CN102151257B - Busulfan injection and preparation method thereof - Google Patents
Busulfan injection and preparation method thereof Download PDFInfo
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- CN102151257B CN102151257B CN201110039360.9A CN201110039360A CN102151257B CN 102151257 B CN102151257 B CN 102151257B CN 201110039360 A CN201110039360 A CN 201110039360A CN 102151257 B CN102151257 B CN 102151257B
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- 229940111214 busulfan injection Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims description 21
- 239000003814 drug Substances 0.000 claims abstract description 41
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims abstract description 34
- 229960002092 busulfan Drugs 0.000 claims abstract description 34
- 239000012046 mixed solvent Substances 0.000 claims abstract description 32
- 229940079593 drug Drugs 0.000 claims abstract description 29
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000007524 organic acids Chemical class 0.000 claims abstract description 16
- 229940090044 injection Drugs 0.000 claims abstract description 12
- 238000002347 injection Methods 0.000 claims abstract description 12
- 239000007924 injection Substances 0.000 claims abstract description 12
- -1 alkaline earth metal salt Chemical class 0.000 claims abstract description 9
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 72
- 238000001914 filtration Methods 0.000 claims description 34
- 239000012982 microporous membrane Substances 0.000 claims description 34
- 238000003756 stirring Methods 0.000 claims description 34
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 24
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 238000012859 sterile filling Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 7
- 239000011975 tartaric acid Substances 0.000 claims description 7
- 235000002906 tartaric acid Nutrition 0.000 claims description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 3
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- JHECKPXUCKQCSH-UHFFFAOYSA-J calcium;disodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate;hydrate Chemical compound O.[Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O JHECKPXUCKQCSH-UHFFFAOYSA-J 0.000 claims description 3
- 229940069078 citric acid / sodium citrate Drugs 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims 1
- 239000000470 constituent Substances 0.000 abstract description 9
- 239000012535 impurity Substances 0.000 abstract description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002158 endotoxin Substances 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 abstract description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 3
- 230000036512 infertility Effects 0.000 abstract description 2
- 150000001340 alkali metals Chemical class 0.000 abstract 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 abstract 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 abstract 1
- 230000002035 prolonged effect Effects 0.000 abstract 1
- 230000000638 stimulation Effects 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- 239000000047 product Substances 0.000 description 21
- 230000014759 maintenance of location Effects 0.000 description 14
- 239000000243 solution Substances 0.000 description 12
- 238000011835 investigation Methods 0.000 description 10
- 239000003513 alkali Substances 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 150000001261 hydroxy acids Chemical group 0.000 description 7
- 239000000126 substance Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001212 derivatisation Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- FBRCEDOHIHWVET-UHFFFAOYSA-N 6,6-dihydroxy-6-methylsulfonylhexan-2-one Chemical compound S(=O)(=O)(C)C(CCCC(C)=O)(O)O FBRCEDOHIHWVET-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- LMBWSYZSUOEYSN-UHFFFAOYSA-N diethyldithiocarbamic acid Chemical group CCN(CC)C(S)=S LMBWSYZSUOEYSN-UHFFFAOYSA-N 0.000 description 2
- 229950004394 ditiocarb Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- GLRAHDCHUZLKKC-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid;hydrate Chemical compound O.CC#N.OC(=O)C(F)(F)F GLRAHDCHUZLKKC-UHFFFAOYSA-N 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012496 blank sample Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 206010028537 myelofibrosis Diseases 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a busulfan injection. Busulfan is dissolved in a mixed solvent of N,N-dimethyl acetamide with a volume ratio of 33% and polyethylene glycol 400 with a volume ratio of 67%, wherein the concentration of the busulfan is 6mg/ml, and the mixed solvent contains organic acid and alkali metal or alkaline earth metal salt of organic acid, which account for 0.01-5%w/v of the total amount of the mixed solvent; and the organic acid contains more than two carboxyl groups. The stability of main constituents of the busulfan injection provided by the invention can be improved remarkably so that the quality guarantee period of products is prolonged to more than 24 months; and various indices (such as appearance, content of tetrahydrofuran, content of main constituents, content of impurities, endotoxin, sterility test and the like) conform to the requirement of the quality standard. The active constituents and the auxiliary materials of the injection provided by the invention have no injection stimulation, and the injection can be used for clinical injection and can ensure that the medication safety cannot be lowered while the stability of products is improved.
