CN103340866B - Piperacillin sodium-tazobactam sodium medicine composition and preparation method thereof - Google Patents
Piperacillin sodium-tazobactam sodium medicine composition and preparation method thereof Download PDFInfo
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- CN103340866B CN103340866B CN201310291049.2A CN201310291049A CN103340866B CN 103340866 B CN103340866 B CN 103340866B CN 201310291049 A CN201310291049 A CN 201310291049A CN 103340866 B CN103340866 B CN 103340866B
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- avocin
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- tazobactam
- piperacillin
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- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 239000003814 drug Substances 0.000 title claims abstract description 38
- 239000000203 mixture Substances 0.000 title claims abstract description 30
- 229960002292 piperacillin Drugs 0.000 title abstract description 16
- 229960000373 tazobactam sodium Drugs 0.000 title abstract description 6
- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 title 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 claims abstract description 77
- 229960005264 piperacillin sodium Drugs 0.000 claims abstract description 62
- 238000002347 injection Methods 0.000 claims abstract description 41
- 239000007924 injection Substances 0.000 claims abstract description 41
- 239000000843 powder Substances 0.000 claims abstract description 39
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 19
- 239000000126 substance Substances 0.000 claims abstract description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 81
- 229960003865 tazobactam Drugs 0.000 claims description 51
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 48
- 239000000243 solution Substances 0.000 claims description 44
- 239000008194 pharmaceutical composition Substances 0.000 claims description 32
- 239000012046 mixed solvent Substances 0.000 claims description 28
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 26
- 239000000725 suspension Substances 0.000 claims description 26
- 229940079593 drug Drugs 0.000 claims description 23
- 230000032683 aging Effects 0.000 claims description 13
- 239000012065 filter cake Substances 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 13
- 238000001291 vacuum drying Methods 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 13
- 238000012360 testing method Methods 0.000 abstract description 50
- 229920000642 polymer Polymers 0.000 abstract description 29
- 230000007774 longterm Effects 0.000 abstract description 11
- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical compound COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 abstract description 4
- 238000000691 measurement method Methods 0.000 abstract 1
- 230000033228 biological regulation Effects 0.000 description 24
- 239000013068 control sample Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 10
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- 239000000523 sample Substances 0.000 description 7
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- 238000003359 percent control normalization Methods 0.000 description 6
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- 150000001875 compounds Chemical class 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
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- TUPFOYXHAYOHIB-YCAIQWGJSA-M sodium;(2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]h Chemical compound [Na+].C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 TUPFOYXHAYOHIB-YCAIQWGJSA-M 0.000 description 5
- 208000003455 anaphylaxis Diseases 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000003781 beta lactamase inhibitor Substances 0.000 description 4
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 4
- 238000004088 simulation Methods 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- 206010002199 Anaphylactic shock Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 150000002960 penicillins Chemical class 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000002132 β-lactam antibiotic Substances 0.000 description 2
- 229940124586 β-lactam antibiotics Drugs 0.000 description 2
- AHORDIWXQNKXEY-UHFFFAOYSA-N 1-methylpyrrolidin-2-one;propan-1-ol Chemical compound CCCO.CN1CCCC1=O AHORDIWXQNKXEY-UHFFFAOYSA-N 0.000 description 1
- WFIYPADYPQQLNN-UHFFFAOYSA-N 2-[2-(4-bromopyrazol-1-yl)ethyl]isoindole-1,3-dione Chemical compound C1=C(Br)C=NN1CCN1C(=O)C2=CC=CC=C2C1=O WFIYPADYPQQLNN-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 208000010216 atopic IgE responsiveness Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
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- 230000018109 developmental process Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 239000000945 filler Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000000837 restrainer Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
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.Due to the reason such as life-time service and improper use of piperacillin, the therapeutic effect of piperacillin just constantly declines, and this has affected the application of piperacillin to a great extent.Sodium-tazobactam is lactamase restrainer, belongs to the antibacterial strong synergist of the third generation, share and can strengthen the drug effect of the two and extend action time with piperacillin or cefoperazone.Sodium-tazobactam is combined with avocin while use, produce obvious synergism, 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., there is antimicrobial spectrum and indication widely than other the antibacterial complexing agent having used, shown huge advantage overcoming aspect drug resistance.
