CN101129374A - Vinflunine pharmaceutical composition and method of producing the same and application of the same - Google Patents
Vinflunine pharmaceutical composition and method of producing the same and application of the same Download PDFInfo
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- CN101129374A CN101129374A CNA2007100166045A CN200710016604A CN101129374A CN 101129374 A CN101129374 A CN 101129374A CN A2007100166045 A CNA2007100166045 A CN A2007100166045A CN 200710016604 A CN200710016604 A CN 200710016604A CN 101129374 A CN101129374 A CN 101129374A
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- Prior art keywords
- vinflunine
- pharmaceutical composition
- cyclodextrin
- pharmaceutically acceptable
- acceptable salt
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- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 title claims abstract description 110
- 229960000922 vinflunine Drugs 0.000 title claims abstract description 109
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims description 9
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 201000011510 cancer Diseases 0.000 claims abstract description 6
- 238000005352 clarification Methods 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 12
- 239000006174 pH buffer Substances 0.000 claims description 10
- 238000004108 freeze drying Methods 0.000 claims description 9
- 239000002131 composite material Substances 0.000 claims description 6
- 238000007911 parenteral administration Methods 0.000 claims description 6
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 5
- YIHUEPHBPPAAHH-IIQAEXPMSA-N 33mg53c7xw Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@@H]2C[C@@H](C(C)(F)F)CN1C2 YIHUEPHBPPAAHH-IIQAEXPMSA-N 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 229940069078 citric acid / sodium citrate Drugs 0.000 claims description 3
- 239000007974 sodium acetate buffer Substances 0.000 claims description 3
- 239000000872 buffer Substances 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims description 2
- 229940127554 medical product Drugs 0.000 claims description 2
- 230000001954 sterilising effect Effects 0.000 claims description 2
- 238000004659 sterilization and disinfection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 abstract description 17
- 238000002347 injection Methods 0.000 abstract description 17
- 239000000203 mixture Substances 0.000 abstract description 14
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000470 constituent Substances 0.000 abstract 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 229940127557 pharmaceutical product Drugs 0.000 abstract 1
- 210000002784 stomach Anatomy 0.000 abstract 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 30
- 239000000843 powder Substances 0.000 description 29
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 238000012856 packing Methods 0.000 description 18
- 239000012535 impurity Substances 0.000 description 17
- 229940090044 injection Drugs 0.000 description 16
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 13
- 210000004907 gland Anatomy 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 12
- 239000008227 sterile water for injection Substances 0.000 description 12
- 238000005303 weighing Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000001509 sodium citrate Substances 0.000 description 10
- 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 description 10
- 238000000859 sublimation Methods 0.000 description 10
- 230000008022 sublimation Effects 0.000 description 10
- 239000012982 microporous membrane Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 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 description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229940093181 glucose injection Drugs 0.000 description 3
- 238000005374 membrane filtration Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 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 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- 239000000337 buffer salt Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 239000008176 lyophilized powder Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 229960004249 sodium acetate Drugs 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000008354 sodium chloride injection Substances 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000031864 metaphase Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a pharmaceutical composition of Vinflunine, which comprises Vinflunine as the active constituent, pharmaceutically acceptable salts and cyclodextrin, wherein each 1 part of Vinflunine and its pharmaceutically acceptable salt are mixed with a maximum of 0. 5-100 parts by weight ratio of cyclodextrin, and freeze dried injection is prepared. The invention also relates to the process for preparing the composition, and its use in preparing non-stomach administering pharmaceutical products for the treatment of cancer.
Description
Technical field
The present invention relates to a kind of vinflunine pharmaceutical composition, the vinflunine freeze-dried powder injecta medicine composition and method of making the same that relates in particular to a kind of parenteral administration is used for the treatment of the medicinal usage of cancer with it, belongs to medical technical field.
Background technology
Vinflunine is by the up-to-date vinca medicine of French Pierre's method C Compaq screening the earliest, is derived by vinorelbine, by the inhibition tubulin polymerization, makes cell division stop at mitosis metaphase, is the period specific cancer therapy drug.Can be used for nonsmall-cell lung cancer, bladder cancer, tumor treatment such as breast carcinoma, mesothelioma, melanoma, renal carcinoma.