Description
Technical field
The present invention relates to a kind of Busulfan injection, belong to field of pharmaceutical preparations.
Background technology
Busulfan injection is mainly used in treatment chronic myelocytic leukemia and polycythemia vera, myelofibrosis etc.Existing market product sold is only produced by Ben Venue Laboratories, Inc, and the preparation of China's Clinical practice is through Otsuka Pharmaceutical Company, at China's list marketing product after Ltd. subpackage.Preparation about this product has two US Patent No. 5430057 and US5559148, Canadian Patent CA2171738, European Union patent EP 0 725 637 B1.This product is dissolved in the mixed solution of a certain proportion of N,N-dimethylacetamide, PEG400 and/or water and is prepared from by proposition.From busulfan chemical structure analysis, this product unstability mainly concentrates on the ester bond of facile hydrolysis, thus selects the solvent environment be suitable for be the key point solving this product stability to reduce ester linkage hydrolyzing.Obviously, in preparation, the existence of moisture is unfavorable for the stability of main constituent.
Being described as prescription in the said preparation description of FDA approval: busulfan is dissolved in the mixed solvent containing N,N-dimethylacetamide (volume ratio, 33%) and PEG400 (volume ratio, 67%), and concentration is 6mg/ml.Component PEG400 in said preparation very easily absorbs water, the micro-moisture that inevitably moisture absorption that causes of environmental exposure and PEG400, N,N-dimethylacetamide or active constituents of medicine itself carry in process of production is enough to have influence on the stability of product.This shelf life of products is 18 months, and active component busulfan produces virose organic solvent tetrahydrofuran and methanesulfonic acid through degraded, reduces the curative effect of medicine on the one hand, more increases zest and the toxicity of medicine on the other hand.To the control of product safety, stable, effectiveness except selecting supplementary material that purity is higher, increase the stability most important thing especially of product inherence.This is because product from production to clinical practice in patient, very long storage process may be experienced, and the product of degrading during this cannot be refined again and by it removal, thus select a kind of more effectively and the Busulfan injection of safety is very necessary.
By the retrieval to document and previous patent technology, do not find that other method effectively can improve the report of Busulfan injection stability.
Summary of the invention
Technical scheme of the present invention there is provided a kind of more stable Busulfan injection, and another technical scheme of the present invention there is provided the preparation method of this injection.
The invention provides a kind of Busulfan injection, it is that being dissolved in by busulfan containing volume ratio is the N of 33%, N-dimethyl acetylamide and volume ratio are in the mixed solvent of 67% PEG400, the concentration of busulfan is 6mg/ml, containing organic acid, organic acid alkali metal or alkali salt in mixed solvent, its consumption accounts for the 0.01%-5%w/v of mixed solvent total amount; Described organic acid contains two or more hydroxy-acid group.Described bulking value percentage composition refers to the organic acid or its alkalies and alkaline earth salt 0.01-5g that contain two or more hydroxy-acid group in every 100ml injection solution.
Wherein, the described organic acid containing two or more hydroxy-acid group is disodiumedetate, EDTA calcium complex disodium salt, tetrasodium ethylenediamine tetraacetate, tartaric acid, citric acid, succinic acid, fumaric acid.
Further preferably, the described organic acid containing two or more hydroxy-acid group or its alkalies and alkaline earth salt are tartaric acid or citric acid or its alkalies and alkaline earth salt.
Still more preferably, the described organic acid containing two or more hydroxy-acid group or its alkalies and alkaline earth salt are citric acid or its alkalies and alkaline earth salt.
Wherein, citric acid or its alkalies and alkaline earth salt 0.1%-0.3%w/v is contained in mixed solvent.
Present invention also offers a kind of method preparing Busulfan injection, comprise the steps:
A, busulfan is dissolved in containing volume ratio be 33% N,N-dimethylacetamide and volume ratio be in the mixed solvent of 67% PEG400, the concentration of busulfan is 6mg/ml;
Add the organic acid containing two or more hydroxy-acid group or its alkalies and alkaline earth salt in b, mixed solvent, its consumption accounts for the 0.1%-0.3% (w/v) of mixed solvent;
C, the active carbon adding sample dissolution solvent for use volume 0.3% fully stir, and filter; Supplement full dose residual solvent, stir.
