CN110314132A - A kind of ornithine aspartate injection and preparation method thereof - Google Patents
A kind of ornithine aspartate injection and preparation method thereof Download PDFInfo
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- CN110314132A CN110314132A CN201810264318.9A CN201810264318A CN110314132A CN 110314132 A CN110314132 A CN 110314132A CN 201810264318 A CN201810264318 A CN 201810264318A CN 110314132 A CN110314132 A CN 110314132A
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- Prior art keywords
- ornithine
- injection
- ornithine aspartate
- aspartate injection
- sodium
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Abstract
The present invention provides a kind of ornithine aspartate injection, including aspartic acid ornithine, mannitol, sodium pyrosulfite, pH adjusting agent and water for injection, in which: the concentration range of the mannitol is 25mg/ml~150mg/ml；The concentration range of the sodium pyrosulfite is 0.05mg/ml~3mg/ml；The pH value of the ornithine aspartate injection is 6.2-7.0.The present invention also provides the purposes of above-mentioned injection and preparation methods.Ornithine aspartate injection of the invention has excellent stability, and significantly improves the drug safety of ornithine aspartate injection, while production technology simplifies, and is conducive to large-scale industrial production, has highly important medicine and pharmacology meaning.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to arrive a kind of ornithine aspartate injection and its preparation side
Method.
Background technique
Aspartic acid ornithine is the dipeptide compound that L-Orn and L-ASPARTIC ACID are prepared by chemical synthesis.
Ornithine aspartate injection is generally prepared as clinical application.Ornithine aspartate injection enters in human body, door
Aspartic acid ornithine is decomposed into L-aminobutanedioic acid and ornithine, can directly participate in liver cell metabolism, and can activate liver detoxification function
Two key enzymes in energy, it is thus possible to assist to remove the free radical being harmful to the human body, enhance the functions of expelling toxin of liver, drop rapidly
Low excessively high blood ammonia, promotes the reparation and regeneration of liver cell itself, to effectively improve liver function, it is flat to restore human body energy
Weighing apparatus.
Aspartic acid ornithine declares listing in Germany the 1970s by German Merz drugmaker.It passes through within 2000
State Food and Drug Administration's approval enters Chinese market, for domestic exclusive dosage form, trade name Hepa Merz (Hepa-
Merz), specification 10ml:5g, the indication ratified at home be treatment because acute and chronic hepatopathy (such as various hepatitis, cirrhosis,
Fatty liver, posthepatitic syndrome) cause blood ammonia increase and treatment hepatic encephalopathy, such as occur together or secondary to liver detoxification function by
The potentiality or hepatic encephalopathy stage of attack for damaging (such as cirrhosis) are particularly suitable for the consciousness for the treatment of hepatic coma early stage or hepatic coma phase
Fringe.
Aspartic acid ornithine is crystallization or the powder of white or off-white color, has and draws moist, easily dissolves in water, in first
Soluble,very slightly in alcohol or ethyl alcohol.Ornithine aspartate injection ornithine in high temperature, illumination, slight alkali environment is easily cyclic,
Color burn causes impurity to increase, this is the generally existing phenomenon of the import injection that has listed currently on the market.Existing door
Aspartic acid ornithine injection, cannot be using terminal overkill (guaranteeing that sterile horizontal F0 value is greater than 12) due to unstable
Method sterilizing.To prevent aspartic acid ornithine rotten using freeze-dried powder, it not can guarantee sterile horizontal F0 value greater than 12, reach
Less than international sterility requirements, therefore generate drug safety hidden danger.Therefore, a kind of L-aminobutanedioic acid bird that stability is good is researched and developed
Propylhomoserin injection is at current urgent problem to be solved.
Chinese patent CN104173280B discloses a kind of by the way that poloxamer class surfactant (emulsifier) etc. is added
To prepare stable ornithine aspartate injection and method.It is well known that poloxamer class surfactant is for injecting
Agent, when injection, will cause certain vascular stimulation and haemolysis, and there are drug safety hidden danger.