Piperacillin sodium and tazobactam sodium compound preparation domestic existing sale at present, is sterilized powder direct packaging and makes, and it exists a common defect 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 with the weight ratio raw material of 3-4: 0.8-1.2 by avocin and sodium-tazobactam.
Patent documentation CN101265263A has disclosed a kind of employing column chromatography and has prepared high-purity avocin and sodium-tazobactam, is then made into the method for compound recipe injectable powder.
Patent documentation CN101269072A discloses a kind of pharmaceutical composition containing beta-lactamase inhibitor and avocin and preparation method thereof, and described compositions is 1-100 by weight proportion: 1: avocin, beta-lactamase inhibitor and the pH value regulator of 0.001-2 form.
Piperacillin sodium and tazobactam sodium compound preparation described in above-mentioned publication and the same poor defect of preparation stability that exists 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, easily cause anaphylaxis, cause erythra or anaphylactic shock, very harmful to patient.But causing anaphylactoid main allergen is clinically not medicine itself, but due to the polymer existing in 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 piperacillin sodium injection sodium-tazobactam is mainly derived from piperacillin.Therefore, strictly control polymer in avocin crude drug content, improve its stability the quality and the clinical drug safety that ensure piperacillin sodium injection Tazobactam Sodium preparation of sodium seemed to 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 advantages of that stability is high, polymer content is less, thereby has improved patient's drug safety.
For realizing object of the present invention, the present invention adopts following technical scheme:
A pharmaceutical composition for avocin and sodium-tazobactam, wherein, in described pharmaceutical composition, the mass ratio of avocin and sodium-tazobactam is 4～20:1; Wherein said avocin is measured the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 by powder X-ray diffraction algoscopy, its chemical structural formula as shown in the formula (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, easily causes anaphylaxis, causes erythra or anaphylactic shock, very harmful to patient.Great many of experiments and research confirms, and the type Ⅰ hypersensitivity reaction due to beta-lactam antibiotic is not by due to medicine itself, but relevant with the polymer existing in 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, along with the development of crystal engineering, increasing pharmacy worker has turned one's attention to the research of drug crystal forms, for some because of physicochemical property medicine not fully up to expectations, the crystal formation that changes medicine can improve to a certain extent its dissolubility, reduces fusing point, improves stability, reduce polymer content etc., then improves its bioavailability and improves preparation process.The present invention has made a kind of avocin of the crystalline structure that is different from prior art after avocin crude drug has been carried out to a large amount of research, and further measure 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 under accelerated test and long term test condition without significant change.Have that polymer content is lower, the good advantage of stability and the pharmaceutical composition that adopts avocin of the present invention and sodium-tazobactam composition is same.
In the present invention, in described pharmaceutical composition, the mass ratio of avocin part and sodium-tazobactam is 4～8:1.
Preferably, in described pharmaceutical composition, the mass ratio of avocin part and sodium-tazobactam is 4:1 or 8:1.
Described pharmaceutical composition is sterile powder injection.
Avocin is the antibiotic of commonly using clinically, belongs to penicillins.But due to the appearance of fastbacteria, the therapeutic effect of avocin has been greatly diminished, fastbacteria makes avocin lose antibacterial ability by secretion beta-lactamase.Sodium-tazobactam is beta-lactamase inhibitor, and avocin and sodium-tazobactam are combined use, can produce obvious synergism.In order to reach best synergy, in described sterile powder injection, the weight ratio of avocin and sodium-tazobactam is 4～8:1.As preferably, in described sterile powder injection, the weight ratio of avocin and sodium-tazobactam is 4:1 or 8:1.For the ease of using clinically, preferably recipe comprising piperacillin sodium and sodium-tazobactam 1.125～4.5g in per unit preparation.
