CN103340866A - Piperacillin sodium-tazobactam sodium medicine composition and preparation method thereof - Google Patents
Piperacillin sodium-tazobactam sodium medicine composition and preparation method thereof Download PDFInfo
- Publication number
- CN103340866A CN103340866A CN2013102910492A CN201310291049A CN103340866A CN 103340866 A CN103340866 A CN 103340866A CN 2013102910492 A CN2013102910492 A CN 2013102910492A CN 201310291049 A CN201310291049 A CN 201310291049A CN 103340866 A CN103340866 A CN 103340866A
- Authority
- CN
- China
- Prior art keywords
- avocin
- sodium
- pharmaceutical composition
- tazobactam
- piperacillin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicine, and in particular relates to a piperacillin sodium-tazobactam sodium medicine composition and a preparation method of the medicine composition. The medicine composition is a sterile powder injection; the mass ratio of the piperacillin sodium to the tazobactam sodium in the medicine composition is 4-20:1; the X-ray powder diffraction pattern of the piperacillin sodium measured by means of powder X-ray diffraction measurement method is shown in Figure 1; the chemical structural formula of the piperacillin sodium is shown in Formula (I); and the content of the piperacillin sodium polymer in the medicine composition provided by the invention is quite low and is not changed obviously in an accelerated test condition and in a long-term test condition. The medicine composition prepared from the piperacillin sodium and the tazobactam sodium provided by the invention also has the advantages of low polymer content and good stability.
Description
Technical field
The invention belongs to medical technical field, specifically, relate to pharmaceutical composition of a kind of avocin and sodium-tazobactam and preparation method thereof.
Background technology
Piperacillin is a kind of wide spectrum semi-synthetic penicillins antibiotic, has been widely used in clinical.Owing to reasons such as the life-time service of piperacillin and improper uses, the therapeutic effect of piperacillin just constantly descends, and this has influenced the application of piperacillin to a great extent.Sodium-tazobactam is lactamase restrainer, belongs to the antibiotic strong synergist of the third generation, share the drug effect that can strengthen the two and prolongs action time with piperacillin or cefoperazone.Sodium-tazobactam and avocin are united when using, produce the obvious synergistic effect, be widely used in the serious general for the treatment of and local infection, abdominal cavity infection, lower respiratory infection, soft tissue infection, septicemia etc., have antimicrobial spectrum and indication widely than other the antibiotic complexing agent that has used, shown huge advantage aspect the drug resistance overcoming.
Piperacillin sodium and tazobactam sodium compound preparation domestic existing sale at present is the sterilized powder direct packaging and makes, and there is a common defective in it is exactly that preparation stabilization is poor, the prescription that can not satisfy the prescriptive period.
Patent documentation CN1732930A discloses a kind of piperacillin sodium and tazobactam sodium compound preparation for injection, and it is to be mixed by avocin and the sodium-tazobactam weight ratio raw material with 3-4: 0.8-1.2.
Patent documentation CN101265263A has disclosed a kind of employing column chromatography and has prepared high-purity avocin and sodium-tazobactam, is made into the method for compound recipe injectable powder then.
Patent documentation CN101269072A discloses a kind of pharmaceutical composition that contains beta-lactamase inhibitor and avocin and preparation method thereof, and described compositions is 1-100 by weight proportion: 1: the avocin of 0.001-2, beta-lactamase inhibitor and pH value regulator are formed.
The described piperacillin sodium and tazobactam sodium compound preparation of above-mentioned publication and the same defective that exists the preparation stability difference of listing compound preparation, the prescription that can not satisfy the prescriptive period has had a strong impact on clinical efficacy.
And because piperacillin sodium and tazobactam sodium compound preparation belongs to antibiotics, cause anaphylaxis easily, cause erythra or anaphylactic shock, very harmful to the patient.Yet initiation anaphylactoid main anaphylactogen clinically is not medicine itself, but due to the polymer that exists in the medicine." research of piperacillin sodium injection sodium-tazobactam (4:1) polymer determination method " [Liu Junhua. piperacillin sodium injection sodium-tazobactam (4:1) polymer determination method research [J], today pharmacy, 2012,22(11): 664-674] show that the polymer in the piperacillin sodium injection sodium-tazobactam is mainly derived from piperacillin.Therefore, the content of polymer in the strict control avocin crude drug, improve its stability quality and the clinical drug safety that guarantees piperacillin sodium injection Tazobactam Sodium preparation of sodium seemed particularly important.
In view of this, special deduction the present invention.
Summary of the invention
The object of the present invention is to provide the pharmaceutical composition of a kind of avocin and sodium-tazobactam, this pharmaceutical composition has stability height, the less advantage of polymer content, thereby has improved patient's drug safety.
