CN110464706A - A kind of preparation method of potassium aspartate injection - Google Patents
A kind of preparation method of potassium aspartate injection Download PDFInfo
- Publication number
- CN110464706A CN110464706A CN201910652787.2A CN201910652787A CN110464706A CN 110464706 A CN110464706 A CN 110464706A CN 201910652787 A CN201910652787 A CN 201910652787A CN 110464706 A CN110464706 A CN 110464706A
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- China
- Prior art keywords
- injection
- preparation
- potassium aspartate
- aspartic acid
- liquid
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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
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
Abstract
The present invention relates to a kind of preparation methods of potassium aspartate injection, including dissolution in dense preparing tank, dilute with constant volume, filtering and sterilizing in filling.The injection formula that preparation method obtains through the invention is simple, only includes aspartic acid and water for injection, is not required to additional pH adjusting agent and adjusts pH；And isomers D- L-aminobutanedioic acid is free of in injection, endotoxin and sterile level comply with standard.
Description
Technical field
The present invention relates to field of medicinal chemistry, provide a kind of preparation method of pharmaceutical preparation, specially a kind of winter ammonia
The preparation method of sour potassium injection.
Background technique
L-aminobutanedioic acid in potassium aspartate injection can generate oxaloacetic acid under the action of transaminase, and pass through second
The effect synthesizing citric acid of acyl coenzyme A, citrate synthetase, participate in tricarboxylic acid cycle and provide energy, while door for body
Aspartic acid and cell have very strong affinity, can be used as carrier and quickly carry potassium ion into the cell and in mitochondria, have
Improve the dual function of intraor extracellular potassium.Aspartic acid can effectively treat serious hypopotassaemia caused by a variety of causes,
A new selection can be provided for clinical treatment, be worth clinical application.
Potassium aspartate injection is developed by Tanabe Mitsubishi Pharmaceutical Co, and global mainstream country is only in Japan
City, there is the imitation medicines of two approveds in the country, but isomers (D- L-aminobutanedioic acid) content is very high, and that there is production technologies is numerous
The problems such as trivial.
Summary of the invention
The present invention is based on the shortcomings of the prior art, provide that a kind of simple production process, prescription be simple, isomers contains
Measure few potassium aspartate injection.
The preparation process of the potassium aspartate injection is as follows:
(a) water for injection always with liquid product 80% is added into dense preparing tank, temperature is 80 DEG C；
(b) to be injected when being cooled to 25 DEG C -60 DEG C with water, aspartic acid raw material, stirring to whole dissolutions is added；
(c) above-mentioned medical fluid is squeezed into dilute preparing tank, be settled to defined always with liquid product；
(d) after mixing by the medicinal liquid agitating in dilute preparing tank, it is filtered through sterilizing filter, filling sealing, sample detection
The content of injection pH and D- L-aminobutanedioic acid；
(e) it sterilizes.
The w/v of the aspartic acid and water for injection is 1.712:10g/ml；
Preferably, temperature can be 25 DEG C in step (b)；
In the step (d), pH is between 6.3-7.5；The sterilizing filter is 0.22 μm of miillpore filter；
The detection method of the D- L-aminobutanedioic acid potassium content, according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2015) into
Row, specifically:
Injection about 135mg in step (d) is taken, it is accurately weighed, it sets in 100ml measuring bottle, is diluted to scale with mobile phase, shakes
It is even, as test solution；Precision measures appropriate D- L-aminobutanedioic acid, sets in 100ml measuring bottle, is diluted to scale with mobile phase, shakes
It is even, as contrast solution.It separately takes D- L-aminobutanedioic acid reference substance and L-ASPARTIC ACID reference substance each appropriate, adds flowing phased soln and dilute
It releases and is made in every 1ml containing about the solution of 3 μ g and L-ASPARTIC ACID 1mg of D- L-aminobutanedioic acid, shake up, as system suitability solution.
With L- penicillamine coating silica gel be filler (be recommended to use SUMICHIRAL OA-5000,4.6mm × 150mm,
5um chromatographic column), the mobile phase is Salzburg vitriol-isopropanol (95:5) of 0.5g/L；Detection wavelength is 240nm, column temperature
It is 30 DEG C.
