CN101843607B - Composition containing ibutilide fumarate and preparation method and application thereof - Google Patents
Composition containing ibutilide fumarate and preparation method and application thereof Download PDFInfo
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- CN101843607B CN101843607B CN2010101965117A CN201010196511A CN101843607B CN 101843607 B CN101843607 B CN 101843607B CN 2010101965117 A CN2010101965117 A CN 2010101965117A CN 201010196511 A CN201010196511 A CN 201010196511A CN 101843607 B CN101843607 B CN 101843607B
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- 239000000203 mixture Substances 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- PCIOHQNIRPWFMV-WXXKFALUSA-N Ibutilide fumarate Chemical compound OC(=O)\C=C\C(O)=O.CCCCCCCN(CC)CCCC(O)C1=CC=C(NS(C)(=O)=O)C=C1.CCCCCCCN(CC)CCCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 PCIOHQNIRPWFMV-WXXKFALUSA-N 0.000 title abstract description 23
- 229960005472 ibutilide fumarate Drugs 0.000 title abstract description 23
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 48
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000003416 antiarrhythmic agent Substances 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 102
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 36
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 30
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 22
- 238000002347 injection Methods 0.000 claims description 22
- 239000007924 injection Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000001632 sodium acetate Substances 0.000 claims description 16
- 235000017281 sodium acetate Nutrition 0.000 claims description 16
- 239000011780 sodium chloride Substances 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 claims description 10
- 238000005303 weighing Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000001179 sorption measurement Methods 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 206010003119 arrhythmia Diseases 0.000 claims description 3
- 230000006793 arrhythmia Effects 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- 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 description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 15
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 34
- 230000001954 sterilising effect Effects 0.000 description 27
- 238000004659 sterilization and disinfection Methods 0.000 description 23
- 238000002474 experimental method Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000001186 cumulative effect Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000007731 hot pressing Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000013618 particulate matter Substances 0.000 description 3
- 206010003658 Atrial Fibrillation Diseases 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 206010003662 Atrial flutter Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- RLLPVAHGXHCWKJ-UHFFFAOYSA-N permethrin Chemical compound CC1(C)C(C=C(Cl)Cl)C1C(=O)OCC1=CC=CC(OC=2C=CC=CC=2)=C1 RLLPVAHGXHCWKJ-UHFFFAOYSA-N 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a composition containing ibutilide fumarate and a preparation method and application thereof. The pH value of the composition containing ibutilide fumarate is smaller than 4.0. The preparation method comprises the step of adjusting the pH value of the composition to a set pH value by utilizing a pH regulating agent. The application refers to the application of the composition containing ibutililde fumarate in preparing antiarrhythmic drugs. The composition containing ibutilide fumarate has good thermal stability and has little change on the content of the ibutilide fumarate and reduction of impurities after sterilized.
Description
Technical field
The present invention relates to contain the composition and method of making the same and the application of Ibolite fumarate.
Background technology
Ibolite fumarate (Ibutilide Fumarate) is a kind of quick-acting, safe antiarrhythmic drug, effect with quick termination atrial flutter (room is pounced on), atrial fibrillation (atrial fibrillation) is to treat the room at present to pounce on/tremble one of important drugs of changeing rule fast.The pH value of the Ibutilide fumarate injection that sell existing domestic and international market all is controlled at more than 4.0, the Ibutilide fumarate injection of this pH causes the degraded of effective ingredient after sterilization, impurity increases, and active constituent content descends greatlyyer before the deadline, and related substance might surpass the desired ceiling value 1.0% of quality standard.When this product is used for the heart disease first aid, may cause curative effect to reduce, increase the safety of clinical administration risk.
Summary of the invention
In order to solve the injection effective ingredient degraded after sterilizing that exists in the above prior art, impurity increases, and problems such as active constituent content decline before the deadline is bigger the invention provides a kind of composition and method of making the same and application that contains Ibolite fumarate.