For realizing purpose of the present invention, the present invention adopts following technical scheme:
The pharmaceutical composition of a kind of avocin and sodium-tazobactam, wherein, the mass ratio of avocin and sodium-tazobactam is 4～20:1 in the described pharmaceutical composition; Wherein said avocin is measured the X-ray powder diffraction collection of illustrative plates obtain as shown in Figure 1 with the powder X-ray diffraction algoscopy, and its chemical structural formula is suc as formula shown in (I):
Piperacillin is the improved seeds of the semi-synthetic beta-lactam antibiotic of the second filial generation, and Tazobactam Sodium is beta-lactamase inhibitor, strengthens and expanded the antimicrobial spectrum of piperacillin.The compound preparation of avocin and sodium-tazobactam belongs to antibiotics, causes anaphylaxis easily, causes erythra or anaphylactic shock, very harmful to the patient.A large amount of experiments and research confirms, and the type due to the beta-lactam antibiotic is not by due to the medicine itself, but relevant with the polymer that exists in the medicine.Existing research has shown that the polymer in the compound preparation of avocin and sodium-tazobactam is mainly derived from piperacillin.
In recent years, development along with crystal engineering, increasing pharmacy worker has turned one's attention to the research of medicine crystal formation, for some because of physicochemical property medicine not fully up to expectations, the crystal formation that changes medicine can improve its dissolubility to a certain extent, reduces fusing point, improves stability, reduce polymer content etc., improves its bioavailability then and improves preparation process.The present invention has made a kind of avocin that is different from the crystalline structure of prior art after the avocin crude drug has been carried out a large amount of research, and further measured the content of polymer in the avocin of the present invention and prior art by accelerated test and long term test, the polymer content of finding avocin of the present invention lower pleasantly surprisedly, and do not have significant change under accelerated test and long term test condition.And the pharmaceutical composition that adopts avocin of the present invention and sodium-tazobactam to form has equally that polymer content is lower, stability advantage preferably.
Among the present invention, the mass ratio of avocin part and sodium-tazobactam is 4～8:1 in the described pharmaceutical composition.
Preferably, the mass ratio of avocin part and sodium-tazobactam is 4:1 or 8:1 in the described pharmaceutical composition.
Described pharmaceutical composition is sterile powder injection.
Avocin is antibiotic commonly used clinically, belongs to penicillins.But because the appearance of fastbacteria, the therapeutic effect of avocin has been greatly diminished, and fastbacteria makes avocin forfeiture antibacterial ability by the secretion beta-lactamase.Sodium-tazobactam is beta-lactamase inhibitor, and avocin and sodium-tazobactam are united use, can produce the obvious synergistic effect.In order to reach best synergy, the weight ratio of avocin and sodium-tazobactam is 4～8:1 in the described sterile powder injection.As preferably, the weight ratio of avocin and sodium-tazobactam is 4:1 or 8:1 in the described sterile powder injection.For the ease of using recipe comprising piperacillin sodium and sodium-tazobactam 1.125～4.5g in the preferred per unit preparation clinically.
Among the present invention, the preparation method of described avocin is:
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with mixed solvent with the volume ratio of 3～5:1;
2) get the avocin crude drug, be dissolved in the mixed solvent of the isopropyl alcohol of step 1) and N-Methyl pyrrolidone, be stirred to whole dissolvings, get the piperacillin sodium solution;
3) under the condition of 3～8 ℃ of temperature, mixing speed 1800～2200r/min, with step 2) the piperacillin sodium solution join in the acetone, mix, form suspension;
4) treat suspension ageing 5～10min after, sucking filtration, the washing, then with filter cake in 40～45 ℃ of following vacuum dryings, obtain white crystalline powder, be described avocin.
The quality of the avocin crude drug in the above-mentioned preparation method, wherein, step 2) and the volume ratio of mixed solvent are 0.05～0.1g:1ml.
The volume ratio of the acetone described in the step 3) and piperacillin sodium solution is 18～22:1.
Material owing to influenced by various factors, makes in the molecule or the molecular linkage mode changes when crystallization, and it is different to cause molecule or atom to be arranged at lattice vacancy, forms different crystal structures.The inventor is after having carried out a large amount of research to the crude drug avocin, by changing the novel crystal forms chemical compound that recrystallisation solvent, crystallization condition etc. have made a kind of avocin, and pleasantly surprised find that the polymer content of this avocin is lower, and under accelerated test and long term test condition, there is not significant change.And the pharmaceutical composition that adopts avocin of the present invention and sodium-tazobactam to form has equally that polymer content is lower, stability advantage preferably.
The present invention also further provides described preparation of drug combination method.