D, fill: 0.22 μm of filtering with microporous membrane, fill;
Wherein, in described operating process, ambient temperature is no more than 35 DEG C, and relative humidity is no more than 60%.
Inventor finds that the existence of moisture also can have influence on main constituent dissolubility in a solvent and the stability of active component in the lab.Owing to using PEG400 in injection adjuvant of the present invention, there is very strong hygroscopicity, and moisture determines the stability of Busulfan injection storage to a great extent, active carbon is the use except endotoxin/thermal source, and consumption specifically can adjust according to supplementary material endotoxin/thermal source load; And due to busulfan poor heat stability, cannot terminal heat sterilization be carried out, it is degerming to carry out 0.22 μm of filtering with microporous membrane, and fill need be carried out at 100 grades of aseptic areas.Preparation process can ensure to be sucked water quantities reaches product requirement by air in process of producing product to particular/special requirement listed by environment, thus product degradation reaction can be made to be reduced to a certain degree.
The present invention is injectable preparation, proved invention Busulfan injection can significantly improve the stability of main constituent after deliberation, make shelf life of products extend to more than 24 months, and product indices (appearance character, content of tetrahydrofuran, main constituent content, impurity content, endotoxin, sterility test etc.) meet quality criteria requirements.Injection active component of the present invention and adjuvant without injection zest, and can be used as clinical injection use, thus can ensure again to reduce drug safety while raising product stability.
Accompanying drawing explanation
The commercially available Busulfan injection of Fig. 1, does not contain the drug solution of organic acid or its alkalies and alkaline earth salt component, accelerates the high performance liquid chromatography sample collection of illustrative plates of investigations after 5 days through 40 DEG C
Fig. 2 embodiment 1 drug solution, accelerates the high performance liquid chromatography sample collection of illustrative plates of investigation after 5 days through 40 DEG C
Fig. 3 embodiment 2 drug solution, accelerates the high performance liquid chromatography sample collection of illustrative plates of investigation after 5 days through 40 DEG C
Fig. 4 embodiment 3 drug solution, accelerates the high performance liquid chromatography sample collection of illustrative plates of investigation after 5 days through 40 DEG C
Fig. 5 embodiment 4 drug solution, accelerates the high performance liquid chromatography sample collection of illustrative plates of investigation after 5 days through 40 DEG C
Fig. 6 embodiment 5 drug solution (selecting 0.15% succinic acid), accelerates the high performance liquid chromatography sample collection of illustrative plates of investigation after 5 days through 40 DEG C
Fig. 7 embodiment 6 drug solution, accelerates the high performance liquid chromatography sample collection of illustrative plates of investigation after 5 days through 40 DEG C
Fig. 8 embodiment 7 drug solution, accelerates the high performance liquid chromatography sample collection of illustrative plates of investigation after 5 days through 40 DEG C
Fig. 9 embodiment 8 drug solution, accelerates the high performance liquid chromatography sample collection of illustrative plates of investigation after 5 days through 40 DEG C
Figure 10 embodiment 9 drug solution, accelerates the high performance liquid chromatography sample collection of illustrative plates of investigation after 5 days through 40 DEG C
Detailed description of the invention
The preparation of embodiment 1 Busulfan injection of the present invention
Get busulfan crude drug 60mg, citric acid 1mg (accounting for the 0.01%w/v of mixed solvent total amount), add 3.3ml N,N-dimethylacetamide, be stirred to dissolve.Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane.Add 6.7ml PEG400, stir, 0.22 μm of filtering with microporous membrane, sterile filling.
The preparation of embodiment 2 Busulfan injection of the present invention
Get busulfan crude drug 60mg, citric acid/sodium citrate (1: 1, m/m) 20mg (accounting for the 0.2%w/v of mixed solvent total amount), add 3.3ml N,N-dimethylacetamide, be stirred to dissolve.Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane.Add 6.7ml PEG400, stir.0.22 μm of filtering with microporous membrane, sterile filling.