It takes 50 μ l of system suitability solution to inject liquid chromatograph, records chromatogram, L-ASPARTIC ACID and D- L-aminobutanedioic acid
Successively appearance, the separating degree between two chromatographic peaks should meet the requirements.It is protected as aobvious with D- L-aminobutanedioic acid in test solution chromatogram
The peak of time consistency is stayed, peak area is not greater than 0.3 times (0.3%) of contrast solution main peak area.
Preferably, in step (e), sterilization method is high steam, 115 DEG C of temperature, sterilization time 30min.
The beneficial effects of the present invention are:
1) highly-safe without isomers D- L-aminobutanedioic acid in the potassium aspartate injection that the present invention obtains.
2) in step (d) of the present invention, the pH of gained medical fluid is not required to additionally add hydrochloric acid, hydroxide between 6.3-7.5
The pH adjusting agents such as sodium, potassium hydroxide, potassium carbonate, saleratus adjust pH, and solution component is simpler.
3) it without activated carbon adsorption in potassium aspartate injection preparation process of the invention, avoids introducing active carbon dirt
Dye, so that the level of endotoxin of supplementary material packaging material meets regulation.
4) potassium aspartate injection of the invention, (2 year validity period) is not detected within the effect phase under normal storage conditions
D- L-aminobutanedioic acid isomers.
5) preparation process of injection of the present invention is simply controllable, and with during liquid, temperature is lower, avoids scald risk.
Specific embodiment
Below in conjunction with specific embodiment, the invention will be further described, and the following description is only intended to explain the invention,
Protection scope of the present invention is not limited to these examples, it should be understood by those skilled in the art that made by the content of present invention
Equivalent replacement, or be correspondingly improved, it still falls within protection scope of the present invention.
Embodiment 1
It takes 80 DEG C of waters for injection of 75L to be added in concentrated compounding filling, is cooled to 25 DEG C, aspartic acid 18.28kg is added (with door
Aspartic acid potassium meter), constant temperature stirs to dissolve, until completely dissolved, squeeze into it is dilute add 25 DEG C of waters for injection to 100L with filling, use
0.22 μm of filtering with microporous membrane, sealing, by the ampoule that has sealed in 25 DEG C filling in middle borosilicate glass ampoule with every 10ml
Under the conditions of constant temperature place, respectively 0h, 4h, 8h sample detection isomers.
Embodiment 2
It takes 80 DEG C of waters for injection of 75L to be added in concentrated compounding filling, is cooled to 40 DEG C, aspartic acid 18.28kg is added (with door
Aspartic acid potassium meter), constant temperature stirs to dissolve, until completely dissolved, squeeze into it is dilute add 40 DEG C of waters for injection to 100L with filling, use
0.22 μm of filtering with microporous membrane, sealing, by the ampoule that has sealed in 40 DEG C filling in middle borosilicate glass ampoule with every 10ml
Under the conditions of constant temperature place, respectively 0h, 4h, 8h sample detection isomers.
Embodiment 3
It takes 80 DEG C of waters for injection of 75L to be added in concentrated compounding filling, is cooled to 60 DEG C, aspartic acid 18.28kg is added (with door
Aspartic acid potassium meter), constant temperature stirs to dissolve, until completely dissolved, squeeze into it is dilute add 60 DEG C of waters for injection to 100L with filling, use
0.22 μm of filtering with microporous membrane, sealing, by the ampoule that has sealed in 60 DEG C filling in middle borosilicate glass ampoule with every 10ml
Under the conditions of constant temperature place, respectively 0h, 4h, 8h sample detection isomers.
Embodiment 4
It takes 80 DEG C of waters for injection of 75L to be added in concentrated compounding filling, is cooled to 80 DEG C, aspartic acid 18.28kg is added (with door
Aspartic acid potassium meter), constant temperature stirs to dissolve, until completely dissolved, squeeze into it is dilute add 80 DEG C of waters for injection to 100L with filling, use
0.22 μm of filtering with microporous membrane, sealing, by the ampoule that has sealed in 80 DEG C filling in middle borosilicate glass ampoule with every 10ml
Under the conditions of constant temperature place, respectively 0h, 4h, 8h sample detection isomers.