Chinese patent CN101987094A discloses a kind of ornithine aspartate injection, and pH is controlled in 5.2-
6.0, impurity I (ornithine lactams salt) can be controlled 0.1% or so, but still need to the activity that liquor capacity 0.1% is added
Charcoal adsorbs pyrogen present in injection.However, there are molten in adsorption process since active carbon itself contains plurality of impurities
Risk of the impurity into injection out, and the form of these impurity and the amount of dissolution are unknown, to generate drug safety hidden danger.So
And if without using pyrogen present in activated carbon adsorption ornithine aspartate injection, ornithine aspartate injection
Aseptic be difficult to ensure, this produces drug safety hidden danger again.
With this, it is necessary to a kind of ornithine aspartate injection is researched and developed, to overcome drawbacks described above in the prior art.
Summary of the invention
The first purpose of this invention is to provide a kind of ornithine aspartate injection, have excellent stability,
Impurity content is low, and can be sterilized using the method for terminal overkill, significantly reduces drug safety hidden danger, significantly improves
The drug safety of ornithine aspartate injection.
To achieve the above object, the invention adopts the following technical scheme:
A kind of ornithine aspartate injection, including aspartic acid ornithine, mannitol, sodium pyrosulfite, pH are adjusted
Agent and water for injection, in which:
The concentration of the mannitol is 25mg/ml~150mg/ml；The concentration of the sodium pyrosulfite be 0.05mg/ml~
3.0mg/ml；The pH value of the ornithine aspartate injection is 6.2~7.0.
According to the present invention, the concentration of the mannitol is 80mg/ml~150mg/ml.
Preferably, the concentration of the mannitol is preferably 100mg/ml.
According to the present invention, the concentration of the sodium pyrosulfite is 1.0mg/ml~3.0mg/ml.
Preferably, the concentration of the sodium pyrosulfite is preferably 2mg/ml.
According to the present invention, the concentration of aspartic acid ornithine is 0.1g/ml~1g/ml.
According to the present invention, the pH adjusting agent is one or more of sodium bicarbonate, sodium hydroxide, sodium citrate.
Further, the pH adjusting agent is sodium hydroxide.
According to the present invention, bacterial endotoxin≤0.02Eu/mg of the aspartic acid ornithine.
According to the present invention, bacterial endotoxin≤0.01Eu/mg of the mannitol, the bacterium endogenous toxic material of the sodium pyrosulfite
Element≤0.01Eu/mg, bacterial endotoxin≤0.01Eu/mg of the sodium hydroxide.
Second object of the present invention is to provide the purposes of above-mentioned ornithine aspartate injection, is used to prepare treatment
The drug of hepatic encephalopathy.
Third object of the present invention is to provide the preparation method of above-mentioned ornithine aspartate injection, including as follows
Step:
1) mannitol, the sodium pyrosulfite of formula ratio are weighed, solubilization in the water for injection of 50%~70% dose volume,
It is uniformly mixed, the aspartic acid ornithine of formula ratio is then added, after aspartic acid ornithine all dissolution, with pH tune
It saves agent and adjusts pH, the pH value for controlling the ornithine aspartate injection is 6.2~7.0, then mends to inject water to and match
Total volume processed；
2) to step 1) preparation ornithine aspartate injection carry out aseptic filtration, filling nitrogen charging, sealing, sterilizing,
Lamp inspection, packaging.
The aseptic filtration in the step 2) can filter for film, be removed for example, by using 0.22 μm of miillpore filter
Bacterium filtering.
Ornithine aspartate injection production technology of the invention simplifies, stable product quality, is conducive to large-scale
Industrialized production.
According to the present invention, in the step 1), the pH value for controlling the ornithine aspartate injection is 6.4~6.8.
According to the present invention, the sterilization process in the step 2) is sterilized using the method for terminal overkill.
