CN1148957A - Aqueously soluble powder preparation of taxinol and its preparing method - Google Patents
Aqueously soluble powder preparation of taxinol and its preparing method Download PDFInfo
- Publication number
- CN1148957A CN1148957A CN 96112502 CN96112502A CN1148957A CN 1148957 A CN1148957 A CN 1148957A CN 96112502 CN96112502 CN 96112502 CN 96112502 A CN96112502 A CN 96112502A CN 1148957 A CN1148957 A CN 1148957A
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- China
- Prior art keywords
- phospholipid
- injectable powder
- paclitaxel
- organic solvent
- injection
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- 239000000843 powder Substances 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000004108 freeze drying Methods 0.000 claims abstract description 3
- 229930012538 Paclitaxel Natural products 0.000 claims description 25
- 229960001592 paclitaxel Drugs 0.000 claims description 25
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 25
- 239000003960 organic solvent Substances 0.000 claims description 8
- 150000003904 phospholipids Chemical class 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 229940099352 cholate Drugs 0.000 claims description 6
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 6
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 3
- 230000009514 concussion Effects 0.000 claims description 3
- 239000008344 egg yolk phospholipid Substances 0.000 claims description 3
- 239000010408 film Substances 0.000 claims description 3
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000008347 soybean phospholipid Substances 0.000 claims description 3
- AWDRATDZQPNJFN-VAYUFCLWSA-N taurodeoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 AWDRATDZQPNJFN-VAYUFCLWSA-N 0.000 claims description 3
- 239000010409 thin film Substances 0.000 claims description 3
- 238000007738 vacuum evaporation Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims 1
- 229940090044 injection Drugs 0.000 abstract description 9
- 239000007924 injection Substances 0.000 abstract description 9
- 238000002347 injection Methods 0.000 abstract description 9
- 239000002904 solvent Substances 0.000 abstract description 8
- 208000003455 anaphylaxis Diseases 0.000 abstract description 6
- 206010002198 Anaphylactic reaction Diseases 0.000 abstract description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 2
- 206010033128 Ovarian cancer Diseases 0.000 abstract description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 abstract description 2
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 abstract description 2
- 229940093181 glucose injection Drugs 0.000 abstract description 2
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 abstract description 2
- 239000008389 polyethoxylated castor oil Substances 0.000 abstract description 2
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 abstract 1
- 229910001948 sodium oxide Inorganic materials 0.000 abstract 1
- 239000004552 water soluble powder Substances 0.000 abstract 1
- -1 polyoxy Polymers 0.000 description 18
- 102000029749 Microtubule Human genes 0.000 description 7
- 108091022875 Microtubule Proteins 0.000 description 7
- 210000004688 microtubule Anatomy 0.000 description 7
- 229940108949 paclitaxel injection Drugs 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000006166 lysate Substances 0.000 description 3
- 230000036783 anaphylactic response Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000008521 reorganization Effects 0.000 description 2
- 210000000582 semen Anatomy 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000028185 Angioedema Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000001946 anti-microtubular Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A water-soluble powder injection of taxusol for curing ovary cancer and mastocarcincma features to use 5% glucose injection or 0.9% sodium oxide injection as solvent instead of cremophor EL. It has the advantages of no anaphylactic reaction, high stability and better water solubility. The said powder injection is prepared by special prescription and freeze drying process.
Description
The taxol soluble injectable powder belongs to a kind of category that does not contain polyoxy ethyl Semen Ricini wet goods organic solvent.
Paclitaxel (Paclitaxel) trade name taxol (TAXOL), it is a kind of new anti-microtubule type antitumor drug, can promote the microtubule dimer to be assembled into microtubule then by preventing that the multimerization process from making the microtubule stabilisation, this static stabilization suppresses the normal kinetics reorganization of microtubule net, and the reorganization pair cell life interval and the splitting function of microtubule net are necessary.This medicine can also cause the multiple astral generation of microtubule during the unusual and cell division of the arrangement of whole cell cycle microtubule " bundle ".It is the first-selected active drug for the treatment of ovarian cancer and breast carcinoma at present.