Technical scheme provided by the present invention comprises:
The invention provides a kind of compositions that contains Ibolite fumarate, its pH value＜4.0, preferred pH value is 2.5-3.8.
As optimization, also contain sodium acetate, sodium chloride and water in the above-mentioned compositions that contains Ibolite fumarate.Wherein, the concentration of preferred Ibolite fumarate is 0.01～1mg/ml, and the concentration of sodium acetate is 0.02～2mg/ml, and the concentration of sodium chloride is 1～20mg/ml.More preferably the concentration of Ibolite fumarate is 0.1mg/ml.
The present invention also provides preparation the above-mentioned method for compositions that contains Ibolite fumarate, and this method comprises utilizes the pH value regulator that the pH value of described compositions is transferred to set pH value.Described pH value regulator is a kind of or its combination in any that is selected from hydrochloric acid, sulphuric acid, phosphoric acid, citric acid, acetic acid, sodium acetate, sodium citrate and the sodium carbonate.Wherein preferably use hydrochloric acid.
As one of them embodiment, the method for compositions that preparation contains Ibolite fumarate, sodium acetate, sodium chloride and water may further comprise the steps:
(1) both takes by weighing quantitatively Ibolite fumarate and sodium acetate, used water dissolution, got solution one;
(2) both taken by weighing quantitatively sodium chloride, and with adding activated carbon adsorption behind the water dissolution 30 minutes, filtered, and got filtrate and mix with solution one, water is adjusted to final volume, gets solution two;
(3) utilize the pH value regulator that the pH value of described solution two is transferred to described pH value.
The present invention also further provides the above-mentioned application of compositions in the preparation antiarrhythmic drug that contains Ibolite fumarate.Described antiarrhythmic drug is preferably the arrhythmia injection.Described arrhythmia injection is preferably the Ibutilide fumarate injection that contains Ibolite fumarate, sodium acetate, sodium chloride and water.
The compositions that contains Ibolite fumarate of the present invention, pH value is less than 4.0, good thermal stability, sterilize the Ibolite fumarate changes of contents in back 12 months less than 2.0%, and impurity reduces, and the more existing Ibutilide fumarate injection present situation that Ibolite fumarate content reduces more than 4% in back 12 months of sterilizing has clear improvement.
The compositions that contains Ibolite fumarate of the present invention can tolerate the method for excessively killing of F0 〉=12, further improves the aseptic degree of injection.
In addition, particulate matter reduces in the compositions that contains Ibolite fumarate of the present invention.When the intravenous injection Ibutilide fumarate injection, particulate matter causes phlebitis usually.
Based on These characteristics, the compositions that contains Ibolite fumarate of the present invention can reduce the toxic and side effects in the clinical use, has improved clinical drug safety, and improves patient's treatment success rate.
The specific embodiment
Below describe composition and method of making the same and the application that contains Ibolite fumarate of the present invention in detail by specific embodiment and experimental example.
Embodiment 1～5, comparative example 1～5:
Take by weighing Ibolite fumarate and sodium acetate according to consumption shown in the table 1, use water dissolution, get solution one.
Take by weighing sodium chloride according to consumption shown in the table 1, with adding activated carbon adsorption behind the water dissolution 30 minutes, utilize then micropore filter (first 0.45 μ m, back 0.22 μ m, down with) filter, getting filtrate mixes with solution one, water is adjusted to cumulative volume 100ml, gets solution two.
With the regulator of pH value shown in the table 1 pH value of solution two is transferred to the pH value shown in the table 1, must contain the compositions of Ibolite fumarate.
The compositions that then embodiment 1～5, comparative example 1～5 gained is contained Ibolite fumarate is carried out 121 ℃, the excessive sterilization experiment of F0 〉=12 in the hot pressing steam steriliser, steriliser shows pressure 0.12mpa, sterilization time 7 minutes.