Compared with prior art, the present invention has following advantageous effects:
1) ornithine aspartate injection of the invention controls L-aminobutanedioic acid under the specific formulation condition of supplementary material
The pH value of ornithine injection is 6.2~7.0, and the ornithine aspartate injection being prepared has excellent drug substance stable
Property, ornithine aspartate injection is since character change, I (ornithine of impurity occur in high temperature, illumination during overcoming storage
Lactams salt) significant the problem of increasing.Simultaneously as stability is good, so the method sterilizing of terminal overkill, pole can be used
The earth reduces drug safety hidden danger, significantly improves the drug safety of ornithine aspartate injection.
2) preparation method of ornithine aspartate injection of the invention, by control raw material aspartic acid ornithine,
The bacterial endotoxin of mannitol and sodium pyrosulfite is lower than certain value, in conjunction with subsequent aseptic filtration step, without activity
Charcoal carries out the step of absorption is except heat source to injection, and the bacterial endotoxin for producing ornithine aspartate injection still conforms to
Injection quality requirement, is not only able to satisfy the requirement of aseptic, while significantly reducing drug safety hidden danger, simplifies production
Technique reduces production cost, has highly important medicine and pharmacology meaning.
Detailed description of the invention
Fig. 1 is the high-efficient liquid phase chromatogram HPLC map of ornithine aspartate injection of the invention.
Specific embodiment
Ornithine aspartate injection of the invention is described in further detail with reference to embodiments, but not
Limitation of the present invention, all equivalent replacements according to any this field made by the disclosure of invention, belongs to of the invention
Protection scope.
The preparation of embodiment 1-7 ornithine aspartate injection
Ornithine aspartate injection formula is as shown in table 1.
1 ornithine aspartate injection formula of table
Specific preparation method
Ornithine aspartate injection is prepared according to the injection formula of liquid of table 1, the specific steps are as follows:
1) mannitol, the sodium pyrosulfite for weighing formula ratio, are dissolved in the water for injection of 50%~70% dose volume, stir
Mix it is uniformly mixed, then be added formula ratio aspartic acid ornithine, after aspartic acid ornithine all dissolution after, adjusted with pH
Agent adjusts pH, and the pH value for controlling the ornithine aspartate injection is 6.2~7.0, then mends and injects water to preparation
Total volume.
2) to step 1) preparation ornithine aspartate injection carry out aseptic filtration, filling nitrogen charging, sealing, sterilizing,
Lamp inspection, packaging.
In the step 1), bacterial endotoxin≤0.02Eu/mg of the aspartic acid ornithine, the mannitol it is thin
Bacterium endotoxin≤0.01Eu/mg, bacterial endotoxin≤0.01Eu/mg of the sodium pyrosulfite, the bacterium of the sodium hydroxide
Endotoxin≤0.01Eu/mg.
The aseptic filtration in the step 2) can filter for film, for example, by using 0.22 μm of filtering with microporous membrane,
To achieve the purpose that degerming.
The high-efficient liquid phase chromatogram HPLC map of ornithine aspartate injection prepared by embodiment 1 is as shown in Figure 1.
The high-efficient liquid phase chromatogram HPLC map of the ornithine aspartate injection of embodiment 2-7 preparation is identical as Fig. 1.
Embodiment 8, sample stability detection
For the stability for investigating ornithine aspartate injection of the invention, detection embodiment 1-7 is freshly prepared respectively is obtained
Stability after the ornithine aspartate injection (0 day) arrived and storage.
Since conventional storage time is usually 18 months or longer, the present invention is more severe than normal storage conditions
Under conditions of quarter (such as: illumination (4500lx ± 5001x), high temperature (60 DEG C) condition) storage aspartic acid ornithine of the invention
Injection, and detect the stability of the injection after storage.Particular content is as follows:
(1), the character, pH value of the ornithine aspartate injection that is prepared of detection embodiment 1-7, related respectively
Material mass content, aspartic acid ornithine mass content and bacterial endotoxin, testing result are as shown in table 2.
