CN103446065A - Esomeprazole sodium freeze-dried powder injection for injection and preparation method thereof - Google Patents
Esomeprazole sodium freeze-dried powder injection for injection and preparation method thereof Download PDFInfo
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- CN103446065A CN103446065A CN2013104137653A CN201310413765A CN103446065A CN 103446065 A CN103446065 A CN 103446065A CN 2013104137653 A CN2013104137653 A CN 2013104137653A CN 201310413765 A CN201310413765 A CN 201310413765A CN 103446065 A CN103446065 A CN 103446065A
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Abstract
The invention discloses an esomeprazole sodium freeze-dried powder injection for injection, wherein the additive contained in the freeze-dried powder injection includes tromethamine, the freeze-dried powder injection is formed by freeze-drying a confected liquid medicine. The freeze-dried powder disclosed by the invention is high in stability and a little in variety of auxiliary material, therefore the preparation is safer; furthermore, the process is simple, and the requirement of mass production is met.
Description
Technical field
The invention belongs to medical technical field, in particular to a kind of injection esomeprazole sodium freeze-dried powder injection and preparation method thereof.
Background technology
The injection Esomeprazole sodium is aseptic freeze-dried product, and its main component is Esomeprazole sodium, chemistry 5-methoxyl group by name-2-{[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl }-1H-benzimidazole sodium.Esomeprazole, as anti-peptic ulcer drug, can directly act on coat of the stomach inner proton pump, suppresses specifically H
++ K
++ ATP enzyme, thereby gastric acid secretion inhibiting effectively, onset is rapid, and effect is strong, and untoward reaction is few.At present, the injection Esomeprazole sodium has been widely used in treating the acute hemorrhage of upper gastrointestinal tract that duodenal ulcer, gastric ulcer, acute interior mucosa pathological changes, plyability ulcer etc. cause clinically.
The Esomeprazole sodium poor stability, all very sensitive to light, heat, oxygen, water etc., especially, when acid condition, variable color and polymerism, appear in its chemical constitution failure variation.In addition, variable color in process of production, can occur after the Long contact time canister in Esomeprazole freeze-dried preparation, produces the yellowish-brown material, and this material may be relevant with metal ion complex and oxidation impurities.The lyophilized formulations made is after long-term storage, may under the integrated condition effects such as storage temperature, interior packaging material, produce particulate matter, it is defective to cause redissolving rear preparation visible foreign matters and particulate matter, produces untoward reaction when clinical use, increases the clinical application risk.
CN103006585A comprises Esomeprazole sodium, disodium edetate.Disodiumedetate (disodium edetate) is a kind of outstanding complexing of metal ion agent, can be under alkali condition and the most metal ions complexation, thus keep the stable of preparation.But, owing to can following the calcium complexation, after the input human body, may cause calcium loss simultaneously, in body, blood calcium decline may cause a series of clinical problem.Therefore, the stability problem of esomeprazole preparation of sodium long storage time, solve in the urgent need to safe and effective method.
By the retrieval prior art, find, problem for Esomeprazole sodium to metal ion, light, heat, oxygen and water unstable, common solution is that the additives such as Esomeprazole sodium and metal ion chelation agent, antioxidant are prepared into to lyophilized injectable powder, yet metal ion chelation agent can cause the human calcium to be run off, the antioxidant sodium sulfite is irritant to skin, eye, respiratory tract, can cause allergic reaction, corneal injury, blind, asthma, bring hidden danger to patient's drug safety.
In addition, prior art is by adding the additives such as various lyophilizing proppants, metal ion chelation agent and antioxidant, to solve the poor problem of esomeprazole stable sodium.Yet, in " requirement of chemical drugs injection basic fundamental ", to point out, the basic principle that the injection adjuvant is selected is: (1) should adopt and meet the adjuvant that injection requires; (2), under the prerequisite of satisfying the demand, the kind of injection adjuvant used and consumption should be the least possible; (3) should adopt as far as possible injection to commonly use adjuvant.Therefore, under the prerequisite that improves preparation stability, if can adopt adjuvant commonly used in injection, and consumption is as far as possible few, and this is that those skilled in the art and patient are easier to accept.
