CN103505424B - Preparation method for bortezomib for injection - Google Patents
Preparation method for bortezomib for injection Download PDFInfo
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- CN103505424B CN103505424B CN201310466841.7A CN201310466841A CN103505424B CN 103505424 B CN103505424 B CN 103505424B CN 201310466841 A CN201310466841 A CN 201310466841A CN 103505424 B CN103505424 B CN 103505424B
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- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 title claims abstract description 45
- 229960001467 bortezomib Drugs 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 238000002347 injection Methods 0.000 title claims abstract description 18
- 239000007924 injection Substances 0.000 title claims abstract description 18
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 15
- 238000001035 drying Methods 0.000 claims abstract description 14
- 239000000243 solution Substances 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229920000747 poly(lactic acid) Polymers 0.000 claims abstract description 10
- 239000004626 polylactic acid Substances 0.000 claims abstract description 10
- 238000007710 freezing Methods 0.000 claims abstract description 9
- 230000008014 freezing Effects 0.000 claims abstract description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 7
- 229930195725 Mannitol Natural products 0.000 claims abstract description 7
- 239000000594 mannitol Substances 0.000 claims abstract description 7
- 235000010355 mannitol Nutrition 0.000 claims abstract description 7
- 239000011259 mixed solution Substances 0.000 claims abstract description 7
- 238000000859 sublimation Methods 0.000 claims abstract description 5
- 230000008022 sublimation Effects 0.000 claims abstract description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 239000008215 water for injection Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 5
- 230000008901 benefit Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 abstract description 7
- 239000000203 mixture Substances 0.000 abstract description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract 2
- 238000004108 freeze drying Methods 0.000 abstract 2
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 238000009777 vacuum freeze-drying Methods 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 229940079156 Proteasome inhibitor Drugs 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000003207 proteasome inhibitor Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 102100024539 Chymase Human genes 0.000 description 1
- 108090000227 Chymases Proteins 0.000 description 1
- 102100025566 Chymotrypsin-like protease CTRL-1 Human genes 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101000856199 Homo sapiens Chymotrypsin-like protease CTRL-1 Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method for bortezomib for injection. The preparation method comprises the following steps: (1) polylactic acid and tertiary butanol are weighed, and a certain quantity of injection water is added for dissolving to obtain a polylactic acid and tertiary butanol mixed solution; (2) bortezomib raw materials are weighed, added in the mixed solution, and stirred until the raw materials are dissolved totally; (3) mannitol is weighed, added in the solution with the dissolved raw materials, and the injection water is added to account for 70% of the total amount, then is quickly stirred until the mixture is completely dissolved; (4) 5 g of activated carbon is added and stirred for 20 minutes, then is filtered out; (5) the injection water is added to reach 9.5 L; the pH value is regulated to 4.0-7.0 by using sodium hydroxide or hydrochloric acid; then the injection water is added until the total amount achieves 10 L; (6) the vacuum freeze drying technique is adopted for freeze-drying after filling; the freeze-drying technique is as follows: the pre-freezing temperature is kept for -40 DEG C for 3 hours; the sublimation drying time is 16 hours; the resolve drying time is 4 hours; the total time is 23 hours.
Description
Technical field
The present invention relates to a kind of field of pharmaceutical preparations, particularly a kind of safe, stay-in-grade injection bortezomib and preparation method thereof.
Background technology
Bortezomib English Bortezomib for Injection by name, chemical name is [(1R)-3-methyl isophthalic acid-[[(2S)-1-oxygen-3-phenyl-2-[(pyrazinecarboxamide) is amino] propyl group] is amino] butyl] boric acid.