Preparation method provided by the present invention comprises the steps:
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with mixed solvent with the volume ratio of 3～5:1;
2) get the avocin crude drug, be dissolved in the mixed solvent of the isopropyl alcohol of step 1) and N-Methyl pyrrolidone, be stirred to whole dissolvings, get the piperacillin sodium solution;
3) under the condition of 3～8 ℃ of temperature, mixing speed 1800～2200r/min, with step 2) the piperacillin sodium solution join in the acetone, mix, form suspension;
4) treat suspension ageing 5～10min after, sucking filtration, the washing, then with filter cake in 40～45 ℃ of following vacuum dryings, obtain white crystalline powder, be described avocin;
5) will go up the avocin that obtains of step and sodium-tazobactam mixes in proportion and obtains described pharmaceutical composition.
Among the present invention, described preparation method also comprises carries out the aseptic subpackaged sterile powder injection that obtains with described pharmaceutical composition.
Compared with prior art, the present invention has following advantage:
(1) polymer content of avocin provided by the present invention is lower, and does not have significant change under accelerated test and long term test condition;
(2) pharmaceutical composition of avocin provided by the present invention and sodium-tazobactam than prior art compare have that polymer content is lower, stability advantage preferably.
Description of drawings
The X-ray powder diffraction pattern of the avocin that Fig. 1 makes for the embodiment of the invention 1;
The specific embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
The preparation of embodiment 1, avocin
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with mixed solvent with the volume ratio of 3:1;
2) get avocin crude drug 100g, be dissolved in the mixed solvent of the isopropyl alcohol of 1000ml step 1) and N-Methyl pyrrolidone, be stirred to whole dissolvings, get the piperacillin sodium solution;
3) under the condition of 3 ℃ of temperature, mixing speed 2200r/min, with step 2) the piperacillin sodium solution join in the acetone (volume ratio of acetone and piperacillin sodium solution is 18:1), mix, form suspension;
4) treat suspension ageing 10min after, sucking filtration, the washing, then with filter cake in 45 ℃ of following vacuum dryings, obtain white crystalline powder, be described avocin.
The avocin of gained is measured the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 with the powder X-ray diffraction algoscopy.
The preparation of embodiment 2, avocin
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with mixed solvent with the volume ratio of 5:1;
2) get avocin crude drug 50g, be dissolved in the mixed solvent of the isopropyl alcohol of 1000ml step 1) and N-Methyl pyrrolidone, be stirred to whole dissolvings, get the piperacillin sodium solution;
3) under the condition of 8 ℃ of temperature, mixing speed 1800r/min, with step 2) the piperacillin sodium solution join in the acetone (volume ratio of acetone and piperacillin sodium solution is 22:1), mix, form suspension;
4) treat suspension ageing 5min after, sucking filtration, the washing, then with filter cake in 40 ℃ of following vacuum dryings, obtain white crystalline powder, be described avocin.
The avocin of gained is measured the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 with the powder X-ray diffraction algoscopy, consistent with embodiment 1.
The preparation of embodiment 3, avocin
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with mixed solvent with the volume ratio of 4:1;
2) get avocin crude drug 80g, be dissolved in the mixed solvent of the isopropyl alcohol of 1000ml step 1) and N-Methyl pyrrolidone, be stirred to whole dissolvings, get the piperacillin sodium solution;
3) under the condition of 6 ℃ of temperature, mixing speed 2000r/min, with step 2) the piperacillin sodium solution join in the acetone (volume ratio of acetone and piperacillin sodium solution is 20:1), mix, form suspension;
4) treat suspension ageing 8min after, sucking filtration, the washing, then with filter cake in 42 ℃ of following vacuum dryings, obtain white crystalline powder, be described avocin.
The avocin of gained is measured the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 with the powder X-ray diffraction algoscopy, consistent with embodiment 1.
The preparation of embodiment 4, avocin
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with mixed solvent with the volume ratio of 3.5:1;
2) get avocin crude drug 90g, be dissolved in the mixed solvent of the isopropyl alcohol of 1000ml step 1) and N-Methyl pyrrolidone, be stirred to whole dissolvings, get the piperacillin sodium solution;
3) under the condition of 5 ℃ of temperature, mixing speed 1950r/min, with step 2) the piperacillin sodium solution join in the acetone (volume ratio of acetone and piperacillin sodium solution is 19:1), mix, form suspension;
4) treat suspension ageing 6min after, sucking filtration, the washing, then with filter cake in 44 ℃ of following vacuum dryings, obtain white crystalline powder, be described avocin.
The avocin of gained is measured the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 with the powder X-ray diffraction algoscopy, consistent with embodiment 1.