The chemical constitution of paclitaxel has the height lipotropy, is dissolvable in water organic solvent and is not dissolved in water, and commercially available paclitaxel injection is that solvent is made with polyoxy ethyl Oleum Ricini (Cremophor EL) and ethanol all at present.Because there is antigenicity in polyoxy ethyl Oleum Ricini to human body, causes the patient who accepts the paclitaxel injection for curing anaphylactic reactions such as erythra, flushing, dyspnea and blood pressure are low to occur.Rule takes place and accounts for more than 40% in reaction, causes that wherein angioedema and whole body urticaria incidence rate account for 2%.The inside and outside drugmaker in native land sounds a warning when releasing paclitaxel injection: the patient who accepts paclitaxel treatment should use corticosteroid, diphenhydramine and H in advance
2Receptor changes anti-agent, with the serious anaphylactic reaction that prevents to be caused by polyoxy ethyl Oleum Ricini equal solvent.For medicine anaphylaxis medical history person is arranged, can not use paclitaxel injection with the preparation of polyoxy ethyl Oleum Ricini.Be enough to illustrate that with polyoxy ethyl Oleum Ricini be the universality and the order of severity that the paclitaxel injection of solvent preparation causes allergic reaction.
The objective of the invention is to develop a kind of taxol soluble injectable powder type that does not contain polyoxy ethyl Oleum Ricini equal solvent, can be with preceding adding 5% glucose injection or 0.9% sodium chloride injection with medicine dissolution, carry out intravenous drip, can eliminate the anaphylactic reaction that causes because of polyoxy ethyl Oleum Ricini, can prevent oxidation, the hydrolysis of paclitaxel in solution type injection agent again, the physical and chemical stability of goods is obviously improved.Simultaneously, the safety of paclitaxel injection in application process strengthened greatly.
The present invention realizes like this, paclitaxel, phospholipid and the cholate of injection specification are dissolved in the organic solvent, organic solvent is removed in vacuum evaporation, make medicine become a thin film, add water solublity buffer solution and handle dissolving films with the ultrasonic wave concussion method, lysate adopts freeze-drying to make powder, promptly gets the taxol soluble injectable powder.
Taxol soluble injectable powder prescription is: paclitaxel: 0.5--2.0mg/ml; Phospholipid: 25--75mg/ml; Phospholipid and cholate ratio: 0.3--1.0, typical ratios 0.8.
Preparation technology's of the present invention main points are: 1. phospholipid kind: refining soybean phospholipid, the egg lecithin of selecting the injection specification for use; 2. cholate kind: select dexycholate, taurodeoxycholate for use; 3. buffer ionic strength: adopt phosphate buffer; 4.PH value: ph value of buffer solution is 7.4; 5. temperature: 35-45 ℃; 6. organic solvent: select methanol, ethanol for use.
The taxol soluble injectable powder that the present invention makes has following characteristics:
1. this injectable powder does not contain polyoxy ethyl Semen Ricini oils sensitization solvent, can eliminate the anaphylaxis that causes because of polyoxy ethyl Oleum Ricini kind solvent;
2. this injectable powder is the drying solid powder, can prevent the influence of paclitaxel factor such as oxidation, hydrolysis in solution type injection agent, guarantees the stability in the goods storage process;
3. this preparation of injection maturation, constant product quality is convenient to suitability for industrialized production.
Embodiment:
Get injection specification paclitaxel 30mg, soybean phospholipid (or egg lecithin) 1.5g, dexycholate (or taurodeoxycholate) 1.85g, put in the vial, add dehydrated alcohol 15ml, be stirred to whole dissolvings.Whole solvents are removed in lysate vacuum evaporation in 40 ℃ of waters bath with thermostatic control, make medicine form a thin film, add phosphate buffer (PH=7.4) ultrasonic wave concussion method dissolving films.Lysate filters through microporous filter membrane (0.22 micron), and lyophilizing in the freezer dryer is put in filtering, seals.Promptly get every bottle of white that contains paclitaxel 30mg to little yellow taxol soluble injectable powder.
Claims (4)
1, taxol soluble injectable powder is characterized in that this injectable powder composition is:
A. paclitaxel: 0.5-2.0mg/ml;
B. phospholipid: 25-75mg/ml;
C. phospholipid and cholate ratio are 0.3-1.0, and typical ratios is 0.8;
The manufactured goods of this injectable powder are that white is to little yellow solid powder.