Its structural formula:
Bortezomib (bortezomib) is a kind of dipeptides ylboronic acid compound, and new and effective single-minded protease inhibitor, was also referred to as LDP-341 and PS-341 in the past, was developed by Millennium Pharmaceuticals of the U.S., and obtains the approval of FDA May 19 in 2003, with
trade name list marketing is freeze-dried powder.Be mainly used in treatment recurrent and Refractory Multiple Myeloma.And get permission listing in May, 2004 in Britain, after the treatment for previously at least having accepted two kinds of therapies is also treated the last time, there is the multiple myeloma of progress in disease.This medicine is a kind of proteasome inhibitor, can the class chymase (chymotrypsin-like) of 26S proteasome in mammalian cell be suppressed active by specificity, send and have an impact, finally cause cancer cell death to signal a series of in cell.At present in the listing of 46, whole world country.
Injection bortezomib " Bortezomib " is first and is applied to clinical proteasome inhibitor, has certain targeting antitumor action.Since birth, successively win 2004 " annual neoplastic compound prize " and international Prix Galien Grand Prix in 2006, the latter is described as " Nobel Prize of pharmaceutical industry ".
Although this product is only limited to the 2nd large malignant tumor---myeloma of blood system at present, scientist has regarded it as the breakthrough therapy of Therapeutic cancer, and its mechanism of action also should be applicable to other cancers.This medicine is carrying out the clinical research of the cancers such as malignant lymphoma, nonsmall-cell lung cancer, colorectal cancer, carcinoma of prostate, soft tissue sarcoma, hepatocarcinoma at present.Indication likely further expands from now on, wide market.
But, because bortezomib is insoluble in water, in atmosphere very easily oxidation and to photo-labile, so address these problems the major subjects of Cheng Liao research worker.
Pharmaceutical composition of Chinese patent 201310139272.5 1 kinds of bortezomibs and preparation method thereof, describes pharmaceutical composition of a kind of bortezomib and preparation method thereof.Containing bortezomib, the tert-butyl alcohol, sodium chloride and excipient in compositions, wherein, the mass ratio of described bortezomib, the tert-butyl alcohol, sodium chloride and excipient is 1:0.5:1 ~ 5:5 ~ 20.The interpolation of the tert-butyl alcohol can make bortezomib dissolve rapidly, thus fast and the more stable borate of the polyalcohols excipient reaction formation such as mannitol, solves the stability problem of bortezomib lyophilized injectable powder itself.
Chinese patent 201310070127.6 1 kinds of injection bortezomib pharmaceutical compositions, describe a kind of bortezomib pharmaceutical composition, and described pharmaceutical composition comprises the bortezomib and aminoacid that mass ratio is 1:2-100.The present invention can effectively improve bortezomib dissolubility.
Chinese patent 201310038299.5 1 kinds contains freeze-dried composition of bortezomib and preparation method thereof, describes a kind of freeze-dried composition containing bortezomib and preparation method thereof.The object of the invention is to overcome principal agent and dissolve difficulty and the problem to oxygen environment sensitive in environment.In order to realize this goal of the invention, the invention discloses a kind of freeze-dried composition of bortezomib, and the preparation method of this freeze-dried composition, utilize the mixed solvent being added with mannitol, the tert-butyl alcohol, significantly increase the rate of dissolution of bortezomib, the rate of dissolution of bortezomib can be improved simultaneously by the order of addition of material further.Utilization fill nitrogen environment not only liquid preparation time greatly shorten, and effectively prevent the contact of principal agent composition and aerobic environment, reduce the related substance of final finished and total assorted content.
Chinese patent 201,110,134,281 1 kinds of bortezomib freeze-dried powders and preparation method thereof, describe a kind of bortezomib freeze-dried powder and preparation method thereof.After redissolving for bortezomib preparation, the poor and bortezomib preparation of clarity is along with increasing impurity increase problem faster standing time, the invention provides a kind of bortezomib freeze-dried powder, it contains bortezomib, excipient, antioxidant and pH adjusting agent, gained preparation solubility is good, dissolution time is 29 ~ 36 seconds, and after said preparation room temperature places 9 hours simultaneously, total impurities content is not higher than 1.27%, there is good stability, contribute to increasing drug safety.