The pharmaceutically acceptable salt of bibliographical information vinflunine has forms such as bitartrate, sulfate.Liquor epinephrinae bitartratis ophthalmicus vinflunine raw material is very unstable, must be under inert gas shielding, and subzero (15 ℃) stores.But the aqueous solution of liquor epinephrinae bitartratis ophthalmicus vinflunine but can be preserved 2-8 ℃ of condition.Therefore, Pierre's method C Compaq of France applied on the 17th at December in 2004 that the liquor epinephrinae bitartratis ophthalmicus vinflunine was used for the patent of the stable aqueous solution preparation of antineoplaston, and publication number is WO2005070425.Patent disclosure with citric acid/sodium citrate or acetic acid/sodium-acetate buffer or directly be stabilized between the 3-4 with the pH of water for injection with solution, aseptic filtration makes aseptic parenteral solution, places under 5 ℃ ± 3 ℃ the condition, at least 36 months stable.
The specification of liquor epinephrinae bitartratis ophthalmicus vinflunine injection is subjected to the restriction of packing container and the medicine steady concentration in aqueous solution, disclosed optimum medicine concentration is 25mg/ml (containing vinflunine) among the WO2005070425, but the clinical large usage quantity (320mg/m of vinflunine
2), like this, single dose strengthens, and will certainly cause packing to strengthen; Make troubles to medicine preparation, transportation and application.
Because the liquor epinephrinae bitartratis ophthalmicus vinflunine is very easily water-soluble, so liquor epinephrinae bitartratis ophthalmicus vinflunine injectable powder can be avoided this defective, carries out specifications design according to clinical needs, for doctors and patients' medication provides better facility.But, studies show that, the liquor epinephrinae bitartratis ophthalmicus vinflunine injectable powder sample that lyophilizing adjuvant commonly used such as mannitol prepare under conventional amount used, its clarity is greater than No. 2, stability is poor than medicinal liquid before the lyophilizing of liquor epinephrinae bitartratis ophthalmicus vinflunine, can not obtain vinflunine salt lyophilized formulations ideal, high stability.Result of study sees Table 1.
In the experiment: liquor epinephrinae bitartratis ophthalmicus vinflunine and mannitol weight ratio 1: 1, water-soluble, drug level is counted 25mg/ml with vinflunine, lyophilization.
The different vinflunine preparation of table 1 clarity relatively
| Condition | Detect index | Aqueous solution | Dried frozen aquatic products |
| 0 day | Total impurities % | 0.769 | 0.797 |
| Clarity | Clarification | ＞No. 2 turbidity liquid | |
| 100℃4hr | Total impurities % | 2.524 | 3.168 |
Given this, research and development with vinflunine and pharmaceutically acceptable salt thereof be the prescription of the stable lyophilized formulations of principal agent form and preparation method very necessary.
Summary of the invention
At the deficiencies in the prior art, the object of the present invention is to provide a kind of is that the vinflunine freeze-dried powder injecta medicine composition and method of making the same of the parenteral administration made of principal agent and its are used for the treatment of the medicinal usage of cancer with vinflunine and pharmaceutically acceptable salt thereof.
Vinflunine powder medicine administered by injection compositions of the present invention, it is characterized in that: contain active component vinflunine and pharmaceutically acceptable salt thereof, and be mixed with the cyclodextrin of 0.5-100 part part by weight at the most and make powderous preparations in 1 part of vinflunine and pharmaceutically acceptable salt thereof, wherein water content can be controlled in 12%.
Wherein: the preferred vinflunine bitartrate of the pharmaceutically acceptable salt of described vinflunine; The preferred HP-of described cyclodextrin or acetyl-gamma-cyclodextrin.
Vinflunine powder medicine administered by injection compositions of the present invention is characterized in that: contain the pH buffer system, described pH buffer system is made up of acetic acid/sodium acetate buffer agent or citric acid/sodium citrate buffer agent, and its pH value maintains 3.0-4.5.