4 sample of Example 1- embodiment, carries out the detection of isomers, the results are shown in Table 1.
1 embodiment 1-4 injection of table and the comparison of commercially available injection isomers testing result
As shown in Table 1, content of isomer is higher in commercially available potassium aspartate injection, potassium aspartate injection according to
Technical solution of the present invention is prepared and is placed in 8 hours under the conditions of 25 DEG C -60 DEG C, equal isomer-free detection；And in 80 DEG C of conditions
When lower preparation, places 4h and detected isomers, and with the extension of standing time, content of isomer increases, therefore, we select
The configuration temperature of potassium aspartate injection is 25 DEG C -60 DEG C.
Embodiment 5
0h sample in Example 1, high pressure steam sterilization, sterilising conditions are 115 DEG C of 30min.
Embodiment 6
0h sample in Example 1, high pressure steam sterilization, sterilising conditions are 121 DEG C of 15min.
High pressure steam sterilization is that bacterium is killed by steam, and sterilization effect is measured, one with normal sterilization time F0 value
As F0 value should be no less than 8.6 sample of Example 5- embodiment carries out the detection of isomers, the results are shown in Table 2.
Isomers testing result in 2 embodiment 5-6 injection of table
As shown in Table 2,115 DEG C of 30min can satisfy sterilization effect, and not form isomers.
Long-term stable experiment: by the sample of Examples 1 and 2, after 115 DEG C of 30min high pressure sterilizations, in 25 DEG C ± 2 DEG C/
Long-time stability are placed under the conditions of 60%RH ± 5%RH, observe long-time stability, as shown in table 3.
Embodiment 7
Accelerated test: preparing sample for embodiment 1, after 115 DEG C of 30min high pressure sterilizations, in 40 DEG C of ± 2 DEG C/75%RH ±
It is placed under the conditions of 5%RH, 1,3,6,9 month detection content of isomer the results are shown in Table 3.
Embodiment 8
Accelerated test: Example 2 prepares sample, after 115 DEG C of 30min high pressure sterilizations, in 40 DEG C of ± 2 DEG C/75%RH ±
Content of isomer is detected after placing 1,3,6,9 month under the conditions of 5%RH, the results are shown in Table 3.
The content of 3 injection of the present invention isomers under the conditions of normal shelf conditions and accelerated test of table
It can be seen that injection of the present invention in long-term placement process, not will detect that isomers, stability is high, safety
Property is good；Under the conditions of accelerated test, it can place and not detect within 9 months isomers, injection is highly-safe.
Claims (7)
1. a kind of preparation method of potassium aspartate injection, which is characterized in that preparation process is as follows:
(a) water for injection always with liquid product 80% is added into dense preparing tank, temperature is 80 DEG C；
(b) to be injected when being cooled to 25 DEG C -60 DEG C with water, aspartic acid raw material, stirring to whole dissolutions is added；
(c) above-mentioned medical fluid is squeezed into dilute preparing tank, be settled to defined always with liquid product；
(d) after mixing by the medicinal liquid agitating in dilute preparing tank, it is filtered through sterilizing filter, filling sealing, sample detection injection
The content of liquid pH and isomers D- L-aminobutanedioic acid；
(e) it sterilizes.
2. the preparation method of potassium aspartate injection as described in claim 1, which is characterized in that the aspartic acid with
The w/v of water for injection is 1.712:10g/ml.
3. the preparation method of potassium aspartate injection as described in claim 1, which is characterized in that temperature is in step (b)
25℃。
4. the preparation method of potassium aspartate injection as described in claim 1, which is characterized in that in the step (d), pH
Between 6.3-7.5；The sterilizing filter is 0.22 μm of miillpore filter.