Adopt high performance liquid chromatography to investigate the content of the compositions that contains Ibolite fumarate of different pH value then, in chromatogram, the peak of Ibolite fumarate and the peak beyond the solvent peak are considered as impurity, the results are shown in table 1 through the sterilization rear impurity.
The condition of high performance liquid chromatography:
Instrument: Tianjin, island high performance liquid chromatograph LC-2010A
Detector: UV-detector
Chromatographic column: VP-ODS (4.6 * 250mm, 5 μ m)
Mobile phase: acetonitrile-0.02mol/L potassium dihydrogen phosphate aqueous solution (34: 66) (pH6.3)
Flow velocity: 1.0ml/min
Detect wavelength: 228nm
The Ibolite fumarate compositions of the different pH value of table 1 after excessive sterilization sterilization pH and the content of impurity
| Ibolite fumarate (g) | Sodium acetate (g) | Sodium chloride (g) | The pH value regulator | PH value before the sterilization | Sterilization rear impurity content (%) | Sterilization back pH value | |
| Embodiment 1 | ?0.01 | 0.018 | 0.89 | Acetic acid | 2.0 | 0.83 | 2.1 |
| Embodiment 2 | ?0.01 | 0.018 | 0.89 | Acetic acid | 2.5 | 0.52 | 2.5 |
| Embodiment 3 | ?0.01 | 0.018 | 0.89 | Acetic acid | 3.0 | 0.50 | 3.0 |
| Embodiment 4 | ?0.01 | 0.018 | 0.89 | Acetic acid | 3.5 | 0.42 | 3.5 |
| Embodiment 5 | ?0.01 | 0.018 | 0.89 | Acetic acid | 3.8 | 0.54 | 3.8 |
| Comparative example 1 | ?0.01 | 0.018 | 0.89 | Acetic acid | 4.0 | 0.74 | 4.0 |
| Comparative example 2 | ?0.01 | 0.018 | 0.89 | Acetic acid | 4.5 | 1.12 | 4.4 |
| Comparative example 3 | ?0.01 | 0.018 | 0.89 | Acetic acid | 5.0 | 2.11 | 4.9 |
| Comparative example 4 | ?0.01 | 0.018 | 0.89 | Acetic acid | 5.5 | 2.73 | 5.4 |
| Comparative example 5 | ?0.01 | 0.018 | 0.89 | Acetic acid | 6.0 | 2.93 | 5.8 |
The result shows that pH value is less than 4.0, especially pH value is lower than 1.0% in the compositions that contains Ibolite fumarate of 2.5～3.8 scopes through 121 ℃ of excessive sterilizations sterilization rear impurity content.And pH value has obvious increase tendency at the sterilization of the Ibolite fumarate compositions more than 4.0 rear impurity.
Embodiment 6～25, comparative example 6～15:
Take by weighing Ibolite fumarate and sodium acetate according to consumption shown in the table 2, use water dissolution, get solution one.
Take by weighing sodium chloride according to consumption shown in the table 2, with adding activated carbon adsorption behind the water dissolution 30 minutes, utilize micropore filter to filter then, get filtrate and mix with solution one, water is adjusted to cumulative volume 100ml, gets solution two.
With the regulator of pH value shown in the table 2 pH value of solution two is transferred to the pH value shown in the table 2, must contain the compositions of Ibolite fumarate.
Then the compositions that contains Ibolite fumarate of embodiment 6～25, comparative example 6～15 gained is carried out 121 ℃, the excessive sterilization experiment of F0 〉=12 in the hot pressing steam steriliser, steriliser shows pressure 0.12mpa, sterilization time 7 minutes.
Utilize high performance liquid chromatography under the chromatographic condition identical, to investigate the variation of Ibolite fumarate compositions every index after sterilizing of different pH value then, the results are shown in table 2 with embodiment 1～5.