The preparation of embodiment 5, avocin
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with mixed solvent with the volume ratio of 4.5:1;
2) get avocin crude drug 85g, be dissolved in the mixed solvent of the isopropyl alcohol of 1000ml step 1) and N-Methyl pyrrolidone, be stirred to whole dissolvings, get the piperacillin sodium solution;
3) under the condition of 7 ℃ of temperature, mixing speed 2100r/min, with step 2) the piperacillin sodium solution join in the acetone (volume ratio of acetone and piperacillin sodium solution is 21:1), mix, form suspension;
4) treat suspension ageing 9min after, sucking filtration, the washing, then with filter cake in 43 ℃ of following vacuum dryings, obtain white crystalline powder, be described avocin.
The avocin of gained is measured the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 with the powder X-ray diffraction algoscopy, consistent with embodiment 1.
The preparation of embodiment 6, avocin
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with mixed solvent with the volume ratio of 4.8:1;
2) get avocin crude drug 75g, be dissolved in the mixed solvent of the isopropyl alcohol of 1000ml step 1) and N-Methyl pyrrolidone, be stirred to whole dissolvings, get the piperacillin sodium solution;
3) under the condition of 4 ℃ of temperature, mixing speed 1880r/min, with step 2) the piperacillin sodium solution join in the acetone (volume ratio of acetone and piperacillin sodium solution is 19:1), mix, form suspension;
4) treat suspension ageing 7min after, sucking filtration, the washing, then with filter cake in 41 ℃ of following vacuum dryings, obtain white crystalline powder, be described avocin.
The avocin of gained is measured the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 with the powder X-ray diffraction algoscopy, consistent with embodiment 1.
It below is the FORMULATION EXAMPLE of piperacillin sodium injection sodium-tazobactam aseptic powder injection.
The preparation of FORMULATION EXAMPLE 1, piperacillin sodium injection sodium-tazobactam aseptic powder injection
The avocin that sodium-tazobactam crude drug and embodiment 1 are made mixes by the weight ratio of 4:1, packing under hundred grades of conditions of sterilizing room, and every bottle contains 1.125g, namely gets piperacillin sodium injection sodium-tazobactam sterile powder injection.
The preparation of FORMULATION EXAMPLE 2, piperacillin sodium injection sodium-tazobactam aseptic powder injection
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with mixed solvent with the volume ratio of 3:1;
2) get avocin crude drug 100g, be dissolved in the mixed solvent of the isopropyl alcohol of 1000ml step 1) and N-Methyl pyrrolidone, be stirred to whole dissolvings, get the piperacillin sodium solution;
3) under the condition of 3 ℃ of temperature, mixing speed 2200r/min, with step 2) the piperacillin sodium solution join in the acetone (volume ratio of acetone and piperacillin sodium solution is 18:1), mix, form suspension;
4) treat suspension ageing 10min after, sucking filtration, the washing, then with filter cake in 45 ℃ of following vacuum dryings, obtain white crystalline powder, be described avocin;
5) avocin that sodium-tazobactam and last step are made mixes by the weight ratio of 4:1, packing under hundred grades of conditions of sterilizing room, and every bottle contains 3.375g, namely gets piperacillin sodium injection sodium-tazobactam sterile powder injection.
The preparation of FORMULATION EXAMPLE 3, piperacillin sodium injection sodium-tazobactam aseptic powder injection
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with mixed solvent with the volume ratio of 5:1;
2) get avocin crude drug 50g, be dissolved in the mixed solvent of the isopropyl alcohol of 1000ml step 1) and N-Methyl pyrrolidone, be stirred to whole dissolvings, get the piperacillin sodium solution;
3) under the condition of 8 ℃ of temperature, mixing speed 1800r/min, with step 2) the piperacillin sodium solution join in the acetone (volume ratio of acetone and piperacillin sodium solution is 22:1), mix, form suspension;
4) treat suspension ageing 5min after, sucking filtration, the washing, then with filter cake in 40 ℃ of following vacuum dryings, obtain white crystalline powder, be described avocin;
5) avocin that sodium-tazobactam and last step are made mixes by the weight ratio of 8:1, packing under hundred grades of conditions of sterilizing room, and every bottle contains 2.25g, namely gets piperacillin sodium injection sodium-tazobactam sterile powder injection.
The preparation of FORMULATION EXAMPLE 4, piperacillin sodium injection sodium-tazobactam aseptic powder injection
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with mixed solvent with the volume ratio of 3.5:1;
2) get avocin crude drug 90g, be dissolved in the mixed solvent of the isopropyl alcohol of 1000ml step 1) and N-Methyl pyrrolidone, be stirred to whole dissolvings, get the piperacillin sodium solution;
3) under the condition of 5 ℃ of temperature, mixing speed 1950r/min, with step 2) the piperacillin sodium solution join in the acetone (volume ratio of acetone and piperacillin sodium solution is 19:1), mix, form suspension;
4) treat suspension ageing 6min after, sucking filtration, the washing, then with filter cake in 44 ℃ of following vacuum dryings, obtain white crystalline powder, be described avocin;
5) avocin that sodium-tazobactam and last step are made mixes by the weight ratio of 8:1, packing under hundred grades of conditions of sterilizing room, namely get piperacillin sodium injection sodium-tazobactam sterile powder injection, the per unit injectable powder contains 4.5g avocin and sodium-tazobactam.
