CN104224706B - A kind of Rui Jiade loose parenteral solutions and preparation method thereof - Google Patents
A kind of Rui Jiade loose parenteral solutions and preparation method thereof Download PDFInfo
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- CN104224706B CN104224706B CN201410453766.5A CN201410453766A CN104224706B CN 104224706 B CN104224706 B CN 104224706B CN 201410453766 A CN201410453766 A CN 201410453766A CN 104224706 B CN104224706 B CN 104224706B
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Abstract
The invention provides a kind of Rui Jiade loose parenteral solutions and preparation method thereof, using addition Na2HPO4—NaH2PO4The mode of buffer system, adjusts the pH value of solution, adds a certain amount of propane diols and disodium ethylene diamine tetraacetate in injection（EDTA‑2Na）, the stability of Rui Jiade loose parenteral solutions is improved, parenteral solution is sterilized using filtration method twice.Rui Jiade loose parenteral solution stable performances prepared by the preparation method of the present invention.
Description
Technical field
The invention belongs to a kind of appts for medical injection and preparation method thereof, and in particular to a kind of Rui Jiade loose parenteral solutions and its system
Preparation Method.
Background technology
Rui Jiadesong, English name：Regadenoson, molecular formula：C15H18N8O5·H2O, chemical name：2-[4-
[(MethylaMino)carbonyl]-1H-pyrazol-1-yl]adenosine.It is a kind of selective adenosine receptor activator,
Coronary artery can be made to produce diastole.The radionuclide myocardial perfusion that the medicine is used for receiving motion stress test patient is aobvious
Picture.
Rui Jiade loose structure formulas：
The stability of this product has limitation, Rui Jiadesong hydrolyze in parenteral solution, can aoxidize, can be with metal ion
In conjunction with discoloration, the quality of the parenteral solution is affected.When therefore preparing Rui Jiade loose parenteral solutions, it is necessary to overcome its destabilizing factor.
Content of the invention
In order to ensure the security and validity of Rui Jiadesong injections, the present invention provide a kind of Rui Jiade loose parenteral solutions and
Its preparation method, specific as follows：
A kind of Rui Jiade loose parenteral solutions, are the stability for ensureing the parenteral solution, using addition Na2HPO4-NaH2PO4Buffering
The mode of system, adjusts the pH value of solution so as to which pH value is controlled 7.4.
In above-mentioned Rui Jiade loose parenteral solutions, the propane diols of the 0.5%-1.0% of injection total amount can be added, can be dropped
The hydrolysis rate of low Rui Jiadesong, is conducive to the stability for improving Rui Jiade loose parenteral solutions；In addition, for guaranteeing the steady of the injection
Qualitative, add in parenteral solution and may deposit in disodium ethylene diamine tetraacetate (EDTA-2Na) 0.05%, EDTA-2Na and parenteral solution
Complexing of metal ion, to improve the stability of Rui Jiade loose parenteral solutions；Further, for the stability for guaranteeing the injection, note
Liquid sterilizing is penetrated using filtration method twice.
The preparation method of above-mentioned Rui Jiade loose parenteral solutions, based on 200L Rui Jiade loose parenteral solutions, specifically includes following steps：
1) A liquid and B liquid are prepared respectively, then according to A liquid and B liquid are configured to pH7.4 buffer systems by certain ratio,
A liquid：Take NaH2PO4·2H2O 3.12g are dissolved in water for injection, are settled to 100ml；
B liquid：Take Na2HPO4·12H2O 7.17g are dissolved in water for injection, are settled to 100ml；
A liquid+B liquid：Take A liquid 37ml to mix with B liquid 63ml, be settled to 400ml, be adjusted to PH7.4；
2) water for injection 10L is taken, propane diols 1.5kg is added, is stirred.EDTA-2Na 100g are added, is dissolved and is stirred
Mix uniform；
3) 16g injections Rui Jiadesong (based on pure without crystallization water bulk drug) are weighed, is dissolved in 1L waters for injection, then
During under agitation add Rui Jiadesong solution to the aqueous solution for injection of propane diols and EDTA-2Na, pH7.4 phosphoric acid is added
Salt buffer system 400ml, stirs.Water for injection is added to cumulative volume 200L；
4) aseptic for guaranteeing, 0.22 μm of polyether sulfone filter core to be installed and used first is pre-processed, the method for pretreatment
For moist heat sterilization is processed, and moist heat sterilization condition is：121 DEG C, 30min.Take 0.22 μm of pretreated polyether sulfone filter of moist heat sterilization
Used in filter installed by core；
5) the above-mentioned 200L Rui Jiade loose parenteral solutions for preparing (are wherein contained propane diols, EDTA-2Na and pH7.4 phosphoric acid
Salt buffer system) first pass through 0.45 μm of sand stick and filter in advance, then by 0.22 μm of polyether sulfone filter core filtration, that is, obtain aseptic auspicious plus
Moral loose parenteral solution；
6) dispensed to 5ml ampullas again, obtain final product the Rui Jiade loose parenteral solutions that specification is 0.4mg/5ml (0.08mg/ml).