Wherein: the molar concentration of the pH buffer agent in the described pH buffer system is 0.002M-0.2M.
The preparation method of vinflunine powder medicine administered by injection compositions of the present invention comprises following successive step:
(a) cyclodextrin is water-soluble or optionally add in the aqueous solution of pH buffer agent and dissolve;
(b) vinflunine and pharmaceutically acceptable salt thereof are added by weight proportion be dissolved to the solution clarification in the above-mentioned solution;
(c) with conventional method above-mentioned settled solution is removed thermal source and filtration sterilization;
(d) aseptic powdery solid composite medicament is made in lyophilization.
In the preparation method of above-mentioned vinflunine powder medicine administered by injection compositions:
Freeze-drying method described in the step (d) can be sub-packed in medical unit dose package and directly be loaded on the lyophilizing cabinet, carries out lyophilization;
Freeze-drying method described in the step (d), also directly sabot lyophilization, aseptic subpackaged then in medical unit dose package container;
The described freezing dry process of step (d) can blanketing with inert gas.
The aseptic powdery solid composite medicament of gained after the described lyophilization of step (d) seals, packs the vinflunine lyophilized injectable powder that makes parenteral administration through gland.
Utilize the vinflunine freeze-dried powder injecta medicine compositions of the parenteral administration of the method for the invention preparation to be used for the treatment of the application of the medical product of cancer as preparation.
Utilize the vinflunine freeze-dried powder injecta medicine compositions of the parenteral administration of the method for the invention preparation to can be used for treatment for cancer such as nonsmall-cell lung cancer, breast carcinoma, ovarian cancer, lymphoma, the solvent load of described preparation gets final product with enough principal agents and adjuvant dissolving, volume according to the lyophilized solid thing can suitably increase quantity of solvent, and the quantity of solvent that preparation commonly used is every bottle can be at 1-20ml.
The content of principal agent can prepare the 1mg-800mg/ bottle usually in vinflunine.
Vinflunine injectable powder of the present invention is identical with injection in the clinical scope of application.When using clinically, injectable powder is diluted in the normal saline then earlier with behind a small amount of physiological saline solution, and in short time angular vein input, the normal saline flushing vein that instils a large amount of then reduces this product to the venous zest.Clinical administration dosage is 320mg/m
2Once in a week, continuous 4-6 time is a course of treatment.
The vinflunine injectable powder product stability that the present invention makes is better, and product clarity is good, and the effective active composition is difficult for decomposing, and reduces medicine storage life catabolite especially, improves curative effect, the minimizing toxic and side effects of product.
Injectable powder of the present invention can be placed under 5 ℃ ± 3 ℃ condition for a long time.
Injectable powder convenient transportation of the present invention, product appearance is attractive in appearance, helps applying on a large scale clinically.
For further embodying stability of formulation of the present invention, emphasize the particularly effect of HP-of the selected lyophilizing adjuvant of the present invention cyclodextrin, in the list of experiments mode beneficial effect of the present invention is further described in detail below:
(medicinal liquid is sub-packed in the cillin bottle with the injectable powder that contains different proportioning HP-and vinflunine bitartrate and the correlated steadiness of liquor epinephrinae bitartratis ophthalmicus vinflunine aqueous solution, investigating index with high performance liquid chromatography detects) investigate, the results are shown in Table 2:
Table 2: the study on the stability information slip of vinflunine bitartrate (25mg/ml) and cyclodextrin composite
| Liquor epinephrinae bitartratis ophthalmicus vinflunine: HP-weight ratio | 1∶1 | 1∶2 | 1∶3 | 1∶4 | 1∶5 | 1∶6 | Aqueous solution |
| Dried frozen aquatic products clarity | ＞No. 2 turbidity liquid | ＜2 | ＜1 | ＜1 | ≤0.5 | ≤0.5 | ≤0.5 |
| 0 day total impurities % | 0.69 | 0.70 | 0.72 | 0.68 | 0.64 | 0.71 | 0.70 |
| 5 days total impurities % of cold preservation | 0.71 | 0.75 | 0.74 | 0.710 | 0.66 | 0.75 | 0.71 |
| 10 days total impurities % of cold preservation | 0.84 | 0.89 | 0.71 | 0.76 | 0.73 | 0.84 | 0.85 |
| 40 ℃ of 5 days total impurities % | 1.23 | 1.22 | 1.20 | 0.99 | 1.04 | 1.06 | 1.1 |
| 40 ℃ of 10 days total impurities % | 1.51 | 1.42 | 1.34 | 1.08 | 1.04 | 1.03 | 1.04 |
| 60 ℃ of 5 days total impurities % | 1.73 | 1.52 | 1.52 | 1.35 | 1.23 | 1.24 | 1.37 |
| 50 ℃ of 10 days total impurities % | 3.15 | 2.53 | 2.2 | 1.73 | 2.01 | 2.13 | 2.87 |
| 5 days total impurities % of illumination | 3.67 | 2.8 | 2.5 | 1.6 | 1.4 | 1.4 | 6.7 |
| 10 days total impurities % of illumination | 4.50 | 3.53 | 3.1 | 2.50 | 2.40 | 2.45 | 8.0 |
Annotate: the solid preparation sample is diluted to the concentration that principal agent is 25mg/ml with water for injection, carries out the medicinal liquid turbidity relatively.