In the present invention, the preparation method of described avocin is:
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with to mixed solvent with the volume ratio of 3～5:1;
2) get avocin crude drug, be dissolved in the isopropyl alcohol of step 1) and the mixed solvent of N-Methyl pyrrolidone, be stirred to whole dissolvings, obtain piperacillin sodium solution;
3) under the condition of 3～8 DEG C of temperature, mixing speed 1800～2200r/min, by step 2) piperacillin sodium solution join in acetone, mix, form suspension;
4) after suspension ageing 5～10min, sucking filtration, washing, then, by filter cake vacuum drying at 40～45 DEG C, obtains white crystalline powder, is described avocin.
In above-mentioned preparation method, wherein, step 2) described in the quality of avocin crude drug and the volume ratio of mixed solvent be 0.05～0.1g:1ml.
The volume ratio of the acetone described in step 3) and piperacillin sodium solution is 18～22:1.
Material owing to affected by various factors, makes in molecule or molecular linkage mode changes in the time of crystallization, causes molecule or atom to be arranged at lattice vacancy different, forms different crystal structures.The inventor is carrying out after a large amount of research crude drug avocin, made a kind of novel crystal forms compound of avocin by changing recrystallisation solvent, crystallization condition etc., and pleasantly surprised find that the polymer content of this avocin is lower, and under accelerated test and long term test condition without significant change.Have that polymer content is lower, the good advantage of stability and the pharmaceutical composition that adopts avocin of the present invention and sodium-tazobactam composition is same.
The preparation method of the pharmaceutical composition described in the present invention also further provides.
Preparation method provided by the present invention comprises the steps:
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with to mixed solvent with the volume ratio of 3～5:1;
2) get avocin crude drug, be dissolved in the isopropyl alcohol of step 1) and the mixed solvent of N-Methyl pyrrolidone, be stirred to whole dissolvings, obtain piperacillin sodium solution;
3) under the condition of 3～8 DEG C of temperature, mixing speed 1800～2200r/min, by step 2) piperacillin sodium solution join in acetone, mix, form suspension;
4) after suspension ageing 5～10min, sucking filtration, washing, then, by filter cake vacuum drying at 40～45 DEG C, obtains white crystalline powder, is described avocin;
5) avocin upper step being obtained and sodium-tazobactam are mixed to get described pharmaceutical composition in proportion.
In the present invention, described preparation method also comprises carries out the aseptic subpackaged sterile powder injection that obtains by described pharmaceutical composition.
Compared with prior art, tool of the present invention has the following advantages:
(1) polymer content of avocin provided by the present invention is lower, and under accelerated test and long term test condition without significant change;
(2) polymer content is lower, the good advantage of stability compared with having compared with prior art for the pharmaceutical composition of avocin provided by the present invention and sodium-tazobactam.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction pattern of the avocin that makes of the embodiment of the present invention 1;
Detailed description of the invention
Be below the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, instead of restriction the present invention.
The preparation of embodiment 1, avocin
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with to mixed solvent with the volume ratio of 3:1;
2) get avocin crude drug 100g, be dissolved in the isopropyl alcohol of 1000ml step 1) and the mixed solvent of N-Methyl pyrrolidone, be stirred to whole dissolvings, obtain piperacillin sodium solution;
3) under the condition of 3 DEG C of temperature, mixing speed 2200r/min, by step 2) piperacillin sodium solution join in acetone (volume ratio of acetone and piperacillin sodium solution is 18:1), mix, form suspension;
4) after suspension ageing 10min, sucking filtration, washing, then, by filter cake vacuum drying at 45 DEG C, obtains white crystalline powder, is described avocin.
The avocin of gained is measured to the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 by powder X-ray diffraction algoscopy.