2, taxol soluble injectable powder preparation method, it is characterized in that: paclitaxel, phospholipid and the cholate that will inject specification are dissolved in the organic solvent in proportion, organic solvent is removed in vacuum evaporation in water bath with thermostatic control, make medicine become a thin film, the adding pH value is 7.4 phosphate buffer ultrasonic wave concussion method processing dissolving films, and lyophilization is made white to little yellow solid powder.
3, taxol soluble injectable powder according to claim 1 is characterized in that:
A. cholate kind: dexycholate or taurodeoxycholate;
B. phospholipid: soybean phospholipid or egg lecithin.
4, taxol soluble injectable powder preparation method according to claim 2, it is characterized in that: organic solvent is methanol or ethanol, the water bath with thermostatic control temperature is 35-45 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96112502 CN1148957A (en) | 1996-09-02 | 1996-09-02 | Aqueously soluble powder preparation of taxinol and its preparing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96112502 CN1148957A (en) | 1996-09-02 | 1996-09-02 | Aqueously soluble powder preparation of taxinol and its preparing method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1148957A true CN1148957A (en) | 1997-05-07 |
Family
ID=5121471
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 96112502 Pending CN1148957A (en) | 1996-09-02 | 1996-09-02 | Aqueously soluble powder preparation of taxinol and its preparing method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1148957A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002032399A1 (en) * | 2000-10-19 | 2002-04-25 | Nanjing Zhenzhong Bioengineering Company Ltd | Taxol liposome composition for treatment of cancer and preparation thereof |
| WO2008098415A1 (en) * | 2007-02-14 | 2008-08-21 | Beijing Century Biocom Pharmaceutical Technology Co., Ltd. | Pharmaceutical composition containing taxane and its preparation process and application |
| CN100462066C (en) * | 1997-06-27 | 2009-02-18 | 美国生物科学有限公司 | Novel preparation of medicament and preparation and application method thereof |
| CN101579335A (en) * | 1997-06-27 | 2009-11-18 | 阿布拉科斯生物科学有限公司 | New formulation of medicament, preparation method and application method |
| CN101062028B (en) * | 2007-05-28 | 2010-07-21 | 北京世纪博康医药科技有限公司 | Combination including taxanes, the preparing method and the use thereof |
| CN1850276B (en) * | 2006-03-03 | 2011-08-03 | 中国科学院长春应用化学研究所 | Freeze-dried powder injection of paclitaxel polymer bonded drug |
| US8853260B2 (en) | 1997-06-27 | 2014-10-07 | Abraxis Bioscience, Llc | Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof |
-
1996
- 1996-09-02 CN CN 96112502 patent/CN1148957A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100462066C (en) * | 1997-06-27 | 2009-02-18 | 美国生物科学有限公司 | Novel preparation of medicament and preparation and application method thereof |
| CN101579335A (en) * | 1997-06-27 | 2009-11-18 | 阿布拉科斯生物科学有限公司 | New formulation of medicament, preparation method and application method |
| US8853260B2 (en) | 1997-06-27 | 2014-10-07 | Abraxis Bioscience, Llc | Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof |
| CN101579335B (en) * | 1997-06-27 | 2016-08-03 | 阿布拉科斯生物科学有限公司 | The preparation of medicament and methods for making and using same thereof |
| WO2002032399A1 (en) * | 2000-10-19 | 2002-04-25 | Nanjing Zhenzhong Bioengineering Company Ltd | Taxol liposome composition for treatment of cancer and preparation thereof |
| CN1850276B (en) * | 2006-03-03 | 2011-08-03 | 中国科学院长春应用化学研究所 | Freeze-dried powder injection of paclitaxel polymer bonded drug |
| WO2008098415A1 (en) * | 2007-02-14 | 2008-08-21 | Beijing Century Biocom Pharmaceutical Technology Co., Ltd. | Pharmaceutical composition containing taxane and its preparation process and application |
| CN101062028B (en) * | 2007-05-28 | 2010-07-21 | 北京世纪博康医药科技有限公司 | Combination including taxanes, the preparing method and the use thereof |
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| C06 | Publication | ||
| PB01 | Publication | ||
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| C01 | Deemed withdrawal of patent application (patent law 1993) |