By above result as can be seen, along with the increasing of HP-consumption, vinflunine is made after the injectable powder, stability significantly increases, especially heat stability significantly increases, and its stability is compared with WO2005070425 patent prescription aqueous solution, and is more stable.
In view of liquor epinephrinae bitartratis ophthalmicus vinflunine raw material must be under inert gas shielding, subzero (15 ℃) stores, and therefore can also confirm that the present invention has obtained the solid composite medicament more stable than liquor epinephrinae bitartratis ophthalmicus vinflunine.Vinflunine is to photo-labile, and preferably lucifuge stores.
With the liquor epinephrinae bitartratis ophthalmicus vinflunine: the HP-weight ratio is respectively used water dissolution in 1: 6 and 1: 4, vinflunine concentration is 25mg/ml, the concentration of citric acid and sodium citrate buffer salt is 4mM, pH is controlled at 3.0-5.5, lyophilizing preparing product, brown bottle packing, 2-8 ℃ of lucifuge are placed 6 months impurity data and aqueous solution according to WO2005070425 patent prescription preparation liquor epinephrinae bitartratis ophthalmicus vinflunine, be sub-packed in brown ampoule fusion sealing, 2-8 ℃ of lucifuge placed 6 months impurity data and compared.The results are shown in Table 3:
The impurity of table 3 vinflunine injectable powder and aqueous solution is investigated information slip
| Product category | Time | Outward appearance | Total impurities % |
| Liquor epinephrinae bitartratis ophthalmicus vinflunine: HP-weight ratio 1: 6 | 0 month | White solid | 0.54 |
| 1 month | White solid | 0.56 | |
| 2 months | White solid | 0.58 | |
| 3 months | White solid | 0.54 | |
| 6 months | White solid | 0.59 | |
| Liquor epinephrinae bitartratis ophthalmicus vinflunine: HP-weight ratio 1: 4 | 0 month | White solid | 0.56 |
| 1 month | White solid | 0.56 | |
| 2 months | White solid | 0.58 | |
| 3 months | White solid | 0.57 | |
| 6 months | White solid | 0.60 | |
| Aqueous solution | 0 | Colourless clear liquid | 0.56 |
| 1 month | Colourless clear liquid | 0.58 | |
| 2 months | Colourless clear liquid | 0.57 | |
| 3 months | Colourless clear liquid | 0.59 | |
| 6 months | Colourless clear liquid | 0.61 |
With the liquor epinephrinae bitartratis ophthalmicus vinflunine: the HP-weight ratio is respectively and uses water dissolution, vinflunine concentration at 1: 4 is 25mg/ml, and the concentration of citric acid and sodium citrate buffer salt is 4mM, and pH is controlled at 3.0-5.5, lyophilizing preparing product, brown bottle packing.With the compatibility stability test of the concentration of vinflunine 12.8mg/ml and 1.5mg/ml and 0.9% sodium chloride and 5% glucose injection, the results are shown in Table 4 and table 5:
Table 4 vinflunine concentration is the stability test result of 12.8mg/ml
| The solution classification | Time (h) | Labelled amount (%) | Total impurities % | Outward appearance |
| 0.9% sodium chloride injection | 0 | 100.9 | 0.87 | Clarification |