Below by test example illustrate avocin of the present invention and with the beneficial effect of the sterile powder for injection pin of sodium-tazobactam.
Test example 1
This test example detects related substance in the prepared avocin of the embodiment of the invention, this test is carried out according to 2010 editions second appendix VIII P of Chinese Pharmacopoeia residual solvent algoscopy, appendix XIX F medicine impurity analysis guideline, and it the results are shown in Table 1:
The assay of table 1, related substance
| Sample | Isopropyl alcohol | N-Methyl pyrrolidone | Propanol | Other related substance |
| Embodiment 1 product | Up to specification | Up to specification | Up to specification | Up to specification |
| Embodiment 2 products | Up to specification | Up to specification | Up to specification | Up to specification |
| Embodiment 3 products | Up to specification | Up to specification | Up to specification | Up to specification |
| Embodiment 4 products | Up to specification | Up to specification | Up to specification | Up to specification |
| Embodiment 5 products | Up to specification | Up to specification | Up to specification | Up to specification |
| Embodiment 6 products | Up to specification | Up to specification | Up to specification | Up to specification |
Test example 2
This test example is investigated the polymer content of the avocin of the present invention and prior art.
1, instrument and sample
AE240 type electronic balance (Switzerland METTLER-TOLEDO); AK-TAprime Plus type macromolecule impurity analyser (Sweden GE HealthCare).
Test specimen 1: the avocin that the embodiment of the invention 1 makes;
Test specimen 2: the avocin that the embodiment of the invention 2 makes;
Test specimen 3: the avocin that the embodiment of the invention 3 makes;
Control sample 1: Jiangsu Hai Hong pharmaceutical Co. Ltd, the institute for drug control, Jiangsu Province provides;
Control sample 2: the avocin highly finished product that obtain according to the embodiment 4 of CN102807572A " avocin crude product refining " method;
Control sample 3: according to " new technique for synthesizing of avocin " [Li Zhonghua. the new technique for synthesizing of avocin [J], Mountain Western Medicine S University's journal, 2002,33(4): the 333-334 avocin that makes of] new technology.
Piperacillin reference substance: provided by Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
2, chromatographic condition
With sephadex G-10(40～120 μ m) be filler, glass column internal diameter 1.0～1.4cm, column length 30～40cm, mobile phase A is the 0.1mol/L phosphate buffer ［ 0.1mol/L disodium phosphate soln-0.1mol/L sodium dihydrogen phosphate (95:5) ］ of pH8.0, Mobile phase B is water, flow velocity is 1.5ml/min, and the detection wavelength is 254nm.
3, assay method
3.1 the preparation of contrast solution
Get the about 20mg of piperacillin reference substance, the accurate title, decide, and puts in the 200ml measuring bottle, and after ethanol 10ml dissolving, thin up is made the solution that contains 0.1mg among every 1ml approximately, in contrast solution to scale.
3.2 the preparation of need testing solution
It is an amount of to get this product content, mixing, and precision takes by weighing in right amount (being equivalent to piperacillin 0.2g approximately), puts in the 10ml measuring bottle, is dissolved in water and is diluted to scale, shakes up, as need testing solution.
3.3 algoscopy
Precision is measured need testing solution 100～200 μ l injecting chromatographs, is that mobile phase is measured with the mobile phase A, the record chromatogram.Precision is measured contrast solution 100～200 μ l injecting chromatographs in addition, is mobile phase with the Mobile phase B, measures with method.With calculated by peak area, the recipe comprising piperacillin polymer must not cross 0.3% in piperacillin by external standard method.
4, the investigation of piperacillin sodium polymer
4.1 accelerated test is investigated
With above-mentioned test specimen and control sample simulation listing packing, put into temperature and be (40 ± 2) ℃, the relative humidity biochemical incubator for (75 ± 5) %, regularly take a sample during respectively at 0,1,2,3,6 month, according to " 3 assay method " down algoscopy measure polymer content, and compare analysis with 0 month data.The results are shown in Table 2.