Summary of the invention
In view of the deficiencies in the prior art, the object of the invention is to by lot of experiments, additives be screened, provide that a kind of stability is high, supplementary product kind is few, the simple injection esomeprazole of technique sodium freeze-dried powder injection and preparation method thereof.
First purpose of the present invention is achieved in that
A kind of injection esomeprazole sodium freeze-dried powder injection, the additives that contain in wherein said lyophilized injectable powder comprise trometamol.
Preferably, above-mentioned injection esomeprazole sodium freeze-dried powder injection, wherein said lyophilized injectable powder is comprised of Esomeprazole sodium and trometamol.
In the preferred specific embodiment of the present invention, in above-mentioned injection esomeprazole sodium freeze-dried powder injection, Esomeprazole sodium is 1:0.1-0.4 with the weight consumption ratio of trometamol.
In the preferred specific embodiment of the present invention, in above-mentioned injection esomeprazole sodium freeze-dried powder injection, Esomeprazole sodium is 1:0.2 with the weight consumption ratio of trometamol.
Second purpose of the present invention is achieved in that
A kind of preparation method of injection esomeprazole sodium freeze-dried powder injection, the method comprises the wash bottle sterilizing-drying, and butyl rubber plug is processed, and aluminium-plastic cap is processed, medicinal liquid preparation before lyophilizing, fill lyophilizing and roll and cover step; Wherein:
Before described lyophilizing, the medicinal liquid preparation steps operates as follows: the trometamol and the Esomeprazole sodium that take recipe quantity, add in the water for injection that is chilled to 10-30 ℃, stirring and dissolving, circulating filtration, sample presentation detects semi-finished product medicinal liquid content, the medicinal liquid of definite content, through 0.2 μ m microporous filter membrane aseptic filtration, is determined to the fill amount according to content, with to be filled;
Described fill step of freeze drying operates as follows: first the freeze dryer flaggy is cooled in advance below-45 ℃, according to the fill of medicinal liquid content, the false add plug, put into freeze dryer by sample, lyophilizing.
Preferably, the preparation method of above-mentioned injection esomeprazole sodium freeze-dried powder injection, in the front medicinal liquid of wherein said lyophilizing, Esomeprazole sodium is 1:0.1-0.4 with the weight consumption ratio of trometamol.
Further preferably, the preparation method of above-mentioned injection esomeprazole sodium freeze-dried powder injection, in the front medicinal liquid of wherein said lyophilizing, Esomeprazole sodium is 1:0.2 with the weight consumption ratio of trometamol.
Compared with prior art, injection esomeprazole sodium freeze-dried powder injection the present invention relates to and preparation method thereof has following advantage and significant progressive:
(1) stability is high.The inventor creatively is introduced as pH adjusting agent by trometamol, and trometamol is medicinal amino buffer base, and basicity is 10-11.5, the pH to 8.5-11.0 of medicinal liquid before the scalable lyophilizing, thus avoid the Esomeprazole sodium degraded; Simultaneously, trometamol add effective reacting of metal ion and Esomeprazole sodium of having suppressed, this may be relevant with amino structure with the polyhydroxy of trometamol; The acceleration experimental result shows, add trometamol in the esomeprazole sodium freeze-dried powder injection after, preparation stability has obtained the raising of highly significant, has obtained beyond thought technique effect.
(2) supplementary product kind is few, and preparation is safer.When due to adjuvant, bringing useful assosting effect, the side effect that is difficult to expectation also inevitably brought, therefore the inventor is preparing under the prerequisite of stable and controllable for quality, the product that meets clinical needs, tightly hold kind and the more few better principle of consumption of adjuvant simultaneously, a kind of adjuvant is only used in final decision, can reach satisfied preparation effect and expection purpose, greatly having reduced increases because of impurity (related substance) the curative effect problem that the hidden danger brought to patient's drug safety and content descend and brings to the patient.
(3) technique is simple, is applicable to large production requirement.
Specific embodiment
Following examples further describe preparation process of the present invention and beneficial effect; embodiment is only for the purpose of illustration; do not limit the scope of the invention, within the apparent change that those of ordinary skills make according to the present invention simultaneously and modification are also contained in the scope of the invention.