| 2 | 101.2 | 0.93 | Clarification | |
| 4 | 99.1 | 0.92 | Clarification | |
| 8 | 102.2 | 0.90 | Clarification | |
| 12 | 101.8 | 0.95 | Clarification | |
| 24 | 101.8 | 0.96 | Clarification | |
| 5% glucose injection | 0 | 102.7 | 0.86 | Clarification |
| 2 | 102.7 | 0.86 | Clarification | |
| 4 | 101.8 | 0.87 | Clarification | |
| 8 | 101.3 | 0.93 | Clarification | |
| 12 | 101.9 | 0.92 | Clarification | |
| 24 | 102.3 | 0.94 | Clarification |
Table 5 vinflunine concentration is the stability test result of 1.5mg/ml
| The solution classification | Time (h) | Labelled amount (%) | Total impurities % | Outward appearance |
| 0.9% sodium chloride injection | 0 | 101.3 | 0.83 | Clarification |
| 2 | 100.3 | 0.83 | Clarification | |
| 4 | 100.6 | 0.85 | Clarification | |
| 8 | 99.0 | 0.91 | Clarification | |
| 12 | 100.4 | 0.89 | Clarification | |
| 24 | 100.3 | 0.95 | Clarification | |
| 5% glucose injection | 0 | 100.4 | 0.89 | Clarification |
| 2 | 100.3 | 0.92 | Clarification | |
| 4 | 99.8 | 0.90 | Clarification | |
| 8 | 100.5 | 0.97 | Clarification | |
| 12 | 100.5 | 0.97 | Clarification | |
| 24 | 100.8 | 1.06 | Clarification |
Toxicological test proves that also liquor epinephrinae bitartratis ophthalmicus vinflunine aqueous solution compares in liquor epinephrinae bitartratis ophthalmicus vinflunine powder medicine administered by injection compositions of the present invention and the WO2005070425 patent, and toxicity is not seen increase.
The specific embodiment
Following examples will further specify the present invention, but not limit the present invention.
Embodiment 1
Take by weighing HP-205.05g, sterilized water for injection 800ml stirring and dissolving, add liquor epinephrinae bitartratis ophthalmicus vinflunine 34.175g (being equivalent to vinflunine 25g) stirring and make its dissolving, measure the pH value 3.0-4.5 of solution, be settled to 1000ml, add needle-use activated carbon, filter, the filtrate reuse is equipped with 0.22 μ m filtering with microporous membrane, and is canned in aseptic cillin bottle.Freezingly in the lyophilizing cabinet kept 2-3 hour to about-45 ℃ ,-10 ℃～0 ℃ 9 hours sublimation drying, 38 ℃ after dry again 5-10 hour, the inflated with nitrogen outlet is jumped a queue, gland seals, and packing promptly gets injection vinflunine injectable powder.
Embodiment 2
Take by weighing HP-136.7g and citric acid 0.6g, sodium citrate 0.6g, add sterilized water for injection 800ml stirring and dissolving, add liquor epinephrinae bitartratis ophthalmicus vinflunine 34.175g (being equivalent to vinflunine 25g) stirring and make its dissolving, measure the pH value 3.0-4.5 of solution, be settled to 1000ml, add needle-use activated carbon, filter, the filtrate reuse is equipped with 0.22 μ m filtering with microporous membrane, and is canned in aseptic cillin bottle.Freezingly in the lyophilizing cabinet kept 2-3 hour to about-45 ℃ ,-10～0 ℃ of 9 hours sublimation drying, 38 ℃ after dry again 8-10 hour, outlet is jumped a queue, gland seals, and packing promptly gets injection vinflunine injectable powder.