The preparation of embodiment 3 Busulfan injection of the present invention
Get busulfan crude drug 60mg, citric acid 10mg (accounting for the 0.1%w/v of mixed solvent total amount), add 3.3ml N,N-dimethylacetamide, be stirred to dissolve.Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane.Add 6.7ml PEG400, stir.0.22 μm of filtering with microporous membrane, sterile filling.
The preparation of embodiment 4 Busulfan injection of the present invention
Get busulfan crude drug 60mg, tartaric acid 20mg (accounting for the 0.2%w/v of mixed solvent total amount), add 3.3ml N,N-dimethylacetamide, be stirred to dissolve.Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane.Add 6.7ml PEG400, stir.0.22 μm of filtering with microporous membrane, sterile filling.
The preparation of embodiment 5 Busulfan injection of the present invention
Preparation technology is with embodiment 4, and its difference is that tartaric acid can be replaced the various organic acid containing two or more hydroxy-acid group such as disodiumedetate, EDTA calcium complex disodium salt, tetrasodium ethylenediamine tetraacetate, citric acid, succinic acid, fumaric acid or organic acid alkali metal and alkali salt.
The preparation of embodiment 6 Busulfan injection of the present invention
Get busulfan crude drug 60mg, citric acid 500mg (accounting for the 5%w/v of mixed solvent total amount), add 3.3ml N, N-methylacetamide, is stirred to dissolve.Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane.Add 6.7ml PEG400, stir, 0.22 μm of filtering with microporous membrane, sterile filling.
The preparation of embodiment 7 Busulfan injection of the present invention
Get busulfan crude drug 60mg, citric acid 100mg (accounting for the 1%w/v of mixed solvent total amount), add 3.3ml N,N-dimethylacetamide, be stirred to dissolve.Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane.Add 6.7ml PEG400, stir, 0.22 μm of filtering with microporous membrane, sterile filling.
The preparation of embodiment 8 Busulfan injection of the present invention
Get busulfan crude drug 60mg, citric acid 20mg (accounting for the 0.2%w/v of mixed solvent total amount), add 3.3ml N, N-methylacetamide, is stirred to dissolve.Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane.Add 6.7ml PEG400, stir, 0.22 μm of filtering with microporous membrane, sterile filling.
The preparation of embodiment 9 Busulfan injection of the present invention
Get busulfan crude drug 60mg, citric acid 30mg (accounting for the 0.3%w/v of mixed solvent total amount), add 3.3ml N,N-dimethylacetamide, be stirred to dissolve.Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane.Add 6.7ml PEG400, stir, 0.22 μm of filtering with microporous membrane, sterile filling.
Embodiment 10 Busulfan injection stability experiment of the present invention
The busulfan injection prepared by embodiment 1-9 is placed 5 days under 40 DEG C of conditions, compared with commercially available Busulfan injection, detects wherein related impurities.
Sample detection condition:
High performance liquid chromatography is adopted to measure
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler, and acetonitrile-water-trifluoroacetic acid (65: 35: 0.1) is mobile phase, and determined wavelength is 281nm.MABD and the internal standard substance peak relative retention time to busulfan peak is respectively 0.27 and 1.38.
Inside be designated as pentamethylene bromide, derivatization reagent is sodium diethyldithiocarbamate.
Using busulfan standard substance as external standard, calculate impurity/interior mark peak area ratio.
Sample and standard substance are all dissolved in N,N-dimethylacetamide, and interior mark is dissolved in ethanol, and derivatization reagent is dissolved in the water.During mensuration, interior mark is added in sample and standard solution, then after reacting with derivatization reagent, high performance liquid chromatography detects.
In test sample if any with 1-methylsulfonyl-4-acetyl-butanediol (1-mesyl-4-acetyl-butanediol, be called for short MABD) corresponding chromatographic peak (be 0.27 to the relative retention time at busulfan peak), calculate (MABD to the relative response of busulfan under assay item for 1.7) by internal standard method with peak area ratio.The chromatographic peak of the chromatographic peak of chromatogram empty solution display, unreacted sodium diethyldithiocarbamate and oxidation product thereof, is respectively about 0.35,0.49 and 0.65 to the relative retention time at busulfan peak, should give deduction.