Table 2, ornithine aspartate injection testing result
Note: N.D, Not Detect indicate that this is not detected.
(2), the ornithine aspartate injection of detection embodiment 1-7 preparation is in illumination (4500lx ± 5001x) condition
Character, pH value, related material mass content, aspartic acid ornithine mass content and bacterial endotoxin after lower preservation 10 days,
Testing result is as shown in table 3.
Table 3, ornithine aspartate injection testing result
Note: N.D, Not Detect indicate that this is not detected.
(3), the ornithine aspartate injection of detection embodiment 1-7 preparation saves 10 under the conditions of high temperature (60 DEG C)
Character, pH value, related material mass content, aspartic acid ornithine mass content and bacterial endotoxin after it, testing result
As shown in table 4.
Table 4, ornithine aspartate injection testing result
Note: N.D, Not Detect indicate that this is not detected.
In table 2-4, impurity I is ornithine lactams salt, and impurity II is aspartic acid ornithine condensation product.
As shown in Table 2, the 0 day character of ornithine aspartate injection product, pH value of embodiment 1-7 preparation, related
Material mass content is almost the same, no significant difference, and bacteria endotoxin content is qualified.
As shown in Table 3, after being saved 10 days under the conditions of illumination (4500lx ± 5001x), the L-aminobutanedioic acid bird ammonia of embodiment 1-7
Acid injection is faint yellow or colourless clear liquid, and the testing result of the product with 0 day is almost the same, related material mass content
Still very low.
As shown in Table 4, after saving 10 days under the conditions of 60 DEG C of high temperature, the aspartic acid ornithine of embodiment 1-3,5-7 is injected
Liquid becomes yellow or faint yellow clear liquid, and I content of impurity is increased slightly, but content is still very low；The L-aminobutanedioic acid of embodiment 4
Ornithine injection is still colourless clear liquid, consistent with 0 day product characteristics, and I content of impurity with 0 day product without obvious
Difference.
Consolidated statement 2 to 4 detection data of table illustrates that the present invention has in terms of the control of impurity I obviously to be improved, solution
It has determined the excessively high problem of impurity I in ornithine aspartate injection, and product characteristics are in illumination (4500lx ± 5001x) or height
Also without significant change after saving 10 days under the conditions of warm (60 DEG C), illustrate that having for ornithine aspartate injection of the invention is excellent
Different stability significantly improves the drug safety of ornithine aspartate injection.
In addition, heat source is not removed by active carbon, so that L-aminobutanedioic acid in the preparation process of ornithine aspartate injection
Ornithine process for preparing injection liquid simplifies, and product stability is good, up-to-standard, is conducive to large-scale industrial production.
Specific embodiments of the present invention are described in detail above, but it is only used as example, the present invention is not intended to limit
In particular embodiments described above.To those skilled in the art, it any equivalent modifications to the practical progress and replaces
In generation, is also all among scope of the invention.Therefore, without departing from the spirit and scope of the invention made by equal transformation and repair
Change, all should be contained within the scope of the invention.
Claims (10)
1. a kind of ornithine aspartate injection, which is characterized in that including aspartic acid ornithine, mannitol, pyrosulfurous acid
Sodium, pH adjusting agent and water for injection, in which:
The concentration of the mannitol is 25mg/ml~150mg/ml；The concentration of the sodium pyrosulfite be 0.05mg/ml~
3.0mg/ml；The pH value of the ornithine aspartate injection is 6.2~7.0.
2. ornithine aspartate injection according to claim 1, which is characterized in that the concentration of the mannitol is
80mg/ml~150mg/ml.
3. ornithine aspartate injection according to claim 1, which is characterized in that the concentration of the sodium pyrosulfite
For 1.0mg/ml~3.0mg/ml.
4. ornithine aspartate injection according to claim 1, which is characterized in that the pH adjusting agent is bicarbonate
One or more of sodium, sodium hydroxide, sodium citrate.
5. ornithine aspartate injection according to claim 4, which is characterized in that the pH adjusting agent is hydroxide
Sodium.