Table 2, accelerated test sample polymer measurement result
| ? | 0 month | January | February | March | June |
| Test specimen 1 | 0.005％ | 0.006％ | 0.007％ | 0.008％ | 0.008％ |
| Test specimen 2 | 0.006％ | 0.007％ | 0.007％ | 0.008％ | 0.008％ |
| Test specimen 3 | 0.005％ | 0.006％ | 0.007％ | 0.007％ | 0.008％ |
| Control sample 1 | 0.39％ | 0.42％ | 0.48％ | 0.53％ | 0.59％ |
| Control sample 2 | 0.05％ | 0.12％ | 0.17％ | 0.23％ | 0.29％ |
| Control sample 3 | 0.41％ | 0.49％ | 0.56％ | 0.61％ | 0.69％ |
4.2 long term test is investigated
With above-mentioned test specimen and control sample simulation listing packing, be that (25 ± 5) ℃, relative humidity are for placing 12 months under the condition of (60 ± 10) % in temperature, sampling during respectively at 0,3,6,9,12 month, according to " 3 assay method " down algoscopy measure polymer content, and compare analysis with 0 month data.The results are shown in Table 3.
Table 3, long term test sample polymer measurement result
| ? | 0 month | March | June | JIUYUE | December |
| Test specimen 1 | 0.005％ | 0.007％ | 0.008％ | 0.009％ | 0.010％ |
| Test specimen 2 | 0.006％ | 0.007％ | 0.007％ | 0.008％ | 0.010％ |
| Test specimen 3 | 0.005％ | 0.006％ | 0.007％ | 0.007％ | 0.009％ |
| Control sample 1 | 0.39% | 0.48% | 0.56% | 0.63% | 0.69% |
| Control sample 2 | 0.05％ | 0.17％ | 0.26％ | 0.33％ | 0.36％ |
| Control sample 3 | 0.41％ | 0.52％ | 0.59％ | 0.67％ | 0.73％ |
5, conclusion
From accelerated test and long term test sample polymer measurement result as can be seen, the polymer content of avocin of the present invention is significantly less than the avocin of prior art, and under accelerated test and long term test condition, the polymer content of avocin of the present invention does not have significant change.
The prepared avocin of other embodiment of the present invention has also been carried out above-mentioned test, and the result of its acquisition is similar.
Test example 3
This test example is investigated the stability of the piperacillin sodium injection sodium-tazobactam aseptic powder injection of the present invention and prior art.
Test specimen: the piperacillin sodium injection sodium-tazobactam aseptic powder injection that FORMULATION EXAMPLE 1 of the present invention makes;
Control sample 1: according to the piperacillin sodium injection sodium-tazobactam aseptic powder injection that the method for the embodiment of the invention 1 makes, difference is that avocin is the avocin highly finished product that embodiment 4 " the avocin crude product refining " method according to CN102807572A obtains.
Control sample 2: the piperacillin sodium and tazobactam sodium compound recipe injectable powder of the 4:1 that makes according to the method for the embodiment 1 of CN101265263A.
1, accelerated test
With above-mentioned test specimen and control sample simulation listing packing, put into temperature and be (40 ± 2) ℃, the relative humidity biochemical incubator for (75 ± 5) %, regularly take a sample during respectively at 0,1,2,3,6 month, carry out quality examination, and compare analysis with 0 month data.The results are shown in Table 4.
Table 4, accelerated test result
4.2 long term test
With above-mentioned test specimen and control sample simulation listing packing, be that (25 ± 5) ℃, relative humidity are for placing 12 months under the condition of (60 ± 10) % in temperature, quality examination is carried out in sampling during respectively at 0,3,6,9,12 month, and compares analysis with 0 month data.The results are shown in Table 5.
Table 5, long-term test results
From above-mentioned result of the test as can be seen, compare than prior art, piperacillin sodium injection sodium-tazobactam aseptic powder injection of the present invention has significantly reduced polymer content and advantages of excellent stability more.
The prepared piperacillin sodium injection sodium-tazobactam of other embodiment of the present invention aseptic powder injection has also been carried out above-mentioned test, and the result of its acquisition is similar.
Claims (10)
1. the pharmaceutical composition of an avocin and sodium-tazobactam is characterized in that the mass ratio of avocin and sodium-tazobactam is 4～20:1 in the described pharmaceutical composition; Wherein said avocin is measured the X-ray powder diffraction collection of illustrative plates obtain as shown in Figure 1 with the powder X-ray diffraction algoscopy, and its chemical structural formula is suc as formula shown in (I):
2. pharmaceutical composition according to claim 1 is characterized in that, the mass ratio of avocin part and sodium-tazobactam is 4～8:1 in the described pharmaceutical composition.
3. pharmaceutical composition according to claim 2 is characterized in that, the mass ratio of avocin part and sodium-tazobactam is 4:1 in the described pharmaceutical composition.
4. pharmaceutical composition according to claim 2 is characterized in that, the mass ratio of avocin part and sodium-tazobactam is 8:1 in the described pharmaceutical composition.