The variation of the Ibolite fumarate compositions of the different pH value of table 2 every index after excessively sterilizing
| Ibolite fumarate (g) | Sodium acetate (g) | Sodium chloride (g) | The pH value regulator | PH value before the sterilization | Ibolite fumarate content (%) | Impurity content (%) | Sterilization back pH value | |
| Embodiment 6 | 0.01 | 0.2 | 2 | Hydrochloric acid | 2.0 | 97.5 | 0.71 | 2.0 |
| Embodiment 7 | 0.01 | 0.2 | 2 | Hydrochloric acid | 2.5 | 99.8 | 0.53 | 2.4 |
| Embodiment 8 | 0.01 | 0.2 | 2 | Hydrochloric acid | 3.0 | 99.7 | 0.46 | 3.1 |
| Embodiment 9 | 0.01 | 0.2 | 2 | Hydrochloric acid | 3.8 | 99.5 | 0.52 | 3.8 |
| Comparative example 6 | 0.01 | 0.2 | 2 | Hydrochloric acid | 4.0 | 97.0 | 0.76 | 4.0 |
| Comparative example 7 | 0.01 | 0.2 | 2 | Hydrochloric acid | 4.5 | 97.0 | 1.07 | 4.4 |
| Embodiment 10 | 0.01 | 0.002 | 0.1 | Hydrochloric acid | 2.0 | 97.4 | 0.81 | 2.1 |
| Embodiment 11 | 0.01 | 0.002 | 0.1 | Hydrochloric acid | 2.5 | 99.5 | 0.52 | 2.5 |
| Embodiment 12 | 0.01 | 0.002 | 0.1 | Hydrochloric acid | 3.0 | 99.8 | 0.47 | 3.0 |
| Embodiment 13 | 0.01 | 0.002 | 0.1 | Hydrochloric acid | 3.8 | 99.6 | 0.53 | 3.7 |
| Comparative example 8 | 0.01 | 0.002 | 0.1 | Hydrochloric acid | 4.0 | 97.1 | 0.78 | 4.1 |
| Comparative example 9 | 0.01 | 0.002 | 0.1 | Hydrochloric acid | 4.5 | 96.8 | 1.02 | 4.6 |
| Embodiment 14 | 0.01 | 0.018 | 0.89 | Hydrochloric acid | 2.0 | 96.6 | 0.76 | 2.1 |
| Embodiment 15 | 0.01 | 0.018 | 0.89 | Hydrochloric acid | 2.5 | 99.6 | 0.53 | 2.5 |
| Embodiment 16 | 0.01 | 0.018 | 0.89 | Hydrochloric acid | 3.0 | 99.7 | 0.46 | 3.1 |
| Embodiment 17 | 0.01 | 0.018 | 0.89 | Hydrochloric acid | 3.8 | 99.8 | 0.52 | 3.8 |
| Comparative example 10 | 0.01 | 0.018 | 0.89 | Hydrochloric acid | 4.0 | 96.7 | 0.80 | 4.2 |
| Comparative example 11 | 0.01 | 0.018 | 0.89 | Hydrochloric acid | 4.5 | 95.8 | 1.07 | 4.6 |
| Embodiment 18 | 0.1 | 0.07 | 1.1 | Hydrochloric acid | 2.0 | 96.9 | 0.80 | 2.0 |
| Embodiment 19 | 0.1 | 0.07 | 1.1 | Hydrochloric acid | 2.5 | 99.7 | 0.49 | 2.5 |
| Embodiment 20 | 0.1 | 0.07 | 1.1 | Hydrochloric acid | 3.0 | 99.6 | 0.51 | 3.0 |
| Embodiment 21 | 0.1 | 0.07 | 1.1 | Hydrochloric acid | 3.8 | 99.5 | 0.47 | 3.7 |
| Comparative example 12 | 0.1 | 0.07 | 1.1 | Hydrochloric acid | 4.0 | 97.5 | 0.80 | 4.1 |
| Comparative example 13 | 0.1 | 0.07 | 1.1 | Hydrochloric acid | 4.5 | 96.8 | 1.10 | 4.7 |
| Embodiment 22 | 0.001 | 0.018 | 0.89 | Hydrochloric acid | 2.0 | 97.0 | 0.78 | 2.0 |
| Embodiment 23 | 0.001 | 0.018 | 0.89 | Hydrochloric acid | 2.5 | 99.7 | 0.56 | 2.6 |