The preparation of embodiment 2, avocin
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with to mixed solvent with the volume ratio of 5:1;
2) get avocin crude drug 50g, be dissolved in the isopropyl alcohol of 1000ml step 1) and the mixed solvent of N-Methyl pyrrolidone, be stirred to whole dissolvings, obtain piperacillin sodium solution;
3) under the condition of 8 DEG C of temperature, mixing speed 1800r/min, by step 2) piperacillin sodium solution join in acetone (volume ratio of acetone and piperacillin sodium solution is 22:1), mix, form suspension;
4) after suspension ageing 5min, sucking filtration, washing, then, by filter cake vacuum drying at 40 DEG C, obtains white crystalline powder, is described avocin.
The avocin of gained is measured to the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 by 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 to mixed solvent with the volume ratio of 4:1;
2) get avocin crude drug 80g, be dissolved in the isopropyl alcohol of 1000ml step 1) and the mixed solvent of N-Methyl pyrrolidone, be stirred to whole dissolvings, obtain piperacillin sodium solution;
3) under the condition of 6 DEG C of temperature, mixing speed 2000r/min, by step 2) piperacillin sodium solution join in acetone (volume ratio of acetone and piperacillin sodium solution is 20:1), mix, form suspension;
4) after suspension ageing 8min, sucking filtration, washing, then, by filter cake vacuum drying at 42 DEG C, obtains white crystalline powder, is described avocin.
The avocin of gained is measured to the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 by 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 to mixed solvent with the volume ratio of 3.5:1;
2) get avocin crude drug 90g, be dissolved in the isopropyl alcohol of 1000ml step 1) and the mixed solvent of N-Methyl pyrrolidone, be stirred to whole dissolvings, obtain piperacillin sodium solution;
3) under the condition of 5 DEG C of temperature, mixing speed 1950r/min, by step 2) piperacillin sodium solution join in acetone (volume ratio of acetone and piperacillin sodium solution is 19:1), mix, form suspension;
4) after suspension ageing 6min, sucking filtration, washing, then, by filter cake vacuum drying at 44 DEG C, obtains white crystalline powder, is described avocin.
The avocin of gained is measured to the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 by 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 to mixed solvent with the volume ratio of 4.5:1;
2) get avocin crude drug 85g, be dissolved in the isopropyl alcohol of 1000ml step 1) and the mixed solvent of N-Methyl pyrrolidone, be stirred to whole dissolvings, obtain piperacillin sodium solution;
3) under the condition of 7 DEG C of temperature, mixing speed 2100r/min, by step 2) piperacillin sodium solution join in acetone (volume ratio of acetone and piperacillin sodium solution is 21:1), mix, form suspension;
4) after suspension ageing 9min, sucking filtration, washing, then, by filter cake vacuum drying at 43 DEG C, obtains white crystalline powder, is described avocin.
The avocin of gained is measured to the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 by 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 to mixed solvent with the volume ratio of 4.8:1;
2) get avocin crude drug 75g, be dissolved in the isopropyl alcohol of 1000ml step 1) and the mixed solvent of N-Methyl pyrrolidone, be stirred to whole dissolvings, obtain piperacillin sodium solution;
3) under the condition of 4 DEG C of temperature, mixing speed 1880r/min, by step 2) piperacillin sodium solution join in acetone (volume ratio of acetone and piperacillin sodium solution is 19:1), mix, form suspension;
4) after suspension ageing 7min, sucking filtration, washing, then, by filter cake vacuum drying at 41 DEG C, obtains white crystalline powder, is described avocin.
The avocin of gained is measured to the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 by powder X-ray diffraction algoscopy, consistent with embodiment 1.
It is below the example of formulations of piperacillin sodium injection sodium-tazobactam aseptic powder injection.
The preparation of example of formulations 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, subpackage under hundred grades of conditions of sterilizing room, and every bottle containing 1.125g, obtains piperacillin sodium injection sodium-tazobactam sterile powder injection.