Above-mentioned prior art mainly solves bortezomib indissoluble in preparation process, the problems such as instability, but the present inventor finds, bortezomib freeze-dried powder prepared by said method speed of redissolving does not improve, cause in use procedure, need operator repeatedly to dilute and dissolve and could use, existing injection has certain zest for blood vessel simultaneously, also needs to find solution.
The present invention, through research, finds a kind of method improving redissolution speed, reduces the stimulation to blood vessel simultaneously, solve the difficult problem in use procedure.
Summary of the invention
The object of the present invention is to provide that a kind of quality is more stable, the preparation method of safe and effective injection bortezomib.
Further, when the invention provides preparation injection bortezomib, add a certain amount of polylactic acid, the multiple dissolution velocity of injection powder pin can be accelerated, the invention provides following preparation method for this reason:
Injection bortezomib of the present invention, formula is composed as follows:
Solution ph is 4.0 ~ 7.0.
Its preparation method comprises the following steps:
1) take polylactic acid, the tert-butyl alcohol, add a certain amount of water for injection, make dissolving, obtain polylactic acid and tert-butyl alcohol mixed solution;
2) take bortezomib raw material, join in above-mentioned mixed solution, be stirred to whole dissolving;
3) take mannitol, join above-mentioned raw materials medicine and dissolved completely in solution, mend and inject water to 70% of total amount, be stirred to rapidly whole dissolving;
4) add 5g active carbon and stir 20 minutes, leach active carbon;
5) benefit injects water to 9.5L, with sodium hydroxide or salt acid for adjusting pH value to 4.0 ~ 7.0, adds water for injection to 10L;
6), after fill, adopt Vacuum Freezing & Drying Technology lyophilizing, freeze-dry process is: pre-freezing temperature is-40 DEG C, 3 hours, 16 hours sublimation drying time, 4 hours parsing-desiccation time, 23 hours total used times.
The above-mentioned prescription of the present invention is through screening acquisition, and screening process is as follows:
| Supplementary product kind | Multiple dissolution velocity (time: second) | To the stimulation of blood vessel |
| Add polylactic acid | 16 | Without obvious stimulation |
| Add lactose | 19 | Slightly |
| Add arginine | 30 | Slightly |
| Add glycine | 32 | Slightly |
| Add sorbitol | 37 | Moderate |
| Comparative example | ||
| Chinese patent 201310139272.5 | 35 | Moderate |
| Chinese patent 201310070127.6 | 31 | Slightly |
| Chinese patent 201310038299.5 | 25 | Moderate |
The present invention also screens technique to improve multiple dissolution velocity, and the selection result is as follows:
Finished product detection
Detect the sample of embodiment 1, result is as follows:
| Testing index | Embodiment 1 |
| Character | The fast shape thing of white loose |
| PH value | 5.4 |
| Multiple dissolution velocity (second) | 16 |
| Impurity number | 12 |
| Total impurities % | 0.35 |
Shed storage test
Investigate the long-time stability that the sample of embodiment 1 carries out 6 months, result is as follows:
| Minute | Embodiment 1 |
| 0 month | 0.23% |
| June | 0.28% |
Detailed description of the invention
The present invention's raw and auxiliary material used, if no special instructions, is medicinal rank.
Embodiment 1
Solution ph is 4.0 ~ 7.0.
Its preparation method comprises the following steps:
1) take polylactic acid, the tert-butyl alcohol, add a certain amount of water for injection, make dissolving, obtain polylactic acid and tert-butyl alcohol mixed solution;
2) take bortezomib raw material, join in above-mentioned solution, be stirred to whole dissolving;
3) take mannitol, join above-mentioned raw materials medicine and dissolved completely in solution, mend and inject water to 70% of total amount, be stirred to rapidly whole dissolving;
4) add 5g active carbon and stir 20 minutes, leach active carbon;
5) benefit injects water to 9.5L, with sodium hydroxide or salt acid for adjusting pH value to 4.0 ~ 7.0, adds water for injection to 10L;
6), after fill, adopt Vacuum Freezing & Drying Technology lyophilizing, freeze-dry process is: pre-freezing temperature is-40 DEG C, 3 hours, 16 hours sublimation drying time, 4 hours parsing-desiccation time, 23 hours total used times.