6. ornithine aspartate injection according to any one of claims 1-5, which is characterized in that the door winter ammonia
Bacterial endotoxin≤0.02Eu/mg of sour ornithine.
7. ornithine aspartate injection according to claim 6, which is characterized in that the bacterium endogenous toxic material of the mannitol
Element≤0.01Eu/mg, bacterial endotoxin≤0.01Eu/mg of the sodium pyrosulfite, the bacterial endotoxin of the sodium hydroxide
≤0.01Eu/mg。
8. the purposes of ornithine aspartate injection described in any one of -7 according to claim 1 is used it is characterized in that being
In the drug of preparation treatment hepatic encephalopathy.
9. the preparation method of ornithine aspartate injection described in any one of -7 according to claim 1, which is characterized in that
Include the following steps:
1) mannitol, the sodium pyrosulfite for weighing formula ratio, are dissolved in the water for injection of 50%~70% dose volume, are stirred
Uniformly, the aspartic acid ornithine of formula ratio is then added, after aspartic acid ornithine all dissolution, is adjusted with pH adjusting agent
PH, the pH value for controlling the ornithine aspartate injection is 6.2~7.0, then mends and injects water to preparation total volume；
2) aseptic filtration, filling nitrogen charging, sealing, sterilizing, lamp inspection are carried out to the ornithine aspartate injection of step 1) preparation,
Packaging.
10. preparation method according to claim 9, which is characterized in that in the step 1), control the L-aminobutanedioic acid bird
The pH value of propylhomoserin injection is 6.4~6.8.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810264318.9A CN110314132B (en) | 2018-03-28 | 2018-03-28 | Ornithine aspartate injection and preparation method thereof |
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|---|---|---|---|
| CN201810264318.9A CN110314132B (en) | 2018-03-28 | 2018-03-28 | Ornithine aspartate injection and preparation method thereof |
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| CN110314132A true CN110314132A (en) | 2019-10-11 |
| CN110314132B CN110314132B (en) | 2022-11-04 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101987094A (en) * | 2009-08-07 | 2011-03-23 | 上海秀新臣邦医药科技有限公司 | Ornithine aspartate injection and preparation method thereof |
| CN102274166A (en) * | 2011-07-13 | 2011-12-14 | 辽宁科泰生物基因制药股份有限公司 | Medicinal composition containing ornithine aspartate |
| CN104807924A (en) * | 2014-01-28 | 2015-07-29 | 黑龙江天行健医药科技开发有限公司 | Method for detecting specific impurities in ornithine aspartate raw material and preparation thereof |
| CN107441038A (en) * | 2017-08-31 | 2017-12-08 | 济南康和医药科技有限公司 | A kind of ornithine aspartate injection and preparation method thereof |
| CN107510649A (en) * | 2017-07-24 | 2017-12-26 | 海南先通药业有限公司 | A kind of ornithine aspartate injection composition and preparation method thereof |
-
2018
- 2018-03-28 CN CN201810264318.9A patent/CN110314132B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101987094A (en) * | 2009-08-07 | 2011-03-23 | 上海秀新臣邦医药科技有限公司 | Ornithine aspartate injection and preparation method thereof |
| CN102274166A (en) * | 2011-07-13 | 2011-12-14 | 辽宁科泰生物基因制药股份有限公司 | Medicinal composition containing ornithine aspartate |
| CN104807924A (en) * | 2014-01-28 | 2015-07-29 | 黑龙江天行健医药科技开发有限公司 | Method for detecting specific impurities in ornithine aspartate raw material and preparation thereof |
| CN107510649A (en) * | 2017-07-24 | 2017-12-26 | 海南先通药业有限公司 | A kind of ornithine aspartate injection composition and preparation method thereof |
| CN107441038A (en) * | 2017-08-31 | 2017-12-08 | 济南康和医药科技有限公司 | A kind of ornithine aspartate injection and preparation method thereof |
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