Embodiment 1 esomeprazole sodium freeze-dried powder injection prescription and preparation technology thereof
Esomeprazole sodium 40g
Trometamol 4g
Water for injection adds to 2000ml
Preparation technology:
Wash bottle sterilizing-drying: first cillin bottle is passed through to the ultrasonic bottle washing machine washes clean, by the sterilizing drying machine sterilizing and drying, reach bottling department standby.
Butyl rubber plug is processed: by butyl rubber plug after rubber plug cleaning machine cleans up, 121 ℃ of hot steam sterilizers 20 minutes, drying for standby.
Aluminium-plastic cap is processed: by aluminium-plastic cap, through the washing of aluminium lid cleaning machine, sterilizing, dry, and takes out standby.
The preparation of medicinal liquid: the trometamol, the Esomeprazole sodium that take recipe quantity, add in the water for injection that is chilled to 10-15 ℃, stirring and dissolving, circulating filtration, measuring medicinal liquid pH is 8.5, and sample presentation detects semi-finished product medicinal liquid content, will determine that the medicinal liquid of content is through 0.2 μ m microporous filter membrane aseptic filtration, determine the fill amount according to content, with to be filled.
Fill, jump a queue: first the freeze dryer flaggy is cooled in advance below-45 ℃, according to the fill of medicinal liquid content, the false add plug, put into freeze dryer by sample, lyophilizing.
Roll lid: the sample lyophilizing compresses plug under vacuum after finishing, and bleeds off the vacuum in freeze dryer, takes out sample, rolls aluminium lid outward, obtains finished product.
Embodiment 2 esomeprazole sodium freeze-dried powder injection prescription and preparation technologies thereof
Esomeprazole sodium 40g
Trometamol 16g
Water for injection adds to 2000ml
Preparation technology:
Wash bottle sterilizing-drying: first cillin bottle is passed through to the ultrasonic bottle washing machine washes clean, by the sterilizing drying machine sterilizing and drying, reach bottling department standby.
Butyl rubber plug is processed: by butyl rubber plug after rubber plug cleaning machine cleans up, 121 ℃ of hot steam sterilizers 20 minutes, drying for standby.
Aluminium-plastic cap is processed: by aluminium-plastic cap, through the washing of aluminium lid cleaning machine, sterilizing, dry, and takes out standby.
The preparation of medicinal liquid: the trometamol, the Esomeprazole sodium that take recipe quantity, add in the water for injection that is chilled to 20 ℃ of left and right, stirring and dissolving, circulating filtration, measuring medicinal liquid pH is 10.6, and sample presentation detects semi-finished product medicinal liquid content, will determine that the medicinal liquid of content is through 0.2 μ m microporous filter membrane aseptic filtration, determine the fill amount according to content, with to be filled.
Fill, jump a queue: first the freeze dryer flaggy is cooled in advance below-45 ℃, according to the fill of medicinal liquid content, the false add plug, put into freeze dryer by sample, lyophilizing.
Roll lid: the sample lyophilizing compresses plug under vacuum after finishing, and bleeds off the vacuum in freeze dryer, takes out sample, rolls aluminium lid outward.Obtain finished product.
Embodiment 3 esomeprazole sodium freeze-dried powder injection prescription and preparation technologies thereof
Esomeprazole sodium 40g
Trometamol 8g
Water for injection adds to 2000ml
Preparation technology:
Wash bottle sterilizing-drying: first cillin bottle is passed through to the ultrasonic bottle washing machine washes clean, by the sterilizing drying machine sterilizing and drying, reach bottling department standby.
Butyl rubber plug is processed: by butyl rubber plug after rubber plug cleaning machine cleans up, 121 ℃ of hot steam sterilizers 20 minutes, drying for standby.
Aluminium-plastic cap is processed: by aluminium-plastic cap, through the washing of aluminium lid cleaning machine, sterilizing, dry, and takes out standby.
The preparation of medicinal liquid: the trometamol, the Esomeprazole sodium that take recipe quantity, add in the water for injection that is chilled to 15-20 ℃, stirring and dissolving, circulating filtration, measuring medicinal liquid pH is 9.4, and sample presentation detects semi-finished product medicinal liquid content, will determine that the medicinal liquid of content is through 0.2 μ m microporous filter membrane aseptic filtration, determine the fill amount according to content, with to be filled.