Embodiment 3
Take by weighing acetyl group-gamma-cyclodextrin 160.0g and citric acid 0.6g, sodium citrate 0.8g; add sterilized water for injection 800ml stirring and dissolving; add liquor epinephrinae bitartratis ophthalmicus vinflunine 34.175g (being equivalent to vinflunine 25g) stirring and make its dissolving; measure the pH value 3.0-4.5 of solution; be settled to 1000ml, add needle-use activated carbon, filter; the filtrate reuse is equipped with 0.22 micropore considers membrane filtration, canned in aseptic cillin bottle.Freezingly in the lyophilizing cabinet kept 2-3 hour to about-45 ℃ ,-10～0 ℃ of 9 hours sublimation drying, 38 ℃ after dry again 5-10 hour, the inflated with nitrogen outlet is jumped a queue, gland seals, and packing is promptly.
Embodiment 4
Take by weighing HP-136.7g and acetic acid 0.3g, sodium acetate 2.5g, add sterilized water for injection 800ml stirring and dissolving, add liquor epinephrinae bitartratis ophthalmicus vinflunine 34.175g (being equivalent to vinflunine 25g) stirring and make its dissolving, measure the pH value 3.0-4.5 of solution, be settled to 1000ml, add needle-use activated carbon, filter, the filtrate reuse is equipped with 0.22 μ m filtering with microporous membrane, and is canned in aseptic cillin bottle.Freezingly in the lyophilizing cabinet kept 2-3 hour to about-45 ℃ ,-10～0 ℃ of 9 hours sublimation drying, 38 ℃ after dry again 5-10 hour, the inflated with nitrogen outlet is jumped a queue, gland seals, and packing promptly gets injection vinflunine injectable powder.
Embodiment 5
Take by weighing HP-136.7g and citric acid 0.6g, sodium citrate 0.6g, add sterilized water for injection 800ml stirring and dissolving, add liquor epinephrinae bitartratis ophthalmicus vinflunine 34.175g (being equivalent to vinflunine 25g) stirring and make its dissolving, measure the pH value 3.0-4.5 of solution, be settled to 1000ml, add needle-use activated carbon, filter, the filtrate reuse is equipped with 0.22 μ m filtering with microporous membrane, sterile solution is positioned in the deep bid aseptic freeze-dried, pulverizes.Measure the vinflunine content of lyophilized powder, in vinflunine conversion weight packing cillin bottle, behind the inflated with nitrogen, jump a queue, gland seals, packing promptly gets injection vinflunine injectable powder.
Embodiment 6
Take by weighing HP-34.175g and citric acid 0.3g, sodium citrate 0.4g, add sterilized water for injection 500ml stirring and dissolving, add liquor epinephrinae bitartratis ophthalmicus vinflunine 34.175g (being equivalent to vinflunine 25g) stirring and make its dissolving, measure the pH value 3.0-4.5 of solution, be settled to 1000ml, add needle-use activated carbon, filter, the filtrate reuse is equipped with 0.22 μ m filtering with microporous membrane, and is canned in aseptic cillin bottle.Freezingly in the lyophilizing cabinet kept 2-3 hour to about-45 ℃ ,-10～0 ℃ of 9 hours sublimation drying, 38 ℃ after dry again 5-10 hour, outlet is jumped a queue, gland seals, and packing promptly gets injection vinflunine injectable powder.
Embodiment 7
Take by weighing acetyl group-gamma-cyclodextrin 320.0g and citric acid 1.0g, sodium citrate 1.2g; add sterilized water for injection 800ml stirring and dissolving; add liquor epinephrinae bitartratis ophthalmicus vinflunine 34.175g (being equivalent to vinflunine 25g) stirring and make its dissolving; measure the pH value 3.0-4.5 of solution; be settled to 1000ml, add needle-use activated carbon, filter; the filtrate reuse is equipped with 0.22 micropore considers membrane filtration, canned in aseptic cillin bottle.Freezingly in the lyophilizing cabinet kept 2-3 hour to about-45 ℃ ,-10～0 ℃ of 9 hours sublimation drying, 38 ℃ after dry again 5-10 hour, the inflated with nitrogen outlet is jumped a queue, gland seals, and packing is promptly.