The injection technology of preparing main points have in terms of following 5.
1) normal human blood's pH value is 7.34～7.45, is to reduce excitant, is reduced or avoided to blood Acidity of Aikalinity
Affect, it is ensured that drug safety, facilitate clinical application, be conducive to absorbing.The pH value that Rui Jiadesong injections need to be controlled is 7.4, is
Control Rui Jiadesong injection pH7.4, using Na2HPO4-NaH2PO4Buffer system.The buffer system can effective control Rui Jiade
Loose injection pH be 7.4, its pH be influenced by temperature little, buffer solution dilution after pH change little, even if dilution ten times after pH change
Change and be less than 0.1.Rui Jiadesong injections are entered in blood, if the pH value in blood is too high, unnecessary OH-Will be with di(2-ethylhexyl)phosphate
The reaction of hydrogen sodium generates disodium hydrogen phosphate, whereas if when the pH value in blood is too low, unnecessary H+Will be anti-with disodium hydrogen phosphate
Sodium dihydrogen phosphate, Na should be produced2HPO4-NaH2PO4Buffer system guarantees pH stable in safe range.
2) Rui Jiadesong in aqueous, is affected by factors such as temperature, light, metal ion and oxygen, causes auspicious adding
Moral pine such as is dissociated, hydrolyzes, aoxidizing the chemical change, has both affected validity, also impact security.In Rui Jiadesong injections
The solvent propylene glycol for adding 0.5%～1.0% dielectric constant of injection total amount low, reduces the solvent polarity of injection, then
Injection dielectric constant reduces, you can the dissociation of minimizing Rui Jiadesong, hydrolysis, oxidation, is conducive to the stability of Rui Jiadesong.
3), when preparing Rui Jiade loose parenteral solutions, pharmaceutical equipment has the canisters such as stainless steel and pipeline, in the case of normal temperature,
After Rui Jiadesong was contacted with long periods such as canister, pipeline, filters, can directly react, or catalysis oxidation occurs
Deng reaction, injection is caused to darken.Add the stronger complexing of metal ion agent EDTA-2Na of appropriate activity, with Rui Jiade
In loose injection, the metal ion of remaining forms relatively stable complex, can prevent Rui Jiadesong from reacting with metal ion
Or the generation of the reactions such as catalysis oxidation is prevented, reduce injection discoloration.Also be conducive to the stability of Rui Jiadesong.
4) Rui Jiadesong injections sterilize under hot pressing condition and Rui Jiadesong can be caused significantly to degrade, using 0.22 μm of polyethers
Sulfone filter element filtering, polyether sulfone filter core are a kind of aseptic level foldable filter elements of hydrophily, with accounting for filter membrane area more than 80 percent
Microporosity and uniqueness micropore geometry.Big flux filtration, reduces the time of production process, cost-effective. and reduce and change
The number of times of filter core, reduces secondary pollution..And (solution used by challenge test is containing germy to have passed through challenge test
Solution, bacterial concentration are 100 spore/cm2, it is negative findings to collect filtered fluid culture).Pressure sterilizing result of the test and polyethers
Sulfone filter core filtration sterile test result sees attached list 1, and subordinate list 2.