Fill, jump a queue: first the freeze dryer flaggy is cooled in advance below-45 ℃, according to the fill of medicinal liquid content, the false add plug, put into freeze dryer by sample, lyophilizing.
Roll lid: the sample lyophilizing compresses plug under vacuum after finishing, and bleeds off the vacuum in freeze dryer, takes out sample, rolls aluminium lid outward.Obtain finished product.
Comparative example 1 esomeprazole sodium freeze-dried powder injection prescription and preparation technology thereof
Esomeprazole sodium 1 weight portion
Sodium citrate 0.05 weight portion.
Preparation method:
1) dissolve sodium citrate with water for injection, make 30%(g/ml) sodium citrate solution;
2) dissolve Esomeprazole sodium with water for injection, the amount of this water for injection is full dose 50%;
3) to 2) add 1 in the esomeprazole sodium solution that obtains) sodium citrate solution that obtains, until the pH value of this solution is 10 left and right, obtain the Esomeprazole sodium sodium citrate solution;
4) to 3) add needle-use activated carbon in the solution that obtains, to filter, filtrate is supplied water for injection to full dose;
5) by 4) filled with solution that obtains to the lyophilizing bottle, lyophilization.
Comparative example 2 esomeprazole sodium freeze-dried powder injection prescription and preparation technologies thereof
Esomeprazole sodium 40g
Sodium hydroxide is regulated pH
Disodiumedetate 4g
Water for injection adds to 2000ml
Preparation technology:
Wash bottle sterilizing-drying: first cillin bottle is passed through to the ultrasonic bottle washing machine washes clean, by the sterilizing drying machine sterilizing and drying, reach bottling department standby.
Butyl rubber plug is processed: by butyl rubber plug after rubber plug cleaning machine cleans up, 121 ℃ of hot steam sterilizers 20 minutes, drying for standby.
Aluminium-plastic cap is processed: by aluminium-plastic cap, through the washing of aluminium lid cleaning machine, sterilizing, dry, and takes out standby.
The preparation of medicinal liquid: the Esomeprazole sodium, the disodiumedetate that take recipe quantity, add in the water for injection that is chilled to 10 ℃, stirring and dissolving, circulating filtration, it is 9.4 that sodium hydroxide is regulated pH, and sample presentation detects semi-finished product medicinal liquid content, will determine that the medicinal liquid of content is through 0.2 μ m microporous filter membrane aseptic filtration, determine the fill amount according to content, with to be filled.
Fill, jump a queue: first the freeze dryer flaggy is cooled in advance below-45 ℃, according to the fill of medicinal liquid content, the false add plug, put into freeze dryer by sample, lyophilizing.
Roll lid: the sample lyophilizing compresses plug under vacuum after finishing, and bleeds off the vacuum in freeze dryer, takes out sample, rolls aluminium lid outward, obtains finished product.
The study on the stability test of embodiment 4 injection esomeprazole sodium freeze-dried powder injections
1. visible foreign matters and particulate matter are relatively.Product prepared by embodiment 1-3 and comparative example example 1-3 is respectively through 40 ℃, 75%RH accelerated test after 6 months, visible foreign matters and particulate matter contrast.With reference to 2010 editions appendix methods of Chinese Pharmacopoeia, measure.
Table 1 injection Esomeprazole sodium visible foreign matters and particulate matter check result
Experimental result by table 1 is known, and esomeprazole sodium freeze dry prepared by embodiment of the present invention 1-3 is after accelerating investigation, and the visible foreign matters index is up to specification, and particulate matter does not change substantially; After esomeprazole sodium freeze dry prepared by comparative example 1-2 redissolves, the particulate matter number is many, and after accelerating investigation, visible foreign matters is against regulation, and the particulate matter number obviously increases.
2. related substances and assay.
According to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010), measure.Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler, phosphate buffer (is got sodium hydrogen phosphate 1.12g, sodium dihydrogen phosphate 0.18g, be dissolved in water and be diluted to 1000ml, shake up, obtain)-acetonitrile (70:30) is mobile phase, the detection wavelength is 288nm, number of theoretical plate is pressed the Esomeprazole sodium peak and is calculated, and should be not less than 2500.