The preparation of example of formulations 2, piperacillin sodium injection sodium-tazobactam aseptic powder injection
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with to mixed solvent with the volume ratio of 3:1;
2) get avocin crude drug 100g, be dissolved in the isopropyl alcohol of 1000ml step 1) and the mixed solvent of N-Methyl pyrrolidone, be stirred to whole dissolvings, obtain piperacillin sodium solution;
3) under the condition of 3 DEG C of temperature, mixing speed 2200r/min, by step 2) piperacillin sodium solution join in acetone (volume ratio of acetone and piperacillin sodium solution is 18:1), mix, form suspension;
4) after suspension ageing 10min, sucking filtration, washing, then, by filter cake vacuum drying at 45 DEG C, obtains white crystalline powder, is described avocin;
5) avocin sodium-tazobactam and upper step being made mixes by the weight ratio of 4:1, subpackage under hundred grades of conditions of sterilizing room, and every bottle containing 3.375g, obtains piperacillin sodium injection sodium-tazobactam sterile powder injection.
The preparation of example of formulations 3, piperacillin sodium injection sodium-tazobactam aseptic powder injection
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with to mixed solvent with the volume ratio of 5:1;
2) get avocin crude drug 50g, be dissolved in the isopropyl alcohol of 1000ml step 1) and the mixed solvent of N-Methyl pyrrolidone, be stirred to whole dissolvings, obtain piperacillin sodium solution;
3) under the condition of 8 DEG C of temperature, mixing speed 1800r/min, by step 2) piperacillin sodium solution join in acetone (volume ratio of acetone and piperacillin sodium solution is 22:1), mix, form suspension;
4) after suspension ageing 5min, sucking filtration, washing, then, by filter cake vacuum drying at 40 DEG C, obtains white crystalline powder, is described avocin;
5) avocin sodium-tazobactam and upper step being made mixes by the weight ratio of 8:1, subpackage under hundred grades of conditions of sterilizing room, and every bottle containing 2.25g, obtains piperacillin sodium injection sodium-tazobactam sterile powder injection.
The preparation of example of formulations 4, piperacillin sodium injection sodium-tazobactam aseptic powder injection
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with to mixed solvent with the volume ratio of 3.5:1;
2) get avocin crude drug 90g, be dissolved in the isopropyl alcohol of 1000ml step 1) and the mixed solvent of N-Methyl pyrrolidone, be stirred to whole dissolvings, obtain piperacillin sodium solution;
3) under the condition of 5 DEG C of temperature, mixing speed 1950r/min, by step 2) piperacillin sodium solution join in acetone (volume ratio of acetone and piperacillin sodium solution is 19:1), mix, form suspension;
4) after suspension ageing 6min, sucking filtration, washing, then, by filter cake vacuum drying at 44 DEG C, obtains white crystalline powder, is described avocin;
5) avocin sodium-tazobactam and upper step being made mixes by the weight ratio of 8:1, subpackage under hundred grades of conditions of sterilizing room, obtain piperacillin sodium injection sodium-tazobactam sterile powder injection, per unit injectable powder is containing 4.5g avocin and sodium-tazobactam.
By test example, avocin of the present invention and the beneficial effect with the aseptic powder needle for injection of sodium-tazobactam thereof are described below.
Test example 1
This test example detects related substance in the prepared avocin of the embodiment of the present invention, this test is carried out according to 2010 editions second annex VIII P residual solvent algoscopy of Chinese Pharmacopoeia, annex 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 | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| Embodiment 2 products | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| Embodiment 3 products | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| Embodiment 4 products | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| Embodiment 5 products | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| Embodiment 6 products | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
Test example 2
The polymer content of the avocin of this test example to the present invention and prior art is investigated.