Embodiment 8
Take by weighing HP-1708.75g and citric acid 1.6g, sodium citrate 1.6g, add sterilized water for injection 800ml stirring and dissolving, add liquor epinephrinae bitartratis ophthalmicus vinflunine 34.175g (being equivalent to vinflunine 25g) stirring and make its dissolving, measure the pH value 3.0-4.5 of solution, be settled to 1000ml, add needle-use activated carbon, filter, the filtrate reuse is equipped with 0.22 μ m filtering with microporous membrane, sterile solution is positioned in the deep bid aseptic freeze-dried, pulverizes.Measure the vinflunine content of lyophilized powder, in vinflunine conversion weight packing cillin bottle, behind the inflated with nitrogen, jump a queue, gland seals, packing promptly gets injection vinflunine injectable powder.
Embodiment 9
Take by weighing HP-2734.0g and acetic acid 0.9g, sodium acetate 5.5g, add sterilized water for injection 800ml stirring and dissolving, add liquor epinephrinae bitartratis ophthalmicus vinflunine 34.175g (being equivalent to vinflunine 25g) stirring and make its dissolving, measure the pH value 3.0-4.5 of solution, be settled to 1000ml, add needle-use activated carbon, filter, the filtrate reuse is equipped with 0.22 μ m filtering with microporous membrane, and is canned in aseptic cillin bottle.Freezingly in the lyophilizing cabinet kept 2-3 hour to about-45 ℃ ,-10～0 ℃ of 9 hours sublimation drying, 38 ℃ after dry again 5-10 hour, the inflated with nitrogen outlet is jumped a queue, gland seals, and packing promptly gets injection vinflunine injectable powder.
Embodiment 10
Take by weighing HP-683.5g and citric acid 0.9g, sodium citrate 0.9g, add sterilized water for injection 800ml stirring and dissolving, add liquor epinephrinae bitartratis ophthalmicus vinflunine 34.175g (being equivalent to vinflunine 25g) stirring and make its dissolving, measure the pH value 3.0-4.5 of solution, be settled to 1000ml, add needle-use activated carbon, filter, the filtrate reuse is equipped with 0.22 μ m filtering with microporous membrane, and is canned in aseptic cillin bottle.Freezingly in the lyophilizing cabinet kept 2-3 hour to about-45 ℃ ,-10～0 ℃ of 9 hours sublimation drying, 38 ℃ after dry again 5-10 hour, outlet is jumped a queue, gland seals, and packing promptly gets injection vinflunine injectable powder.
Embodiment 11
Take by weighing HP-2500.0g, add sterilized water for injection 800ml stirring and dissolving, add vinflunine 25g stirring and make its dissolving, measure the pH value 3.0-4.5 of solution, be settled to 1000ml, add needle-use activated carbon, filter, the filtrate reuse is equipped with 0.22 μ m filtering with microporous membrane, and is canned in aseptic cillin bottle.Freezingly in the lyophilizing cabinet kept 2-3 hour to about-45 ℃ ,-10～0 ℃ of 9 hours sublimation drying, 38 ℃ after dry again 5-10 hour, the inflated with nitrogen outlet is jumped a queue, gland seals, and packing promptly gets injection vinflunine injectable powder.
Embodiment 12
Take by weighing acetyl group-gamma-cyclodextrin 240.46g and citric acid 0.8g, sodium citrate 1.0g; add sterilized water for injection 800ml stirring and dissolving; add sulphuric acid vinflunine 25.868g (being equivalent to vinflunine 25g) stirring and make its dissolving; measure the pH value 3.0-4.5 of solution; be settled to 1000ml, add needle-use activated carbon, filter; the filtrate reuse is equipped with 0.22 micropore considers membrane filtration, canned in aseptic cillin bottle.Freezingly in the lyophilizing cabinet kept 2-3 hour to about-45 ℃ ,-10～0 ℃ of 9 hours sublimation drying, 38 ℃ after dry again 5-10 hour, the inflated with nitrogen outlet is jumped a queue, gland seals, and packing is promptly.