Data parsing:
In Fig. 1-10, about 28 minutes chromatographic peaks are internal standard substance, and about 20 minutes chromatographic peaks are busulfan main peak, do not indicate retention time chromatographic peak and are blank sample Central Plains and have chromatographic peak, should deduct disregard when impurity calculates in all the other figure.
Specifically see the following form:
Fig. 1 is shown in by commercially available Busulfan injection high performance liquid chromatography sample collection of illustrative plates, and peak table is as follows:
| Peak | Retention time | Peak height | Peak area | Peak area percent |
| 1 | 5.524 | 54780 | 484183 | 6.139 |
| 2 | 5.879 | 338 | 2528 | 0.032 |
| 3 | 8.559 | 11283 | 147042 | 1.865 |
| 4 | 20.538 | 96199 | 2979529 | 37.781 |
| 5 | 28.275 | 101364 | 4273090 | 54.183 |
| Total amount | 263964 | 7886371 | 100.00 |
Fig. 2 is shown in by embodiment 1 medicine high performance liquid chromatography sample collection of illustrative plates, and peak table is as follows:
| Peak | Retention time | Peak height | Peak area | Peak area percent |
| 1 | 5.512 | 900 | 7037 | 0.091 |
| 2 | 5.888 | 632 | 5421 | 0.070 |
| 3 | 8.539 | 2335 | 30627 | 0.395 |
| 4 | 20.460 | 120642 | 3712689 | 47.863 |
| 5 | 28.153 | 95425 | 4001214 | 51.582 |
| Total amount | 219934 | 7756987 | 100.000 |
Fig. 3 is shown in by embodiment 2 medicine high performance liquid chromatography sample collection of illustrative plates, and peak table is as follows:
| Peak | Retention time | Peak height | Peak area | Peak area percent |
| 1 | 5.524 | 1931 | 15568 | 0.186 |
| 2 | 5.896 | 633 | 5508 | 0.066 |
| 3 | 8.552 | 253 | 3273 | 0.039 |
| 4 | 20.536 | 131948 | 4084962 | 48.755 |
| 5 | 28.270 | 101340 | 4269238 | 50.954 |
| Total amount | 236105 | 8378548 | 100.000 |
Fig. 4 is shown in by embodiment 3 medicine high performance liquid chromatography sample collection of illustrative plates, and peak table is as follows:
| Peak | Retention time | Peak height | Peak area | Peak area percent % |
| 1 | 5.525 | 1115 | 8737 | 0.107 |
| 2 | 5.899 | 622 | 5456 | 0.067 |
| 3 | 8.553 | 269 | 3435 | 0.042 |
| 4 | 20.538 | 126021 | 3900351 | 47.675 |
| 5 | 28.272 | 101256 | 4263137 | 52.109 |
| Total amount | 229283 | 8181116 | 100.000 |
Fig. 5 is shown in by embodiment 4 medicine high performance liquid chromatography sample collection of illustrative plates, and peak table is as follows:
| Peak | Retention time | Peak height | Peak area | Peak area percent % |
| 1 | 5.566 | 1761 | 14497 | 0.184 |
| 2 | 5.939 | 539 | 4756 | 0.060 |
| 3 | 8.637 | 5773 | 76422 | 0.970 |
| 4 | 20.775 | 112691 | 3526945 | 44.769 |
| 5 | 28.622 | 99832 | 4255562 | 54.017 |
| Total amount | 220596 | 7878182 | 100.000 |
Fig. 6 is shown in by embodiment 5 medicine high performance liquid chromatography sample collection of illustrative plates, and peak table is as follows:
| Peak | Retention time | Peak height | Peak area | Peak area percent % |
| 1 | 5.858 | 4514 | 38357 | 0493 |
| 2 | 6.284 | 509 | 6331 | 0.081 |
| 3 | 9.221 | 186 | 2343 | 0.030 |
| 4 | 22.863 | 101694 | 3540864 | 45.522 |
| 5 | 31.755 | 87548 | 4190511 | 53.874 |
| Total amount | 194451 | 7778406 | 100.000 |
Fig. 7 is shown in by embodiment 6 medicine high performance liquid chromatography sample collection of illustrative plates, and peak table is as follows:
| Peak | Retention time | Peak height | Peak area | Peak area percent |
| 1 | 5.868 | 908 | 6730 | 0.084 |
| 2 | 6.258 | 793 | 9470 | 0.118 |
| 3 | 22.837 | 105405 | 3745393 | 46.578 |
| 4 | 31.711 | 87673 | 4279460 | 53.220 |
| Total amount | 194779 | 8041053 | 100.000 |
Fig. 8 is shown in by embodiment 7 medicine high performance liquid chromatography sample collection of illustrative plates, and peak table is as follows:
| Peak | Retention time | Peak height | Peak area | Peak area percent % |
| 1 | 6.263 | 998 | 13768 | 0.169 |
| 2 | 22.840 | 109261 | 3886866 | 47.719 |
| 3 | 31.712 | 86923 | 4244724 | 52.112 |
| Total amount | 197182 | 8145358 | 100.000 |
Fig. 9 is shown in by embodiment 8 medicine high performance liquid chromatography sample collection of illustrative plates, and peak table is as follows:
| Peak | Retention time | Peak height | Peak area | Peak area percent |
| 1 | 22.842 | 102715 | 3654996 | 46.358 |
| 2 | 31.716 | 86452 | 4229317 | 53.642 |
| Total amount | 189167 | 7884313 | 100.000 |
Figure 10 is shown in by embodiment 9 medicine high performance liquid chromatography sample collection of illustrative plates, and peak table is as follows:
| Peak | Retention time | Peak height | Peak area | Peak area percent |
| 1 | 6.633 | 32 | 2220 | 0.028 |
| 2 | 22.843 | 105033 | 3743645 | 46.799 |
| 3 | 31.715 | 86772 | 4253566 | 53.173 |
| Total amount | 191837 | 7999432 | 100.000 |
Calculate according to described in detection method, each impurity content contrast of Fig. 1-10 is as following table:
Known by above-mentioned accelerated stability detection experiment, Fig. 1 is commercially available Busulfan injection, and accelerated stability test display total impurities content is apparently higher than busulfan injection of the present invention, and quality is unstable; When the content containing organic acid or its alkalies and alkaline earth salt in busulfan injection of the present invention is 0.01%-5%w/v, there is preferably stability, especially when 0.1-0.3%w/v, optimal stability.Can significantly improve the stability of main constituent, make shelf life of products extend to more than 24 months, and active component and adjuvant are all without injection zest, while raising product stability, can ensure drug safety again.
Claims (11)
1. a Busulfan injection, it is the N of 33% that busulfan is dissolved in containing volume ratio by described injection, N-dimethyl acetylamide and volume ratio are in the mixed solvent of 67% PEG400, the concentration of busulfan is 6mg/ml, it is characterized in that: the organic acid contained in mixed solvent, the consumption of organic acid alkali metal or organic acid alkali salt accounts for the 0.01w/v%-5w/v% of mixed solvent total amount, wherein, described organic acid, organic acid alkali metal salt or organic acid alkali salt are selected from disodiumedetate, EDTA calcium complex disodium salt, tetrasodium ethylenediamine tetraacetate, tartaric acid, citric acid, succinic acid, fumaric acid or sodium citrate.
2. Busulfan injection according to claim 1, is characterized in that: the consumption of the organic acid contained in mixed solvent, organic acid alkali metal or organic acid alkali salt accounts for the 0.1w/v%-0.3w/v% of mixed solvent total amount.
3. prepare a method for Busulfan injection according to claim 1, comprise the steps:
Get busulfan crude drug 60mg, citric acid 1mg, citric acid accounts for the 0.01%w/v of mixed solvent total amount, adds 3.3ml N,N-dimethylacetamide, is stirred to dissolve; Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane; Add 6.7ml PEG400, stir, 0.22 μm of filtering with microporous membrane, sterile filling.
4. prepare a method for Busulfan injection, comprise the steps:
Get busulfan crude drug 60mg, citric acid/sodium citrate (1: 1, m/m) 20mg, citric acid/sodium citrate accounts for the 0.2%w/v of mixed solvent total amount, adds 3.3ml N,N-dimethylacetamide, is stirred to dissolve; Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane; Add 6.7ml PEG400, stir; 0.22 μm of filtering with microporous membrane, sterile filling.