5) 0.22 μm of polyether sulfone filter core is using should be noted at 3 points：
1. pretreatment before installing：Aseptic for guaranteeing, damp and hot going out first is carried out to 0.22 μm of polyether sulfone filter core to be installed and used
Bacterium is processed, and moist heat sterilization condition is：121 DEG C, 30min, after moist heat sterilization process, then used in installing filter.
2. rational condition of work is controlled：Maximum operating temperature：80 DEG C (pressure reduction 0.2MPa),
Maximum positive voltage is poor：0.42MPa (25 DEG C), maximum back-pressure is poor：0.21MPa(25℃).
3. production environment is required：Polyether sulfone filter core strictly controls production environment in process of production, it is ensured that the quality of filter core
And cleaning.
Specific embodiment
Embodiment：Prepare 200L Rui Jiade loose parenteral solutions.
1) pH7.4 phosphate buffers are prepared.Method is：A liquid and B liquid are prepared respectively, then according to certain ratio,
A liquid and B liquid are configured to pH7.4 buffer systems.
A liquid：Take NaH2PO4.2H2O 3.12g are dissolved in water for injection, are settled to 100ml.
B liquid：Take Na2HPO4.12H2O 7.17g are dissolved in water for injection, are settled to 100ml.
A liquid+B liquid：Take A liquid 37ml to mix with B liquid 63ml, be settled to 400ml, be adjusted to PH 7.4.
2) water for injection 10L is taken, propane diols 1.5kg is added, is stirred.EDTA-2Na 100g are added, is dissolved and is stirred
Mix uniform.
3) 16g injections Rui Jiadesong (based on pure without crystallization water bulk drug) are weighed, is dissolved in 1L waters for injection, then
During under agitation add Rui Jiadesong solution to the aqueous solution for injection of propane diols and EDTA-2Na, pH7.4 phosphoric acid is added
Salt buffer system 400ml, stirs.Water for injection is added to cumulative volume 200L.
4) aseptic for guaranteeing, first carry out moist heat sterilization process to 0.22 μm of polyether sulfone filter core to be installed and used, damp and hot go out
Bacterium condition is：121 DEG C, 30min, after moist heat sterilization process, then used in installing filter.
5) the above-mentioned 200L Rui Jiade loose parenteral solutions for preparing (are wherein contained propane diols, EDTA-2Na and pH7.4 phosphoric acid
Salt buffer system) first pass through 0.45 μm of sand stick and filter in advance, then by 0.22 μm of polyether sulfone filter core filtration, that is, obtain aseptic auspicious plus
Moral loose parenteral solution.
Dispensed to 5ml ampullas again, obtain final product the Rui Jiade loose parenteral solutions that specification is 0.4mg/5ml (0.08mg/ml).
It is degerming rear former using polyether sulfone filter core that Tables 1 and 2 sets forth the sterilizing of Rui Jiadesong conventional hot-presses and the present invention
Material medicine degraded measurement result, the degerming method that the present invention is adopted as can be seen from the table, bulk drug less degradation, stable performance.