5. according to any described pharmaceutical composition of claim 1-4, it is characterized in that described pharmaceutical composition is sterile powder injection.
6. according to any described pharmaceutical composition of claim 1-5, it is characterized in that the preparation method of described avocin is:
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with mixed solvent with the volume ratio of 3～5:1;
2) get the avocin crude drug, be dissolved in the mixed solvent of the isopropyl alcohol of step 1) and N-Methyl pyrrolidone, be stirred to whole dissolvings, get the piperacillin sodium solution;
3) under the condition of 3～8 ℃ of temperature, mixing speed 1800～2200r/min, with step 2) the piperacillin sodium solution join in the acetone, mix, form suspension;
4) treat suspension ageing 5～10min after, sucking filtration, the washing, then with filter cake in 40～45 ℃ of following vacuum dryings, obtain white crystalline powder, be described avocin.
7. pharmaceutical composition according to claim 6 is characterized in that step 2) described in the quality of avocin crude drug and the volume ratio of mixed solvent be 0.05～0.1g:1ml.
8. pharmaceutical composition according to claim 6 is characterized in that, the volume ratio of the acetone described in the step 3) and piperacillin sodium solution is 18～22:1.
9. any described preparation of drug combination method of claim 1-8 is characterized in that described preparation method comprises the steps:
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with mixed solvent with the volume ratio of 3～5:1;
2) get the avocin crude drug, be dissolved in the mixed solvent of the isopropyl alcohol of step 1) and N-Methyl pyrrolidone, be stirred to whole dissolvings, get the piperacillin sodium solution;
3) under the condition of 3～8 ℃ of temperature, mixing speed 1800～2200r/min, with step 2) the piperacillin sodium solution join in the acetone, mix, form suspension;
4) treat suspension ageing 5～10min after, sucking filtration, the washing, then with filter cake in 40～45 ℃ of following vacuum dryings, obtain white crystalline powder, be described avocin;
5) will go up the avocin that obtains of step and sodium-tazobactam mixes in proportion and obtains described pharmaceutical composition.
10. preparation method according to claim 9 is characterized in that, described preparation method also comprises carries out the aseptic subpackaged sterile powder injection that obtains with described pharmaceutical composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310291049.2A CN103340866B (en) | 2013-07-11 | 2013-07-11 | Piperacillin sodium-tazobactam sodium medicine composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310291049.2A CN103340866B (en) | 2013-07-11 | 2013-07-11 | Piperacillin sodium-tazobactam sodium medicine composition and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103340866A true CN103340866A (en) | 2013-10-09 |
| CN103340866B CN103340866B (en) | 2014-08-06 |
Family
ID=49275728
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310291049.2A Active CN103340866B (en) | 2013-07-11 | 2013-07-11 | Piperacillin sodium-tazobactam sodium medicine composition and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103340866B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104644637A (en) * | 2015-01-27 | 2015-05-27 | 华北制药股份有限公司 | Piperacillin sodium tazobactam sodium preparation for injection and preparation method thereof |
| CN105616415A (en) * | 2016-01-15 | 2016-06-01 | 齐鲁天和惠世制药有限公司 | Preparation method of piperacillin sodium and tazobactam sodium for injection |
| CN107942004A (en) * | 2017-11-24 | 2018-04-20 | 深圳市华星光电技术有限公司 | For dissolving the double solvents and liquid crystal test method of liquid crystal |
| CN112409381A (en) * | 2020-12-03 | 2021-02-26 | 山东安信制药有限公司 | Piperacillin sodium and tazobactam sodium co-amorphous substance and preparation method thereof |
| CN113209030A (en) * | 2021-04-27 | 2021-08-06 | 海南通用康力制药有限公司 | Preparation method of piperacillin sodium and tazobactam sodium sterile powder injection |
| CN115554298A (en) * | 2021-07-01 | 2023-01-03 | 北京诺康达医药科技股份有限公司 | Tazobactam and piperacillin combined preparation and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101265263A (en) * | 2008-05-12 | 2008-09-17 | 海南百那医药发展有限公司 | Method for producing piperacillin sodium tazobactam sodium compound injection |
-
2013
- 2013-07-11 CN CN201310291049.2A patent/CN103340866B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101265263A (en) * | 2008-05-12 | 2008-09-17 | 海南百那医药发展有限公司 | Method for producing piperacillin sodium tazobactam sodium compound injection |
Non-Patent Citations (1)
| Title |
|---|
| 刘俊华等: "注射用哌拉西林钠他唑巴坦钠（4:1）聚合物测定方法研究", 《今日药学》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104644637A (en) * | 2015-01-27 | 2015-05-27 | 华北制药股份有限公司 | Piperacillin sodium tazobactam sodium preparation for injection and preparation method thereof |