Claims (10)
1. a vinflunine pharmaceutical composition is characterized in that: contain active component vinflunine and pharmaceutically acceptable salt thereof, cyclodextrin.
2. according to the described vinflunine pharmaceutical composition of claim 1, it is characterized in that: contain active component vinflunine and pharmaceutically acceptable salt thereof, and in 1 part of vinflunine and pharmaceutically acceptable salt thereof, be mixed with the cyclodextrin of 0.5-100 part part by weight at the most and make powderous preparations.
3. according to claim 1 or 2 described vinflunine pharmaceutical compositions, it is characterized in that: the pharmaceutically acceptable salt of described vinflunine is the vinflunine bitartrate.
4. according to claim 1 or 2 described vinflunine pharmaceutical compositions, it is characterized in that: described cyclodextrin is HP-or acetyl-gamma-cyclodextrin.
5. according to claim 1 or 2 described vinflunine pharmaceutical compositions, it is characterized in that: contain the pH buffer system.
6. according to the described vinflunine pharmaceutical composition of claim 5, it is characterized in that: described pH buffer system is made up of acetic acid/sodium acetate buffer agent or citric acid/sodium citrate buffer agent, and its pH value maintains 3.0-4.5.
7. according to the described vinflunine pharmaceutical composition of claim 5, it is characterized in that: the molar concentration of the pH buffer agent in the described pH buffer system is 0.002M-0.2M.
8. one kind prepares the method for vinflunine pharmaceutical composition as claimed in claim 1 or 2, comprises following successive step:
(a) cyclodextrin is water-soluble or optionally add in the aqueous solution of pH buffer agent and dissolve;
(b) vinflunine and pharmaceutically acceptable salt thereof are added by weight proportion be dissolved to the solution clarification in the above-mentioned solution;
(c) with conventional method above-mentioned settled solution is removed thermal source and filtration sterilization;
(d) aseptic powdery solid composite medicament is made in lyophilization.
9. as the preparation method of vinflunine pharmaceutical composition as described in the claim 8, it is characterized in that: the process blanketing with inert gas of the aseptic powdery solid composite medicament that described lyophilization makes.
10. claim 1 or 2 described vinflunine pharmaceutical compositions are used for the treatment of the application of medical product of the parenteral administration of cancer as preparation.
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| CN2007100166045A CN101129374B (en) | 2007-06-26 | 2007-06-26 | Vinflunine pharmaceutical composition and method of producing the same and application of the same |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2007100166045A CN101129374B (en) | 2007-06-26 | 2007-06-26 | Vinflunine pharmaceutical composition and method of producing the same and application of the same |
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| CN101129374A true CN101129374A (en) | 2008-02-27 |
| CN101129374B CN101129374B (en) | 2010-09-08 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102151249A (en) * | 2010-02-11 | 2011-08-17 | 石药集团中奇制药技术（石家庄）有限公司 | Medical composition of vinflunine |
| CN102188394A (en) * | 2010-03-05 | 2011-09-21 | 石药集团中奇制药技术（石家庄）有限公司 | Vinflunine freeze-drying medicinal composition |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2863891B1 (en) * | 2003-12-23 | 2006-03-24 | Pf Medicament | PHARMACEUTICAL COMPOSITION OF VINFLUNIN FOR PARENTAL ADMINISTRATION, PROCESS FOR PREPARATION AND USE |
| CN100438855C (en) * | 2006-01-19 | 2008-12-03 | 浙江大学 | Vinorelbine bitartrate liposome and its freeze-dried powder injection and preparation method |
-
2007
- 2007-06-26 CN CN2007100166045A patent/CN101129374B/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102151249A (en) * | 2010-02-11 | 2011-08-17 | 石药集团中奇制药技术（石家庄）有限公司 | Medical composition of vinflunine |
| CN102188394A (en) * | 2010-03-05 | 2011-09-21 | 石药集团中奇制药技术（石家庄）有限公司 | Vinflunine freeze-drying medicinal composition |
| CN102188394B (en) * | 2010-03-05 | 2013-03-27 | 石药集团中奇制药技术（石家庄）有限公司 | Vinflunine freeze-drying medicinal composition |
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