5. prepare a method for the Busulfan injection described in claim 1-2 any one, comprise the steps:
Get busulfan crude drug 60mg, citric acid 10mg, citric acid accounts for the 0.1%w/v of mixed solvent total amount, adds 3.3ml N,N-dimethylacetamide, is stirred to dissolve; Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane; Add 6.7ml PEG400, stir; 0.22 μm of filtering with microporous membrane, sterile filling.
6. prepare a method for the Busulfan injection described in claim 1-2 any one, comprise the steps:
Get busulfan crude drug 60mg, tartaric acid 20mg, tartaric acid accounts for the 0.2%w/v of mixed solvent total amount, adds 3.3ml N,N-dimethylacetamide, is stirred to dissolve; Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane; Add 6.7ml PEG400, stir; 0.22 μm of filtering with microporous membrane, sterile filling.
7. prepare a method for Busulfan injection according to claim 1, comprise the steps:
Get busulfan crude drug 60mg, citric acid 500mg, citric acid accounts for the 5%w/v of mixed solvent total amount, adds 3.3ml N,N-dimethylacetamide, is stirred to dissolve; Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane; Add 6.7ml PEG400, stir, 0.22 μm of filtering with microporous membrane, sterile filling.
8. prepare a method for Busulfan injection according to claim 1, comprise the steps:
Get busulfan crude drug 60mg, citric acid 100mg, citric acid accounts for the 1%w/v of mixed solvent total amount, adds 3.3ml N,N-dimethylacetamide, is stirred to dissolve; Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane; Add 6.7ml PEG400, stir, 0.22 μm of filtering with microporous membrane, sterile filling.
9. prepare a method for the Busulfan injection described in claim 1-2 any one, comprise the steps:
Get busulfan crude drug 60mg, citric acid 20mg, citric acid accounts for the 0.2%w/v of mixed solvent total amount, adds 3.3ml N,N-dimethylacetamide, is stirred to dissolve; Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane; Add 6.7ml PEG400, stir, 0.22 μm of filtering with microporous membrane, sterile filling.
10. prepare a method for the Busulfan injection described in claim 1-2 any one, comprise the steps:
Get busulfan crude drug 60mg, citric acid 30mg, citric acid accounts for the 0.3%w/v of mixed solvent total amount, adds 3.3ml N,N-dimethylacetamide, is stirred to dissolve; Add the active carbon of liquor capacity 0.3%, stirring at room temperature 30 minutes, 0.45 μm of filtering with microporous membrane; Add 6.7ml PEG400, stir, 0.22 μm of filtering with microporous membrane, sterile filling.
11. methods according to claim 3-10 any one, is characterized in that: the ambient temperature in described Busulfan injection preparation process is no more than 35 DEG C, and relative humidity is no more than 60%.
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| CN102408363B (en) * | 2011-10-12 | 2013-07-24 | 陈剑戈 | Method for synthesizing busulfan |
| CN103446045B (en) * | 2012-06-01 | 2015-08-12 | 四川科瑞德凯华制药有限公司 | A kind of stable Busulfan injection |
| WO2014089957A1 (en) * | 2012-12-11 | 2014-06-19 | 四川科瑞德凯华制药有限公司 | Stable busulfan injection |
| CN105726467A (en) * | 2014-12-09 | 2016-07-06 | 四川科瑞德制药有限公司 | Busulfan injection and preparation method thereof |
| CN104546698B (en) * | 2014-12-17 | 2017-06-20 | 华润双鹤药业股份有限公司 | Busulfan parenteral solution and preparation method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5430057A (en) * | 1993-09-30 | 1995-07-04 | Board Of Regents, The University Of Texas System | Parenteral busulfan for treatment of malignant disease |
| CN101181229A (en) * | 2007-12-14 | 2008-05-21 | 山东蓝金生物工程有限公司 | Busulfan sustained-release implantation agent for curing entity tumour |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5430057A (en) * | 1993-09-30 | 1995-07-04 | Board Of Regents, The University Of Texas System | Parenteral busulfan for treatment of malignant disease |
| CN101181229A (en) * | 2007-12-14 | 2008-05-21 | 山东蓝金生物工程有限公司 | Busulfan sustained-release implantation agent for curing entity tumour |
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