5. the preparation method of potassium aspartate injection as described in claim 1, which is characterized in that the D- L-aminobutanedioic acid contains
Amount, is detected according to high performance liquid chromatography, specifically:
Testing conditions are as follows: it is filler that L- penicillamine, which coats silica gel, and the mobile phase is Salzburg vitriol-isopropyl of 0.5g/L
Alcohol (95:5)；Detection wavelength is 240nm, and column temperature is 30 DEG C；
Detection method are as follows: injection about 135mg in step (d) is taken, it is accurately weighed, it sets in 100ml measuring bottle, is diluted to mobile phase
Scale shakes up, as test solution；Precision weighs appropriate D- L-aminobutanedioic acid reference substance, sets in 100ml measuring bottle, uses mobile phase
It is diluted to scale, is shaken up, as contrast solution.It separately takes D- L-aminobutanedioic acid reference substance and L-ASPARTIC ACID reference substance each appropriate, adds
Flowing phased soln and diluting is made in every 1ml containing about the solution of 3 μ g and L-ASPARTIC ACID 1mg of D- L-aminobutanedioic acid, shakes up, as being
System applicability solution；It takes 50 μ l of system suitability solution to inject liquid chromatograph, records chromatogram, take test sample, liquid is added
In chromatography, chromatogram is recorded.
6. the preparation method of potassium aspartate injection as described in claim 1, which is characterized in that in step (e), sterilizing side
Formula is high pressure steam sterilization, 115 DEG C of temperature, sterilization time 30min.
7. the potassium aspartate injection that the preparation method of potassium aspartate injection according to claim 1 obtains.
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| CN201910652787.2A CN110464706A (en) | 2019-07-19 | 2019-07-19 | A kind of preparation method of potassium aspartate injection |
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| CN201910652787.2A CN110464706A (en) | 2019-07-19 | 2019-07-19 | A kind of preparation method of potassium aspartate injection |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1439629A (en) * | 2003-03-21 | 2003-09-03 | 于航 | Laevo potassium aspartate material and preparation therefrom and preparing method thereof |
| CN101032477A (en) * | 2007-02-15 | 2007-09-12 | 北京京卫信康医药科技发展有限公司 | Electrolyte complementary medical combination for injection |
| CN101234992A (en) * | 2008-03-10 | 2008-08-06 | 北京京卫信康医药科技发展有限公司 | Method for preparing aspartic acid |
| CN106137950A (en) * | 2015-04-03 | 2016-11-23 | 西藏卫信康医药股份有限公司 | Potassium aspartate pharmaceutical composition and preparation method |
| CN106309481A (en) * | 2015-07-09 | 2017-01-11 | 辽宁药联制药有限公司 | Compound potassium aspartate-glucose injection and preparation method thereof |
| CN107303279A (en) * | 2016-04-21 | 2017-10-31 | 辽宁药联制药有限公司 | A kind of aspartate for injection potassium freeze-dried powder and preparation method thereof |
| CN108272819A (en) * | 2018-03-16 | 2018-07-13 | 辽宁药联制药有限公司 | A kind of aspartic acid Multiple electrolytes injection and preparation method thereof |
-
2019
- 2019-07-19 CN CN201910652787.2A patent/CN110464706A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1439629A (en) * | 2003-03-21 | 2003-09-03 | 于航 | Laevo potassium aspartate material and preparation therefrom and preparing method thereof |
| CN101032477A (en) * | 2007-02-15 | 2007-09-12 | 北京京卫信康医药科技发展有限公司 | Electrolyte complementary medical combination for injection |
| CN101234992A (en) * | 2008-03-10 | 2008-08-06 | 北京京卫信康医药科技发展有限公司 | Method for preparing aspartic acid |
| CN106137950A (en) * | 2015-04-03 | 2016-11-23 | 西藏卫信康医药股份有限公司 | Potassium aspartate pharmaceutical composition and preparation method |
| CN106309481A (en) * | 2015-07-09 | 2017-01-11 | 辽宁药联制药有限公司 | Compound potassium aspartate-glucose injection and preparation method thereof |
| CN107303279A (en) * | 2016-04-21 | 2017-10-31 | 辽宁药联制药有限公司 | A kind of aspartate for injection potassium freeze-dried powder and preparation method thereof |
| CN108272819A (en) * | 2018-03-16 | 2018-07-13 | 辽宁药联制药有限公司 | A kind of aspartic acid Multiple electrolytes injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| DANIEL E. SCHWASS等: "Heat and Alkaline Damage to Proteins: Racemization and Lysinoalanine Formation", 《J. AGRIC. FOOD CHEM》 * |
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Application publication date: 20191119 |