Comparative example
Solution ph is 4.0 ~ 7.0.
Its preparation method comprises the following steps:
1) take the tert-butyl alcohol, add a certain amount of water for injection, make dissolving, obtain t-butanol solution;
2) take bortezomib raw material, join in above-mentioned t-butanol solution, be stirred to whole dissolving;
3) take mannitol, join above-mentioned raw materials medicine and dissolved completely in solution, mend and inject water to 70% of total amount, be stirred to rapidly whole dissolving;
4) add 5g active carbon and stir 20 minutes, leach active carbon;
5) benefit injects water to 9.5L, with sodium hydroxide or salt acid for adjusting pH value to 4.0 ~ 7.0, adds water for injection to 10L;
6), after fill, adopt Vacuum Freezing & Drying Technology lyophilizing, freeze-dry process is: pre-freezing temperature is-40 DEG C, 3 hours, 16 hours sublimation drying time, 4 hours parsing-desiccation time, 23 hours total used times.
Claims (1)
1. a preparation method for injection bortezomib, described injection bortezomib formula is composed as follows:
Its preparation method comprises the following steps:
1) take polylactic acid, the tert-butyl alcohol, add a certain amount of water for injection, make dissolving, obtain polylactic acid and tert-butyl alcohol mixed solution;
2) take bortezomib raw material, join in above-mentioned mixed solution, be stirred to whole dissolving;
3) take mannitol, join above-mentioned raw materials medicine and dissolved completely in solution, mend and inject water to 70% of total amount, be stirred to rapidly whole dissolving;
4) add 5g active carbon and stir 20 minutes, leach active carbon;
5) benefit injects water to 9.5L, with sodium hydroxide or salt acid for adjusting pH value to 4.0 ~ 7.0, adds water for injection to 10L;
6), after fill, adopt Vacuum Freezing & Drying Technology lyophilizing, freeze-dry process is: pre-freezing temperature is-40 DEG C, 3 hours, 16 hours sublimation drying time, 4 hours parsing-desiccation time, 23 hours total used times.
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| CN201310466841.7A CN103505424B (en) | 2013-10-09 | 2013-10-09 | Preparation method for bortezomib for injection |
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| CN103505424B true CN103505424B (en) | 2015-03-11 |
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| CN105056205A (en) * | 2015-06-29 | 2015-11-18 | 杭州华东医药集团新药研究院有限公司 | Bortezomib-containing medicinal composition and preparation method thereof |
| CN107151255A (en) * | 2016-03-06 | 2017-09-12 | 复旦大学 | Boric acid compound and its production and use |
| CN105664134B (en) * | 2016-03-13 | 2019-04-26 | 浙江药苑生物科技有限公司 | It is a kind of for treating the pharmaceutical composition of osteocarcinoma |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102784114A (en) * | 2011-05-14 | 2012-11-21 | 山东新时代药业有限公司 | Bortezomib freeze-dried powder injection and preparation method thereof |
| CN103070835A (en) * | 2013-01-31 | 2013-05-01 | 江苏奥赛康药业股份有限公司 | Freeze-dried composition containing bortezomib and preparation method of freeze-dried composition |
| CN103212055A (en) * | 2013-04-19 | 2013-07-24 | 海南锦瑞制药股份有限公司 | Drug composition of bortezomib and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102784114A (en) * | 2011-05-14 | 2012-11-21 | 山东新时代药业有限公司 | Bortezomib freeze-dried powder injection and preparation method thereof |
| CN103070835A (en) * | 2013-01-31 | 2013-05-01 | 江苏奥赛康药业股份有限公司 | Freeze-dried composition containing bortezomib and preparation method of freeze-dried composition |
| CN103212055A (en) * | 2013-04-19 | 2013-07-24 | 海南锦瑞制药股份有限公司 | Drug composition of bortezomib and preparation method thereof |
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