Bulk drug degraded measurement result under 1. Rui Jiadesong conventional hot-press sterilising conditions of table
| Process conditions | Total impurities relative peak area (%) |
| 116 DEG C of -40min- not nitrogen charging | 0.58 |
| 116 DEG C of -40min- nitrogen charging | 0.56 |
| 121 DEG C of -15min- not nitrogen charging | 0.44 |
| 121 DEG C of -15min- nitrogen charging | 0.43 |
| 121 DEG C of -30min- not nitrogen charging | 0.6 |
| 121 DEG C of -30min- nitrogen charging | 0.59 |
| Not nitrogen charging-unsterilised | 0.21 |
| Nitrogen charging-unsterilised | 0.22 |
The degerming bulk drug degraded measurement result of 2. Rui Jiadesong polyether sulfone filter cores of table
| Process conditions | Always miscellaneous relative peak area (%) |
| 0.45 μm of polyether sulfone filter core, not nitrogen charging | 0.23 |
| 0.45 μm of polyether sulfone filter core, nitrogen charging | 0.21 |
| 0.22 μm of polyether sulfone filter core, not nitrogen charging | 0.22 |
| 0.22 μm of polyether sulfone filter core, nitrogen charging | 0.21 |
| Do not filter, not nitrogen charging | 0.22 |
| Do not filter, nitrogen charging | 0.23 |
Claims (3)
1. a kind of preparation method of Rui Jiade loose parenteral solutions, based on 200L Rui Jiade loose parenteral solutions, it is characterised in that including following
Step：
1）Prepare A liquid and B liquid respectively, then by A liquid with B liquid according to certain proportions into pH7.4 buffer systems；Described
A liquid, the compound method of B liquid are：
A liquid：Take NaH2PO4.2H2O 3.11-3.13g are dissolved in water for injection, are settled to 100ml；
B liquid：Take Na2HPO4.12H2O 7.16-7.18g are dissolved in water for injection, are settled to 100ml；
A liquid+B liquid：Take A liquid 36-38ml to mix with B liquid 62-64ml, be settled to 400ml, be adjusted to PH 7.4, obtain pH7.4 phosphorus
Hydrochlorate buffer system；
2）Water for injection 10L is taken, propane diols 1.4-1.6kg is added, is stirred, add EDTA-2Na 100g, dissolve and stir
Mix uniform；
3）15-17g injections Rui Jiadesong are weighed, based on pure without crystallization water bulk drug, is dissolved in 1L waters for injection, then
Rui Jiadesong solution is added to step 2 under stirring）In the propane diols for preparing and the aqueous solution for injection of EDTA-2Na, then plus
Enter 400 ml of pH7.4 phosphate buffers, stir, water for injection is added to cumulative volume 200L；
4）0.22 m polyether sulfones filter core is pre-processed using moist heat sterilization, is then installed in filter；
5）By the above-mentioned 200L Rui Jiade loose parenteral solutions for preparing, filtered by 0.45 m sand sticks in advance, then poly- through 0.22 m
Ether sulfone filter core is filtered, that is, obtain aseptic Rui Jiade loose parenteral solutions, it is desirable to, temperature during filtration is less than 80 DEG C；
6）Dispensed to 5 ml ampullas again, obtain final product the Rui Jiade loose parenteral solutions that specification is 0.4 mg/5ml.
2. the preparation method of Rui Jiade loose parenteral solutions according to claim 1, it is characterised in that：Step 4）Described in wet
The sterilising temp of heat sterilization process is 121 DEG C, sterilization time is 30min.
3. the preparation method of Rui Jiade loose parenteral solutions according to claim 1, it is characterised in that：Using 0.22 m polyether sulfones
When filter core is filtered, it is desirable to, temperature is less than 80 DEG C, 0.2 MPa of pressure reduction；When 25 DEG C, maximum positive voltage is poor：0.42 MPa, maximum back-pressure
Difference：0.21 MPa.
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| CN105997852B (en) * | 2016-05-15 | 2018-10-09 | 南京海融医药科技股份有限公司 | A kind of Rui Jianuosheng injections and preparation method thereof |
| CN106943347B (en) * | 2017-04-17 | 2018-11-13 | 南京健友生化制药股份有限公司 | The amplification production method of Rui Jiade loose parenteral solutions |
| CN113908117B (en) * | 2020-12-23 | 2022-11-08 | 常州方圆制药有限公司 | Injection of regadenoson and its preparation |
| CN113143857A (en) * | 2021-05-08 | 2021-07-23 | 珠海润都制药股份有限公司 | Preparation method of regadenoson injection |
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Address after: 232000 No.16 Chaoyang East Road, Huainan Economic and Technological Development Zone, Anhui Province Patentee after: CHINA NATIONAL MEDICINES GUORUI PHARMACEUTICAL Co.,Ltd. Address before: 232035 north side of Chaoyang East Road, Huainan Economic and Technological Development Zone, Anhui Province Patentee before: CHINA NATIONAL MEDICINES GUORUI PHARMACEUTICAL Co.,Ltd. |