| Embodiment 24 | 0.001 | 0.018 | 0.89 | Hydrochloric acid | 3.0 | 99.8 | 0.49 | 3.0 |
| Embodiment 25 | 0.001 | 0.018 | 0.89 | Hydrochloric acid | 3.8 | 99.5 | 0.54 | 3.7 |
| Comparative example 14 | 0.001 | 0.018 | 0.89 | Hydrochloric acid | 4.0 | 97.6 | 0.85 | 4.1 |
| Comparative example 15 | 0.001 | 0.018 | 0.89 | Hydrochloric acid | 4.5 | 96.3 | 1.03 | 4.5 |
The result shows that pH value is less than 4.0, especially pH value meets the requirements in the Ibolite fumarate compositions of 2.5～3.8 scopes each investigation project after excessive sterilization.
Embodiment 26～37, comparative example 16～21
Take by weighing Ibolite fumarate and sodium acetate according to consumption shown in the table 3, use water dissolution, get solution one.
Take by weighing sodium chloride according to consumption shown in the table 3, with adding activated carbon adsorption behind the water dissolution 30 minutes, utilize micropore filter to filter then, get filtrate and mix with solution one, water is adjusted to cumulative volume 20000ml, gets solution two.
With the regulator of pH value shown in the table 3 pH value of solution two is transferred to the pH value shown in the table 3, embedding, Ibutilide fumarate injection.
Then the Ibutilide fumarate injection of embodiment 26～37, comparative example 16～21 gained is carried out 121 ℃, the excessive sterilization experiment of F0 〉=12 in the hot pressing steam steriliser, steriliser shows pressure 0.12mpa, sterilization time 7 minutes.
Utilize high performance liquid chromatography under the chromatographic condition identical, to detect the content of effective ingredient Ibolite fumarate and impurity then, the results are shown in table 4 with embodiment 1～5.
In addition, abide by state-promulgated pharmacopoeia stability study guideline, the Ibutilide fumarate injection after the sterilization of use the foregoing description 26～37, comparative example 16～21 carries out stability experiment.In the study on the stability instrument, 25 ℃ ± 2 ℃ of design temperatures were placed 12 months, sampling in the 3rd, 6,9,12 month.In another study on the stability instrument, 40 ℃ ± 2 ℃ of design temperatures were placed 6 months, sampling in the 1st, 2,3,6 month.Abide by the method stipulated in the Chinese Pharmacopoeia appendix to visible foreign matters, pH value, character and aseptic the test, and utilize high performance liquid chromatography under the chromatographic condition identical, to detect the content of Ibolite fumarate and the content of impurity with embodiment 1～5, the results are shown in table 5, table 6.