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 present invention 1 makes;
Test specimen 2: the avocin that the embodiment of the present invention 2 makes;
Test specimen 3: the avocin that the embodiment of the present invention 3 makes;
Control sample 1: Jiangsu Haihong Pharmaceutical Co., Ltd., institute for drug control, Jiangsu Province provides;
Control sample 2: the avocin highly finished product that obtain according to the embodiment of CN102807572A 4 " refining of avocin crude product " method;
Control sample 3: according to " new technique for synthesizing of avocin " [Li Zhonghua. the new technique for synthesizing [J] of avocin, Mountain Western Medicine S University's journal, 2002,33(4): 333-334] the 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 be m) 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 detection wavelength is 254nm.
3, assay method
The preparation of 3.1 contrast solutions
Get the about 20mg of piperacillin reference substance, accurately weighed, put in 200ml measuring bottle, after dissolving with ethanol 10ml, be diluted with water to scale, make the solution that approximately contains 0.1mg in every 1ml, solution in contrast.
The preparation of 3.2 need testing solutions
Get this product content appropriate, mix, precision takes in right amount (being approximately equivalent to piperacillin 0.2g), puts in 10ml measuring bottle, is dissolved in water and is diluted to scale, shakes up, as need testing solution.
3.3 algoscopy
Precision measures need testing solution 100～200 μ l injecting chromatographs, measures as mobile phase taking mobile phase A, records chromatogram.Another precision measures contrast solution 100～200 μ l injecting chromatographs, taking Mobile phase B as mobile phase, is measured in the same method.By external standard method, with calculated by peak area, recipe comprising piperacillin polymer, in piperacillin, must not cross 0.3%.
4, the investigation of piperacillin sodium polymer
4.1 accelerated tests are investigated
By above-mentioned test specimen and control sample simulation listing packaging, put into the biochemical cultivation case that temperature is (75 ± 5) % for (40 ± 2) DEG C, relative humidity, during respectively at 0,1,2,3,6 month, regularly sample, measure polymer content according to " 3 assay method " lower algoscopy, and compare analysis with the data of 0 month.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 tests are investigated
By above-mentioned test specimen and control sample simulation listing packaging, under the condition that is (60 ± 10) % for (25 ± 5) DEG C, relative humidity in temperature, place 12 months, sampling during respectively at 0,3,6,9,12 month, measure polymer content according to " 3 assay method " lower algoscopy, and compare analysis with the data of 0 month.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
Can find out from accelerated test and long term test sample polymer measurement result, 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 is without significant change.
The prepared avocin of other embodiment of the present invention has also been carried out to above-mentioned test, and the result of its acquisition is similar.
Test example 3
The stability of the piperacillin sodium injection sodium-tazobactam aseptic powder injection of this test example to the present invention and prior art is investigated.
Test specimen: the piperacillin sodium injection sodium-tazobactam aseptic powder injection that example of formulations 1 of the present invention makes;
Control sample 1: the piperacillin sodium injection sodium-tazobactam aseptic powder injection making according to the method for the embodiment of the present invention 1, difference is that avocin is the avocin highly finished product that obtain according to the embodiment of CN102807572A 4 " refining of avocin crude product " method.
Control sample 2: the piperacillin sodium and tazobactam sodium compound recipe injectable powder of the 4:1 making according to the method for the embodiment of CN101265263A 1.
1, accelerated test
By above-mentioned test specimen and control sample simulation listing packaging, put into the biochemical cultivation case that temperature is (75 ± 5) % for (40 ± 2) DEG C, relative humidity, during respectively at 0,1,2,3,6 month, regularly sample, carry out quality examination, and compare analysis with the data of 0 month.The results are shown in Table 4.
Table 4, accelerated test result
4.2 long term test
By above-mentioned test specimen and control sample simulation listing packaging, under the condition that is (60 ± 10) % for (25 ± 5) DEG C, relative humidity in temperature, place 12 months, during respectively at 0,3,6,9,12 month, sampling, carries out quality examination, and compares analysis with the data of 0 month.The results are shown in Table 5.