Determination: get under the content uniformity item content appropriate (approximately being equivalent to esomeprazole 20mg), accurately weighed, add mobile phase appropriate, dissolves and dilute and make every 1ml and approximately contain the need testing solution of 50 μ g; Precision measures 20 μ l injection liquid chromatographies, records chromatogram, measures peak area; Separately get the Esomeprazole sodium reference substance and be measured in the same method in right amount,, obtain with calculated by peak area by external standard method.
Determination of related substances: need testing solution under the assay item is got to 1ml, dilute 100 times, product solution in contrast, precision measures 20 μ l injection liquid chromatographies, records chromatogram.The limit of impurities must not cross 0.3%.
The related substances and assay of table 2 injection Esomeprazole sodium
Experimental result by table 2 is known, and esomeprazole sodium freeze dry prepared by the embodiment of the present invention is after accelerated test is investigated, and its related substance, content are substantially constant; And esomeprazole sodium freeze dry prepared by comparative example 1-2 is after accelerated test is investigated, related substance all increases obviously, and content has to a certain degree decline.
Claims (7)
1. an injection esomeprazole sodium freeze-dried powder injection, is characterized in that: in described lyophilized injectable powder, contain trometamol.
2. injection esomeprazole sodium freeze-dried powder injection according to claim 1, it is characterized in that: described lyophilized injectable powder is comprised of Esomeprazole sodium and trometamol.
3. injection esomeprazole sodium freeze-dried powder injection according to claim 1 and 2 is characterized in that: in described lyophilized injectable powder Esomeprazole sodium with the weight consumption of trometamol than being 1:0.1-0.4.
4. injection esomeprazole sodium freeze-dried powder injection according to claim 3 is characterized in that: in described lyophilized injectable powder Esomeprazole sodium with the weight consumption of trometamol than being 1:0.2.
5. the preparation method of an injection esomeprazole sodium freeze-dried powder injection according to claim 2, it is characterized in that: described preparation method comprises the wash bottle sterilizing-drying, and butyl rubber plug is processed, and aluminium-plastic cap is processed, medicinal liquid preparation before lyophilizing, fill lyophilizing and roll and cover step;
Before described lyophilizing, the medicinal liquid preparation steps operates as follows: the trometamol and the Esomeprazole sodium that take recipe quantity, add in the water for injection that is chilled to 10-30 ℃, stirring and dissolving, circulating filtration, sample presentation detects semi-finished product medicinal liquid content, the medicinal liquid of definite content, through 0.2 μ m microporous filter membrane aseptic filtration, is determined to the fill amount according to content, with to be filled;
Described fill step of freeze drying operates as follows: first the freeze dryer flaggy is cooled in advance below-45 ℃, according to the fill of medicinal liquid content, the false add plug, put into freeze dryer by sample, lyophilizing.
6. the preparation method of injection esomeprazole sodium freeze-dried powder injection according to claim 5 is characterized in that: before described lyophilizing in medicinal liquid the weight consumption of Esomeprazole sodium and trometamol than being 1:0.1-0.4.
7. the preparation method of injection esomeprazole sodium freeze-dried powder injection according to claim 6 is characterized in that: before described lyophilizing in medicinal liquid the weight consumption of Esomeprazole sodium and trometamol than being 1:0.2.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107982261A (en) * | 2017-11-30 | 2018-05-04 | 乐普药业股份有限公司 | A kind of esomeprazole sodium freeze dry and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102302463A (en) * | 2011-09-21 | 2012-01-04 | 湖北荷普药业股份有限公司 | Lansoprazole lyophilized powder for injection and preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102302463A (en) * | 2011-09-21 | 2012-01-04 | 湖北荷普药业股份有限公司 | Lansoprazole lyophilized powder for injection and preparation method |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107982261A (en) * | 2017-11-30 | 2018-05-04 | 乐普药业股份有限公司 | A kind of esomeprazole sodium freeze dry and preparation method thereof |
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Application publication date: 20131218 |