The composition of table 3 Ibutilide fumarate injection and pH value
| Ibolite fumarate (g) | Sodium acetate (g) | Sodium chloride (g) | The pH value regulator | PH value | |
| Embodiment 26 | 0.2 | 3.78 | 178 | Hydrochloric acid | 2.0 |
| Embodiment 27 | 0.2 | 3.78 | 178 | Hydrochloric acid | 2.5 |
| Embodiment 28 | 0.2 | 3.78 | 178 | Hydrochloric acid | 2.8 |
| Embodiment 29 | 0.2 | 3.78 | 178 | Hydrochloric acid | 3.8 |
| Comparative example 16 | 0.2 | 3.78 | 178 | Hydrochloric acid | 4.0 |
| Comparative example 17 | 0.2 | 3.78 | 178 | Hydrochloric acid | 4.5 |
| Embodiment 30 | 2 | 3.78 | 178 | Hydrochloric acid | 2.0 |
| Embodiment 31 | 2 | 3.78 | 178 | Hydrochloric acid | 2.5 |
| Embodiment 32 | 2 | 3.78 | 178 | Hydrochloric acid | 2.8 |
| Embodiment 33 | 2 | 3.78 | 178 | Hydrochloric acid | 3.8 |
| Comparative example 18 | 2 | 3.78 | 178 | Hydrochloric acid | 4.0 |
| Comparative example 19 | 2 | 3.78 | 178 | Hydrochloric acid | 4.5 |
| Embodiment 34 | 20 | 3.78 | 178 | Hydrochloric acid | 2.0 |
| Embodiment 35 | 20 | 3.78 | 178 | Hydrochloric acid | 2.5 |
| Embodiment 36 | 20 | 3.78 | 178 | Hydrochloric acid | 2.8 |
| Embodiment 37 | 20 | 3.78 | 178 | Hydrochloric acid | 3.8 |
| Comparative example 20 | 20 | 3.78 | 178 | Hydrochloric acid | 4.0 |
| Comparative example 21 | 20 | 3.78 | 178 | Hydrochloric acid | 4.5 |
The testing result of table 4 Ibutilide fumarate injection every index behind 121 ℃, the sterilization of F0 〉=12
| The content of Ibolite fumarate (%) | Impurity content (%) | Sterilization back pH value | Visible foreign matters | Particulate matter | Aseptic detection | |
| Embodiment 26 | 98.6 | 0.84 | 2.1 | Up to specification | Up to specification | Up to specification |
| Embodiment 27 | 99.7 | 0.55 | 2.6 | Up to specification | Up to specification | Up to specification |
| Embodiment 28 | 99.6 | 0.50 | 2.8 | Up to specification | Up to specification | Up to specification |
| Embodiment 29 | 99.7 | 0.58 | 3.8 | Up to specification | Up to specification | Up to specification |
| Comparative example 16 | 98.2 | 0.83 | 4.0 | Up to specification | Up to specification | Up to specification |
| Comparative example 17 | 97.4 | 0.99 | 4.6 | Up to specification | Up to specification | Up to specification |
| Embodiment 30 | 97.6 | 0.78 | 2.0 | Up to specification | Up to specification | Up to specification |
| Embodiment 31 | 99.5 | 0.51 | 2.5 | Up to specification | Up to specification | Up to specification |
| Embodiment 32 | 99.7 | 0.53 | 2.7 | Up to specification | Up to specification | Up to specification |
| Embodiment 33 | 99.9 | 0.55 | 3.8 | Up to specification | Up to specification | Up to specification |
| Comparative example 18 | 97.9 | 0.82 | 4.1 | Up to specification | Up to specification | Up to specification |
| Comparative example 19 | 97.8 | 1.10 | 4.5 | Up to specification | Up to specification | Up to specification |
| Embodiment 34 | 98.0 | 0.83 | 2.0 | Up to specification | Up to specification | Up to specification |
| Embodiment 35 | 99.7 | 0.57 | 2.4 | Up to specification | Up to specification | Up to specification |
| Embodiment 36 | 99.5 | 0.54 | 2.8 | Up to specification | Up to specification | Up to specification |
| Embodiment 37 | 99.7 | 0.56 | 3.7 | Up to specification | Up to specification | Up to specification |
| Comparative example 20 | 98.0 | 0.80 | 4.2 | Up to specification | Up to specification | Up to specification |
| Comparative example 21 | 97.6 | 1.07 | 4.6 | Up to specification | Up to specification | Up to specification |
The result shows, the pH value of test preparation less than 4.0, especially pH value behind 121 ℃, the sterilization of F0 〉=12, every index all meets the quality standard requirement at the Ibutilide fumarate injection of 2.5～3.8 scopes.