Table 5, long-term test results
Can find out from above-mentioned result of the test, compare compared with prior art, piperacillin sodium injection sodium-tazobactam aseptic powder injection of the present invention has significantly reduced polymer content and better stability.
The prepared piperacillin sodium injection sodium-tazobactam of other embodiment of the present invention aseptic powder injection has also been carried out to above-mentioned test, and the result of its acquisition is similar.
Claims (10)
1. a pharmaceutical composition for avocin and sodium-tazobactam, is characterized in that, in described pharmaceutical composition, the mass ratio of avocin and sodium-tazobactam is 4～20:1; Wherein said avocin is measured the X-ray powder diffraction collection of illustrative plates that obtains as shown in Figure 1 by powder X-ray diffraction algoscopy, and its chemical structural formula is suc as formula shown in (I):
Formula (I).
2. pharmaceutical composition according to claim 1, is characterized in that, in described pharmaceutical composition, the mass ratio of avocin and sodium-tazobactam is 4～8:1.
3. pharmaceutical composition according to claim 2, is characterized in that, in described pharmaceutical composition, the mass ratio of avocin and sodium-tazobactam is 4:1.
4. pharmaceutical composition according to claim 2, is characterized in that, in described pharmaceutical composition, the mass ratio of avocin and sodium-tazobactam is 8:1.
5. according to the pharmaceutical composition described in claim 1-4 any one, it is characterized in that, described pharmaceutical composition is sterile powder injection.
6. pharmaceutical composition according to claim 5, is characterized in that, the preparation method of described avocin is:
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with to mixed solvent with the volume ratio of 3～5:1;
2) get avocin crude drug, be dissolved in step 1) isopropyl alcohol and the mixed solvent of N-Methyl pyrrolidone in, be stirred to whole dissolvings, obtain piperacillin sodium solution;
3) under the condition of 3～8 DEG C of temperature, mixing speed 1800～2200r/min, by step 2) piperacillin sodium solution join in acetone, mix, form suspension;
4) after suspension ageing 5～10min, sucking filtration, washing, then, by filter cake vacuum drying at 40～45 DEG C, obtains white crystalline powder, is 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 step 3) described in acetone and the volume ratio of piperacillin sodium solution be 18～22:1.
9. a preparation method for the pharmaceutical composition described in claim 1-8 any one, is characterized in that, described preparation method comprises the steps:
1) isopropyl alcohol and N-Methyl pyrrolidone are mixed with to mixed solvent with the volume ratio of 3～5:1;
2) get avocin crude drug, be dissolved in step 1) isopropyl alcohol and the mixed solvent of N-Methyl pyrrolidone in, be stirred to whole dissolvings, obtain piperacillin sodium solution;
3) under the condition of 3～8 DEG C of temperature, mixing speed 1800～2200r/min, by step 2) piperacillin sodium solution join in acetone, mix, form suspension;
4) after suspension ageing 5～10min, sucking filtration, washing, then, by filter cake vacuum drying at 40～45 DEG C, obtains white crystalline powder, is described avocin;
5) avocin upper step being obtained and sodium-tazobactam are mixed to get described pharmaceutical composition in proportion.
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 by described pharmaceutical composition.
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| CN105616415B (en) * | 2016-01-15 | 2018-01-09 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of piperacillin sodium and tazobactam sodium for injection |
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| CN112409381B (en) * | 2020-12-03 | 2022-03-01 | 山东安信制药有限公司 | Piperacillin sodium and tazobactam sodium co-amorphous substance and preparation method thereof |
| 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 |
| CN115554298B (en) * | 2021-07-01 | 2024-10-01 | 北京诺康达医药科技股份有限公司 | Combined preparation of tazobactam and piperacillin and preparation method thereof |
| CN115561351B (en) * | 2022-09-23 | 2025-03-04 | 海南通用康力制药有限公司 | Detection Method of Related Substances Ⅱ in Piperacillin Sodium and Tazobactam Sodium for Injection |
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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 |
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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. |