| CN104644637B (en) * | 2015-01-27 | 2017-11-10 | 华北制药股份有限公司 | A kind of piperacillin sodium and tazobactam sodium for injection preparation and preparation method thereof |
| CN105616415A (en) * | 2016-01-15 | 2016-06-01 | 齐鲁天和惠世制药有限公司 | Preparation method of piperacillin sodium and tazobactam sodium for injection |
| CN107942004A (en) * | 2017-11-24 | 2018-04-20 | 深圳市华星光电技术有限公司 | For dissolving the double solvents and liquid crystal test method of liquid crystal |
| CN112409381A (en) * | 2020-12-03 | 2021-02-26 | 山东安信制药有限公司 | Piperacillin sodium and tazobactam sodium co-amorphous substance and preparation method thereof |
| CN113209030A (en) * | 2021-04-27 | 2021-08-06 | 海南通用康力制药有限公司 | Preparation method of piperacillin sodium and tazobactam sodium sterile powder injection |
| CN113209030B (en) * | 2021-04-27 | 2023-04-25 | 海南通用康力制药有限公司 | Preparation method of piperacillin sodium and tazobactam sodium sterile powder injection |
| CN115554298A (en) * | 2021-07-01 | 2023-01-03 | 北京诺康达医药科技股份有限公司 | Tazobactam and piperacillin combined preparation and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103340866B (en) | 2014-08-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103340866B (en) | Piperacillin sodium-tazobactam sodium medicine composition and preparation method thereof | |
| CN101411710A (en) | Pemetrexed disodium freeze-dried injection and preparation method thereof | |
| CN102526040B (en) | Method for preparing composition of mezlocillin sodium and sulbactam sodium for injection in ratio of 4: 1 | |
| CN103553996A (en) | Anticholinergic pharmaceutical composition | |
| CN102784382A (en) | Argatroban drug composition and preparation method and application of argatroban drug composition | |
| CN105193819A (en) | Medicine cefotiam hydrochloride composition for treating bacterial infection | |
| CN106474048A (en) | A kind of more stable desonide gel preparation of quality | |
| CN105168224B (en) | A kind of fasudil hydrochloride injection and preparation method thereof | |
| CN105147599B (en) | Netilmicin sulfate injection and preparation method | |
| CN101592637A (en) | A kind of detection method of new compound CTX sodium-tazobactam sodium | |
| CN103536566A (en) | Ramosetron hydrochloride injection and preparation method thereof | |
| CN104922126B (en) | A kind of piperacillin sodium and tazobactam sodium sterile powder injection and preparation method thereof | |
| CN101642429A (en) | Method for preparing stable rifamycin sodium injection and rifamycin sodium and sodium chloride (glucose) injection | |
| AU2012389714B2 (en) | Cocrystal of piperacillin sodium and sulbactam sodium and preparation method thereof, as well as pharmaceutical compositions containing same and uses thereof | |
| CN102973569A (en) | Pharmaceutical composition with cefminox sodium sterile mixed powder form | |
| CN105213301B (en) | Netilmicin sulfate injection and its quality control method | |
| CN103304604B (en) | Clindamycin phosphate compound and preparation method and pharmaceutical composition thereof | |
| CN109745546A (en) | Isotonic composition and preparation method thereof for improving teicopanin for injection stability | |
| CN107789324A (en) | A kind of injection De Lasha star meglumines and preparation method thereof | |
| CN103222953B (en) | Fasudil hydrochloride injection composition and its preparation method | |
| CN103655460B (en) | Injection medicinal composition containing aztreonam, as well as preparation method and application thereof | |
| CN103040758B (en) | A kind of pharmaceutical composition containing cefathiamidine compound and preparation method thereof | |
| CN103142616B (en) | Pharmaceutical composition for improving pharmaceutical stability | |
| CN104758242A (en) | Sodium fusidate ointment medicine composition and preparing method thereof | |
| CN103877016B (en) | Pharmaceutical composition of naloxone hydrochloride injection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20131009 Assignee: Hainan General Sanyang Pharmaceutical Co., Ltd. Assignor: Sichuan Province Huida Pharmaceutical Co., Ltd. Contract record no.: 2015460000017 Denomination of invention: Piperacillin sodium-tazobactam sodium medicine composition and preparation method thereof Granted publication date: 20140806 License type: Exclusive License Record date: 20151216 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160226 Address after: 570312 Hainan Province, Haikou City Xiuying District No. 8 Haililu Patentee after: Hainan General Sanyang Pharmaceutical Co., Ltd. Address before: 610015, No. 5, building 39, pharmaceutical building, 502-509 Dongsheng street, Qingyang District, Sichuan, Chengdu Patentee before: Sichuan Province Huida Pharmaceutical Co., Ltd. |