The long-term experiment of table 5 Ibutilide fumarate injection
The accelerated tests of table 6 Ibutilide fumarate injection
The result shows that the long-time stability of Ibutilide fumarate injection of the present invention and accelerated stability meet national standard.And existing Ibutilide fumarate injection is through long-term experiment, and impurity content does not meet national standard greater than 1.0%.Accelerated stability experiment shows, pH value can be stablized at 40 ℃ at the Ibutilide fumarate injection of 2.5-3.8 scope and preserves in 6 months, therefore, but Ibutilide fumarate injection normal temperature storage of the present invention, safety is good,
Obviously, those skilled in the art can carry out various changes and modification to the present invention and not break away from design of the present invention and scope.If of the present invention these are revised and modification belongs within the scope of claim of the present invention and equivalent technologies thereof, then the present invention also is intended to comprise these changes and modification interior.
Claims (9)
1. contain the compositions of Ibolite fumarate, it is characterized in that, described compositions contains Ibolite fumarate, sodium acetate, sodium chloride and water, its pH value＜3.5.
2. compositions according to claim 1 is characterized in that, the pH value of described compositions is 2.5-3.0.
3. compositions according to claim 1 and 2 is characterized in that, in the described compositions, the concentration of Ibolite fumarate is 0.01～1mg/ml, and the concentration of sodium acetate is 0.02～2mg/ml, and the concentration of sodium chloride is 1～20mg/ml.
4. compositions according to claim 3 is characterized in that, in the described compositions, the concentration of Ibolite fumarate is 0.1mg/ml, and the concentration of sodium acetate is 0.02～2mg/ml, and the concentration of sodium chloride is 1～20mg/ml.
5. preparation claim 1 or 2 described method for compositions is characterized in that described method comprises utilizes the pH value regulator that the pH value of described compositions is transferred to described pH value.
6. method according to claim 5 is characterized in that, described pH value regulator is selected from a kind of or its combination in any in hydrochloric acid, sulphuric acid, phosphoric acid, citric acid, acetic acid, sodium citrate and the sodium carbonate.
7. preparation claim 1 or 2 described method for compositions is characterized in that, may further comprise the steps:
(1) takes by weighing Ibolite fumarate and sodium acetate, use water dissolution, get solution one;
(2) take by weighing sodium chloride, with adding activated carbon adsorption behind the water dissolution 30 minutes, filter, get filtrate and mix with solution one, water is adjusted to final volume, gets solution two;
(3) utilize the pH value regulator that the pH value of described solution two is transferred to described pH value.
8. claim 1 or the 2 described compositionss application in the preparation antiarrhythmic drug.
9. application according to claim 8 is characterized in that, described antiarrhythmic drug is the arrhythmia injection.
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| CN2010101965117A CN101843607B (en) | 2010-06-10 | 2010-06-10 | Composition containing ibutilide fumarate and preparation method and application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1977827A (en) * | 2005-12-02 | 2007-06-13 | 浙江九旭药业有限公司 | Ibutilide fumarate lyophilized powderinjection preparation and its preparing method |
| CN101664385A (en) * | 2009-10-28 | 2010-03-10 | 蚌埠丰原涂山制药有限公司 | Ibutilide fumarate injection and preparation method thereof |
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2010
- 2010-06-10 CN CN2010101965117A patent/CN101843607B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1977827A (en) * | 2005-12-02 | 2007-06-13 | 浙江九旭药业有限公司 | Ibutilide fumarate lyophilized powderinjection preparation and its preparing method |
| CN101664385A (en) * | 2009-10-28 | 2010-03-10 | 蚌埠丰原涂山制药有限公司 | Ibutilide fumarate injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 李桂玲，等.注射用富马酸伊布利特的制备及质量研究.《中国新药杂志》.2007,第16卷(第3期),234-236. * |
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