneously, obtains insulin Glargine-glycerite, metacresol-glycerite and zinc chloride-glycerite;
(3) described insulin Glargine-glycerite mixes with metacresol-glycerite, stirs, obtains mixed solution I;
(4) stir under, add in described mixed solution I hydrochloric acid solution to pH=3.0 ~ 3.5 and solution clarification;
(5) add described zinc chloride-glycerite in the solution obtained in step 4, stir;
(6), under stirring, sodium hydroxide solution is added in the solution obtained in step 5 to pH=3.5 ~ 4.5;
(7) final volume is settled to water for injection.
2. preparation method according to claim 1, is characterized in that, in described step 1, the consumption of water for injection accounts for 60% ~ 80% of described insulin glargine injecta cumulative volume.
3. preparation method according to claim 1 and 2, is characterized in that, in described step 2, the glycerite for the preparation of described insulin Glargine-glycerite is no less than 30% of described glycerite cumulative volume; Glycerite for the preparation of described metacresol-glycerite is no less than 50% of described glycerite cumulative volume; Remaining glycerite is for the preparation of described zinc chloride-glycerite.
4. preparation method according to claim 3, is characterized in that, in described step 2, the glycerite for the preparation of described insulin Glargine-glycerite accounts for 30% ~ 40% of described glycerite cumulative volume;
Preferably, in described step 2, the glycerite for the preparation of described metacresol-glycerite accounts for 50% ~ 60% of described glycerite cumulative volume;
Preferred further, in described step 2, described glycerite is divided into three parts according to volume ratio 3 ~ 4:5 ~ 6:2 ~ 1, adds insulin Glargine, metacresol and zinc chloride respectively, mix homogeneously, obtains insulin Glargine-glycerite, metacresol-glycerite and zinc chloride-glycerite.
5. preparation method according to any one of claim 1 to 4, is characterized in that, in described step 4, the concentration of described hydrochloric acid solution is 0.1mol/L;
Preferably, in described step 4, regulate pH=3.1 ~ 3.2.
6. preparation method according to any one of claim 1 to 5, is characterized in that, in described step 6, the concentration of described sodium hydroxide solution is 0.1mol/L;
Preferably, in described step 6, regulate pH=4.0.
7. a preparation method for insulin glargine injecta, described insulin glargine injecta is made up of insulin Glargine, glycerol, metacresol, zinc chloride, hydrochloric acid, sodium hydroxide and water for injection; Concrete operating procedure comprises:
(1) the glycerol water for injection accounting for described insulin glargine injecta cumulative volume 60% ~ 80% dissolves, and is mixed with glycerite;
(2) described glycerite is divided into three parts according to volume ratio 3 ~ 4:5 ~ 6:2 ~ 1, adds insulin Glargine, metacresol and zinc chloride respectively, mix homogeneously, obtains insulin Glargine-glycerite, metacresol-glycerite and zinc chloride-glycerite;
(3) described insulin Glargine-glycerite mixes with metacresol-glycerite, stirs, obtains mixed solution I;
(4) stir under, add in described mixed solution I 0.1mol/L hydrochloric acid solution to pH=3.1 ~ 3.2 and solution clarification;
(5) add described zinc chloride-glycerite in the solution obtained in step 4, stir;
(6), under stirring, 0.1mol/L sodium hydroxide solution is added in the solution obtained in step 5 to pH=4.0;
(7) final volume is settled to water for injection.
8. preparation method according to any one of claim 1 to 7, is characterized in that, also comprises filtration sterilization.
9. an insulin glargine injecta, is characterized in that, is obtained by preparation method according to any one of claim 1 to 8.
10. insulin glargine injecta according to claim 9, is characterized in that, in described insulin glargine injecta, containing insulin Glargine 40-500IU/mL, glycerol 9.2-23mg/mL, metacresol 1.7-5.0mg/mL, zinc 5 μ g-200 μ g/mL;
Preferably, described insulin glargine injecta contains insulin Glargine 100IU/mL, glycerol 17mg/mL, metacresol 2.7mg/mL, zinc 30 μ g/mL;
Also preferred, described insulin glargine injecta contains insulin Glargine 100IU/mL, glycerol 16mg/mL, metacresol 3.2mg/mL, zinc 27 μ g/mL.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105527357A (en) * | 2016-02-04 | 2016-04-27 | 广东省医疗器械质量监督检验所 | Method for determining antioxidant BHT in insulin glargine injection |
| CN105597087A (en) * | 2016-01-06 | 2016-05-25 | 山东新时代药业有限公司 | Insulin glargine injection and preparation method thereof |
| CN106729639A (en) * | 2017-01-10 | 2017-05-31 | 鲁南制药集团股份有限公司 | A kind of insulin glargine injecta and preparation method thereof |
| CN115702880A (en) * | 2021-08-12 | 2023-02-17 | 山东新时代药业有限公司 | Recombinant insulin glargine injection and preparation process thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN102319422A (en) * | 2010-05-19 | 2012-01-18 | 赛诺菲-安万特 | Insulin Glargin |
| CN103830189A (en) * | 2014-03-04 | 2014-06-04 | 山东新时代药业有限公司 | Recombinant insulin glargine preparation and preparation method thereof |
-
2015
- 2015-02-05 CN CN201510061595.6A patent/CN104688678B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102319422A (en) * | 2010-05-19 | 2012-01-18 | 赛诺菲-安万特 | Insulin Glargin |
| 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 |
| CN103830189A (en) * | 2014-03-04 | 2014-06-04 | 山东新时代药业有限公司 | Recombinant insulin glargine preparation and preparation method thereof |
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| CN105597087A (en) * | 2016-01-06 | 2016-05-25 | 山东新时代药业有限公司 | Insulin glargine injection and preparation method thereof |
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| CN106729639A (en) * | 2017-01-10 | 2017-05-31 | 鲁南制药集团股份有限公司 | A kind of insulin glargine injecta and preparation method thereof |
| 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 |
| CN115702880A (en) * | 2021-08-12 | 2023-02-17 | 山东新时代药业有限公司 | Recombinant insulin glargine injection and preparation process 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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